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Clinical research – Wikipedia

Posted: December 20, 2021 at 1:56 am


Medical research using human test subjects

Clinical research is a branch of healthcare science that determines the safety and effectiveness (efficacy) of medications, devices, diagnostic products and treatment regimens intended for human use. These may be used for prevention, treatment, diagnosis or for relieving symptoms of a disease. Clinical research is different from clinical practice. In clinical practice established treatments are used, while in clinical research evidence is collected to establish a treatment.

The term "clinical research" refers to the entire bibliography of a drug/device/biologic, in fact any test article from its inception in the lab to its introduction to the consumer market and beyond. Once the promising candidate or the molecule is identified in the lab, it is subjected to pre-clinical studies or animal studies where different aspects of the test article (including its safety toxicity if applicable and efficacy, if possible at this early stage) are studied.[1][2][3]

In the United States, when a test article is unapproved or not yet cleared by the Food and Drug Administration (FDA), or when an approved or cleared test article is used in a way that may significantly increase the risks (or decreases the acceptability of the risks), the data obtained from the pre-clinical studies or other supporting evidence, case studies of off label use, etc. are submitted in support of an Investigational New Drug (IND) application[4] to the FDA for review prior to conducting studies that involve even one human and a test article if the results are intended to be submitted to or held for inspection by the FDA at any time in the future (in the case of an already approved test article, if intended to submit or hold for inspection by the FDA in support of a change in labeling or advertising). Where devices are concerned the submission to the FDA would be for an Investigational Device Exemption (IDE) application if the device is a significant risk device or is not in some way exempt from prior submission to the FDA. In addition, clinical research may require Institutional Review Board (IRB) or Research Ethics Board (REB) and possibly other institutional committee reviews, Privacy Board, Conflict of Interest Committee, Radiation Safety Committee, Radioactive Drug Research Committee, etc. approval whether or not the research requires prior submission to the FDA. Clinical research review criteria will depend on which federal regulations the research is subject to (e.g., (Department of Health and Human Services (DHHS) if federally funded, FDA as already discussed) and will depend on which regulations the institutions subscribe to, in addition to any more stringent criteria added by the institution possibly in response to state or local laws/policies or accreditation entity recommendations. This additional layer of review (IRB/REB in particular) is critical to the protection of human subjects especially when you consider that often research subject to the FDA regulation for prior submission is allowed to proceed, by those same FDA regulations, 30 days after submission to the FDA unless specifically notified by the FDA not to initiate the study.

Clinical research is often conducted at academic medical centers and affiliated research study sites. These centers and sites provide the prestige of the academic institution as well as access to larger metropolitan areas, providing a larger pool of medical participants. These academic medical centers often have their internal Institutional Review Boards that oversee the ethical conduct of medical research.[5]

The clinical research ecosystem involves a complex network of sites, pharmaceutical companies and academic research institutions. This has led to a growing field of technologies used for managing the data and operational factors of clinical research. Clinical research management is often aided by eClinical systems to help automate the management and conducting of clinical trials.

In the European Union, the European Medicines Agency (EMA) acts in a similar fashion for studies conducted in their region. These human studies are conducted in four phases in research subjects that give consent to participate in the clinical trials.

Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV is 'post-approval' studies.

Phase I includes 20 to 100 healthy volunteers or individuals with the disease/condition. This study typically lasts several months and its purpose is safety and dosage. Phase II includes a larger number of individual participants ranging 100300, and phase III includes Approximately 1000-3000 participants to collect more data about the drug.[6] 70% of drugs advance to the next phase.[7]

Before pharmaceutical companies start clinical trials on a drug, they conduct extensive pre-clinical studies.

Clinical Research affects the treatment methods of various patient populations in the medical industry. As more diverse individuals participate in medical clinical trials, the treatments for diverse patients will improve. [8] Clinical trials test various medications and treatment plans for people. This can be important as different people respond to different medications, so it is valuable to know how people will respond to treatments.

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Clinical research - Wikipedia

Psychedelic medicine: a re-emerging therapeutic paradigm

Posted: at 1:56 am


CMAJ. 2015 Oct 6; 187(14): 10541059.

School of Population and Public Health (Tupper, Wood); Department of Medicine, Faculty of Medicine (Wood), University of British Columbia, Vancouver, BC; Department of Psychiatry and Behavioral Sciences (Johnson), Johns Hopkins University School of Medicine, Baltimore, Md.; Multidisciplinary Association for Psychedelic Studies Canada (Yensen), Vancouver, BC; Orenda Institute (Yensen), Mansons Landing, BC

In clinical research settings around the world, renewed investigations are taking place on the use of psychedelic substances for treating illnesses such as addiction, depression, anxiety and posttraumatic stress disorder (PTSD). Since the termination of a period of research from the 1950s to the early 1970s, most psychedelic substances have been classified as drugs of abuse with no recognized medical value. However, controlled clinical studies have recently been conducted to assess the basic psychopharmacological properties and therapeutic efficacy of these drugs as adjuncts to existing psychotherapeutic approaches. Central to this revival is the re-emergence of a paradigm that acknowledges the importance of set (i.e., psychological expectations), setting (i.e., physical environment) and the therapeutic clinicianpatient relationship as critical elements for facilitating healing experiences and realizing positive outcomes.1,2

The public is often well-versed in the potential harms of psychedelic drugs, but much of this knowledge is from cases involving patients who used illicit substances in unsupervised nonmedical contexts. We discuss the emerging research for therapeutic purposes involving human subjects, considering both the possible benefits and the potential harms of using psychedelic agents as adjuncts to psychotherapy or counselling for mental illness.

Psychedelic drugs include a range of substances with varying pharmacological profiles that all have strong effects on conscious experience ().318 We will focus on two classes of psychedelics: classic psychedelics and entactogens.

Psychedelic agents currently under investigation for their potential benefits as adjuncts to psychotherapy

5-HT2A (serotonin) agonist of pyramidal neurons

Dizziness, weakness, tremors, paresthesia

Altered consciousness (visions, auditory distortions, ideations)

Altered mood (happy, sad, fearful, irritable)

Distorted sense of space, time

Addiction (e.g., alcohol)3

Anxiety associated with terminal illness4,5

5-HT2A (serotonin) agonist of pyramidal neurons

Dizziness, weakness, tremors, paresthesia

Altered consciousness (visions, auditory distortions, ideations)

Altered mood (happy, sad, fearful, irritable)

Distorted sense of space, time

Addiction (tobacco, alcohol)6,7

Anxiety associated with terminal illness8

5-HT2A (serotonin) agonist of pyramidal neurons

Dizziness, weakness, tremors, paresthesia

Nausea, emesis

Altered consciousness (visions, auditory distortions, ideations)

Altered mood (happy, sad, fearful, irritable)

Distorted sense of space, time

Addiction (alcohol, cocaine, tobacco)9,10

Depression, anxiety1114

5-HT2A (serotonin) agonist of pyramidal neurons

Dizziness, weakness, tremors, paresthesia

Altered consciousness (visions, auditory distortions, ideations)

Altered mood (happy, sad, fearful, irritable)

Distorted sense of space, time

Serotonin, dopamine and noradrenaline agonist

Euphoria

Arousal

Perceptual alteration

Enhanced empathy and sociability

The classic psychedelics exert primary activity as agonists at the 5-HT2A receptor (e.g., lysergic acid diethylamide [LSD], psilocybin, dimethyltryptamine [DMT] and mescaline).19 Many of these substances are found or are close analogues of chemicals found in plants or fungi used traditionally for millennia in spiritual or folk healing rituals, such as the ergot fungus (Claviceps purpurea) from Eurasia, morning glory (Turbina corymbosa) and peyote cactus (Lophophora williamsii) from Central and North America, and the ayahuasca brew (Banisteriopsis caapi and Psychotria viridis) from the Amazon.20

The second class of psychedelic substances, the entactogens, includes methylenedioxymethamphetamine (MDMA), which acts primarily as a serotonin-releasing agent and has effects that somewhat overlap but are substantially distinct from classic psychedelics.21

Other substances that are sometimes classified as psychedelic such as ketamine (a dissociative anesthetic), scopolamine (an anticholinergic) or ibogaine (a substance with a complex neuropharmacology) are beyond the scope of this review. This article will focus on clinically relevant studies with patient populations in which psychedelic drugs are used as adjuncts to psychotherapy. Besides a few brief mentions, we do not cover findings from research on healthy participants, although such studies have been the basis of renewed neuropharmacologic science in this field.

Some of the mental disorders for which psychedelic-assisted treatments are currently being researched include anxiety, addiction and PTSD. The findings presented in this analysis are preliminary, and most are results from small-scale pilot studies with relatively few participants. Further study is warranted before any unambiguous clinical utility may be confirmed, but the new generation of investigators is attempting to overcome some of the methodological weaknesses of earlier research on these substances.

In 2014, a small randomized controlled trial in Switzerland suggested LSD-assisted psychotherapy had the potential to reduce the anxiety associated with terminal illness.4 Twelve participants with life-threatening illness were enrolled in the study to receive treatment that involved drug-free psychotherapy sessions supplemented with two LSD-assisted sessions two to three weeks apart. The participants were randomly assigned to either the treatment group (receiving 200 g LSD [n = 8]) or the active control group (20 g LSD [n = 4], with an open-label crossover to 200 g LSD after the initial blinding was unmasked). At two months follow-up, the StateTrait Anxiety Inventory (STAI) showed nonsignificant reductions in trait anxiety, but significant reductions in state anxiety.

Follow-up with nine participants one year after treatment showed a sustained therapeutic benefit with no acute or chronic drug-related severe adverse events, and there were no adverse effects lasting more than one day after an LSD-assisted session.4

Psilocybin has likewise shown promise as a treatment for anxiety in patients with terminal illness.8 A 2008 study on ameliorating end-of-life anxiety focused on 12 participants with end-stage cancer.8 After several nondrug-assisted therapy sessions, participants underwent a within-subject crossover study in which they received the experimental medication (0.2 mg/kg psilocybin) and the active placebo (250 mg of niacin) across two sessions a few weeks apart. Findings showed that psilocybin-assisted psychotherapy lowered anxiety and improved mood, without clinically significant adverse effects.8

MDMA-assisted therapy is also being studied as a treatment for social anxiety in adults with autism, although findings have yet to be published.22

Researchers in the 1950s and 1960s studied the use of psychedelic-assisted therapy for the treatment of addictions such as alcohol dependence,23 some key findings of which were recently reviewed in a meta-analysis that suggested a significant beneficial effect.3 In renewed clinical research on treating alcohol dependence with psilocybin-assisted therapy, a New Mexico team recruited 10 participants with a diagnosis of active alcohol dependence (and no concurrent mental illness or other substance use disorder).6 Participants received pre- and post-psychosocial support (motivational enhancement therapy) over 12 weeks, with one or two intervening open-label sessions at weeks four (0.3 mg/kg psilocybin, n = 10) and eight (0.4 mg/kg psilocybin, n = 6, or 0.3 mg/kg psilocybin, n = 1). Among the participants who completed the study, the self-reported mean percent drinking days and percent heavy drinking days were reduced by more than half of what had been reported at baseline.6 Acute adverse effects such as nausea and mild headaches were reported by some participants, but no clinically significant or lasting harms resulted from the administration of psilocybin.

Other recent research on psilocybin-assisted psychotherapy for addiction includes a pilot study of treatment for tobacco dependence. This investigation was an open-label design involving 15 participants who smoked at least 10 cigarettes per day and had multiple previous unsuccessful cessation attempts.7 Participants received cognitive behavioural therapy before and after treatment with psilocybin. Treatment included two or three psilocybin-assisted psychotherapy sessions (doses of either 20 mg/70 kg or 30 mg/70 kg), with the first session occurring on the target quit date. At six months follow-up, 12 of the 15 participants were abstinent (biologically verified by exhaled carbon monoxide and urinary cotinine levels).7 Smoking cessation outcomes were significantly correlated with a measure of mystical experience on session days, as well as retrospective ratings of personal meaning and spiritual significance of psilocybin sessions.24 The same research team is currently designing a follow-up randomized controlled study to compare a similar psilocybin intervention with nicotine-replacement therapy.

The Amazonian folk medicine ayahuasca is a plant-based preparation with the psychoactive constituents DMT, which is chemically related to psilocybin, and harmala alkaloids, which are reversible monoamine oxidase inhibitors. An observational study of an ayahuasca-assisted intervention in a Coast Salish First Nations community in British Columbia for people (n = 12) seeking treatment for addictions to substances such as alcohol and cocaine showed statistically significant improvements in measures of mental health and reductions in self-reported use of these substances after six months, with no lasting adverse physical or psychological effects.9

Observational research involving members of Brazilian religious groups who regularly drink ayahuasca sacramentally has shown that, compared with a matched control group, long-term regular drinkers of ayahuasca tend to have a lower prevalence of substance use,10 structural brain changes that do not suggest evident pathology11 and better neuropsychological performance and psychosocial adaptation.12 Other studies involving similar populations of long-term drinkers of ayahuasca have shown lower rates of psychoactive substance use and psychopathology.13,14

Canadian researchers are currently coordinating an international research study to investigate ayahuascas potential as a treatment for addiction, with clinical sites in Brazil, Peru and Mexico.25

Ayahuasca differs from the other substances covered in this review, inasmuch as it is a plant-based preparation of variable composition and strength, and typically used in ceremonial contexts, which makes it more difficult for researchers to isolate the factors that may contribute to therapeutic efficacy.26,27

In a pilot randomized controlled trial investigating MDMA-assisted psychotherapy to treat chronic treatment-resistant PTSD in the United States, outcomes from 20 participants with a mean illness duration of 19 years showed that the experimental treatment may improve upon the best currently available pharmacotherapies and psychotherapies.16 The clinical protocol involved several weeks of preparatory and follow-up nondrug-assisted psychotherapy, during which the members of the experimental group received two MDMA-assisted sessions. No serious adverse effects were reported. Outcomes included a significant and sustained reduction in PTSD symptoms as measured by the Clinician-Administered PTSD Scale (CAPS), with 83% of participants in the experimental group (v. 25% in the placebo group) showing a reduction in symptom severity of more than 30%. Furthermore, some members of the experimental group no longer met criteria for PTSD as stated in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV).16 A long-term follow-up study involving the same participants showed that, although two patients relapsed, 74% (14/19) of patients still showed meaningful, sustained reductions in their CAPS scores three and a half years later.17

An additional small (n = 12) randomized controlled trial investigating MDMA-assisted psychotherapy for PTSD was recently completed in Switzerland.18 This study compared three full-dose MDMA-assisted sessions per patient (with nondrug-assisted therapy before and after) with low-dose active placebo in a crossover design. Participants had no serious drug-related adverse events, and although reductions in CAPS scores were not statistically significant, self-assessment of PTSD symptoms as measured by the Posttraumatic Diagnostic Scale questionnaire was significantly reduced.

In 2015, researchers in Vancouver began a similar pilot study of MDMA-assisted psychotherapy for patients with PTSD, the first clinical study involving psychedelic drugs in Canada in more than 40 years.

Experience from previous research both positive and negative has provided important lessons for current methodological designs, ethical strictures and clinical protocols and for renewed research on psychedelics involving human participants. In the 1950s and 1960s, methodological challenges confounded the advancement of psychedelic medicine, with researchers disagreeing about the suitability of randomized controlled trials and the possibility of double-blinding.28 More infamously, egregious violations of ethical protocols, such as lack of informed consent (in some cases through military or intelligence agencysupported research) resulted in substantial and long-lasting harms to some patients.23 Furthermore, unsupported claims about purported benefits of psychedelics, and sometimes explicit encouragement for non-clinical use, by some members of the research community, may have contributed to unsupervised and uncontrolled recreational use of psychedelic substances. Consequently, by the mid-1970s, clinical access to and professional interest in psychedelic drugs waned, leading to a quiescence in research for several decades.

Although methodological and political challenges remain to some degree,27 recent clinical studies have shown that studies on psychedelics as therapeutic agents can conform to the rigorous scientific, ethical and safety standards expected of contemporary medical research.29 For example, patients undergo careful screening, fully informed consent is obtained and protocols are approved by ethics review boards. In addition, contemporary investigators are mindful of the checkered history of psychedelic research, and are thus cautiously reserved in reporting their findings, doing so with appropriate caveats and limitations.

Most psychedelic drugs are classified and legally scheduled as having no or very limited medical purpose, a high potential for abuse and a lack of accepted safety for use under medical supervision.30 Potential health risks of these substances include the precipitation of psychotic breaks in patients with psychotic disorders or a predisposition to these disorders.31 Thus, participation in contemporary psychedelic research typically excludes people with a personal or family history of psychosis or bipolar disorder.29

A further risk associated with psychedelic drugs is Hallucinogen Persisting Perception Disorder (HPPD), sometimes known as flashbacks, although HPPD is more uncommon and more clinically severe than the flashbacks or visual distortions sometimes described in the days following illicit use of psychedelics.32,33 However, the incidence of adverse effects such as psychosis or HPPD in the general population is believed to be relatively low, and these effects are generally associated with the use of illicitly procured psychedelic substances, which often involves polysubstance use in uncontrolled settings without supervision.34 In light of these concerns, it is worth noting that lifetime use of classic psychedelics at the population level is associated with decreased psychological distress;35 thus, potential individual instances of harm may be overshadowed by instances in which people experience benefit or no harm.

The most common adverse effects from the administration of psychedelics under clinical supervision are limited to the time of drug action, such as acute increases in anxiety, fear, heart rate and blood pressure.29 Without careful supervision, fearful responses could lead to dangerous behaviour (e.g., fleeing the study site). In addition, delayed-onset headache is sometimes caused by psilocybin use and possibly by other classic psychedelics.36 Although adverse effects of MDMA overlap somewhat with those of classic psychedelics, cardiovascular effects (e.g., tachycardia) are generally greater with MDMA, whereas adverse psychological reactions are more likely with classic psychedelics. It is important to note that acute adverse effects are readily managed,37 and that, as described previously, none of the new clinical research studies have reported long-term harms.

The clinical protocols for contemporary psychedelic studies draw on lessons learned from the earlier era of psychedelic research, and incorporate some common elements to minimize risks and maximize potential therapeutic benefit. After obtaining fully informed consent from the patient, clinical sessions take place in health care facilities, in quiet treatment rooms with pleasant and comfortable decor. Headphones deliver music, hospital and laboratory equipment are minimal and discreetly placed, and a two-person cotherapist team is in attendance throughout the drugs action. During a session, interaction between patient and therapists is kept to a minimum, with the patient encouraged to spend much of the time engaging in self-reflection while listening to carefully selected music. Follow-up sessions that are non-drug assisted provide opportunities to integrate the insights gleaned from the experimental sessions. As research on psychedelic medicine advances, further refinements in screening, safety and therapeutic protocols will be possible.

Numerous scientific and empirical questions remain in the field of psychedelic medicine. With respect to basic neuroscience research, progress in understanding the human brain and its functional relationship to mind and consciousness would be substantially advanced by further determining how psychedelic drugs work neuropharmacologically.30 This kind of knowledge would in turn be useful in applied fields such as psychology, psychiatry and addiction medicine, both to help explain mechanisms for the therapeutic results that renewed psychedelic studies are yielding and to advance understanding about optimal therapeutic protocols for these forms of treatment. With respect to clinical applications, different psychedelic medications may be indicated for different specific illnesses. Further research should elucidate not only respective efficacy, but also optimal pharmacotherapeutic and ancillary psychotherapeutic choices.

Beyond basic research on neuropharmacological mechanisms and clinical outcomes are potential economic arguments for psychedelic therapies. Substance dependence and mental disorders, such as depression and anxiety, are substantial and growing sources of illness and health system costs worldwide.38,39 Given these trends, investment of resources into researching novel treatments for mental and substance use disorders is warranted. Because preliminary evidence suggests psychedelic therapies require relatively time-limited interventions (i.e., they do not involve long-term ongoing courses of pharmacotherapeutic intervention), they may prove to be economically viable in comparison with currently available treatments.

Renewed scientific interest in psychedelic medicine is generating new knowledge about a class of pharmacologic substances that humans have long used for ceremonial, therapeutic and cultural purposes. As this field of research evolves, medical school curricula may need to be updated to include the latest knowledge about psychedelic drugs. This would encompass scientific evidence about relative risks and harms of psychedelic drugs which is largely absent in current drug control scheduling classifications40 and reflects adverse outcomes from uncontrolled recreational use rather than supervised clinical settings. In addition, it would encompass knowledge about the potential therapeutic uses of these agents, particularly because patients may query their physicians about research findings reported in the media. If further scientific evidence accumulates on the therapeutic value of psychedelic medicines, specialized clinical training for physicians, nurses, psychologists and other health professionals will be required to meet an increased demand for such treatments.

It behooves policy-makers to be aware of and open to new approaches to treatments emerging in the field of psychedelic medicine. This is particularly important for those concerned about the growing prevalence of mental illness, including addiction, as well as its associated human, social and economic costs. This applies not only to elected officials, but also to civil servants in health ministries and research granting agencies, where advances and innovations are translated from the clinical research laboratory into options for health care improvements that are in the public interest. Currently, international drug control scheduling classifications and popular misconceptions about the relative risks and harms of psychedelic drugs make research involving humans difficult. However, continued medical research and scientific inquiry into psychedelic drugs may offer new ways to treat mental illness and addiction in patients who do not benefit from currently available treatments. The re-emerging paradigm of psychedelic medicine may open clinical and therapeutic doors long closed.

Medical interest in psychedelic drugs as treatments for illnesses such as anxiety, addiction and posttraumatic stress disorder has been renewed.

Small-scale studies involving human participants in the United States, Europe and Canada are showing that such research can be conducted in a safe and scientifically rigorous manner.

Preliminary findings show some successful results for these treatments, with significant clinical improvements and few if any serious adverse effects.

The emerging results may have implications for future medical and neuroscientific research, medical education and training, and public policy.

CMAJ Podcasts: author interview at https://soundcloud.com/cmajpodcasts/141124-ana

Competing interests: Richard Yensen is an investigator with the Multidisciplinary Association for Psychedelic Studies Canada. No other competing interests were declared.

This article has been peer reviewed.

Contributors: Kenneth Tupper and Evan Wood conceived the idea for the article. Kenneth Tupper drafted the article. Evan Wood, Richard Yensen and Matthew Johnson analyzed and interpreted the reviewed literature, and revised the manuscript critically for important intellectual content; all of the authors have approved the final version to be published and agree to act as guarantors of the work.

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Psychedelic medicine: a re-emerging therapeutic paradigm

A Systematic Review of Topical Finasteride in the …

Posted: at 1:56 am


J Drugs Dermatol. Author manuscript; available in PMC 2019 Jul 3.

Published in final edited form as:

PMCID: PMC6609098

NIHMSID: NIHMS1035387

1University of California, Irvine, Department of Dermatology, 843 Health Sciences Road, Irvine, CA, 92697

1University of California, Irvine, Department of Dermatology, 843 Health Sciences Road, Irvine, CA, 92697

1University of California, Irvine, Department of Dermatology, 843 Health Sciences Road, Irvine, CA, 92697

1University of California, Irvine, Department of Dermatology, 843 Health Sciences Road, Irvine, CA, 92697

1University of California, Irvine, Department of Dermatology, 843 Health Sciences Road, Irvine, CA, 92697

1University of California, Irvine, Department of Dermatology, 843 Health Sciences Road, Irvine, CA, 92697

Currently, only topical minoxidil (MNX) and oral finasteride (FNS) are approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of androgenetic alopecia. Although FNS is efficacious for hair regrowth, its systemic use is associated with side effects limiting long-term utilization. Exploring topical FNS as an alternative treatment regimen may prove promising.

A search was conducted to identify studies regarding human in vivo topical FNS treatment efficacy including clinically relevant case reports, randomized controlled trials (RCTs), and prospective studies.

Seven articles were included in this systematic review. In all studies, there was significant decrease in the rate of hair loss, increase in total and terminal hair counts, and positive hair growth assessment with topical FNS. Both scalp and plasma DHT significantly decreased with application of topical FNS, however no changes in serum testosterone were noted.

Preliminary results on the use of topical FNS are limited but safe and promising. Continued research into drug-delivery, ideal topical concentration and application frequency, side effects and use for other alopecias will help to elucidate the full extent of topical FNS use.

Keywords: topical finasteride, androgenetic alopecia, efficacy, adverse events

Androgenetic alopecia (AGA) is a common chronic, cutaneous condition encountered by dermatologists globally. AGA is androgen-dependent and characterized by an hereditary inheritance pattern, beginning with the advent of puberty; in predisposed males and females scalp hair progressively thins in a defined pattern, most often at the vertex, with non-scarring, progressive miniaturization of the hair follicle and shaft.1 Unfortunately, AGA is often accompanied by low self-esteem and negatively impacts quality of life. Despite its prevalence and patient morbidity, Food and Drug Administration (FDA) and the European Medicines Agency (EMA)-approved therapeutic options for AGA are limited to oral finasteride (FNS; Propecia, Merck Pharmaceuticals, for men only) and topical minoxidil (MNX; Rogaine, Johnson and Johnson Healthcare Products, for men and women).2,8 In the absence of other therapeutic modalities, practitioners may use surgical hair transplant; however, patients often encounter increased cost because most insurance plans do not cover the procedure. In addition, transplants are associated with risks such as bleeding and infection.3

Pathogenesis of AGA is related to the purported binding of dihydrotestosterone (DHT) to androgen receptors (AR) located at the hair follicle. DHT is produced by conversion of testosterone using 5--reductase type 2, an enzyme located in the follicle dermal papilla. DHT levels are affected by factors including the abundance of weak androgens, testosterone conversion, activity of androgen inactivating enzymes, and abundance of AR.45 AGA predisposed dermis exhibits high levels of DHT and increased expression of AR.6

Systemic FNS, a 5-reductase inhibitor 4-aza-3-oxosteroid compound, has been extensively studied and is clinically used for the treatment of benign prostate hyperplasia (BPH) and AGA.7 FNS works by competitively inhibiting 5-reductase type 2, resulting in the inhibition of the conversion of testosterone to DHT, markedly suppressing serum DHT levels. The mean terminal half-life of FNS is approximately five to six hours in men 1860 years, and eight hours in men greater than 70 years of age. DHT levels return to normal within 14 days of treatment discontinuation. It is expected that after systemic FNS use for the treatment of AGA is stopped, reversal of hair regrowth occurs within 12 months.8 In its systemic form, various side effects such as gynecomastia, breast tenderness, malignant neoplasms of the male breast, decreased ejaculate volume, decrease in testicular size, testicular pain, reduction in penile curvature, reduction in penile size, sexual disorder, male infertility, high grade prostate cancer, and prostatitis have been reported.8 These side effects are often prohibitive as male patients are sensitive to sexual side effects.

Animal studies have shown that topical FNS may have protective effects against AGA. Comparing topical FNS 2% solution to a fern extract (Adiantum capillus-veneris) in a testosterone-induced alopecia albino mouse model demonstrated higher follicular density and anagen:telogen ratios in groups treated with topical FNS.9 In humans, topical FNS application for the treatment of AGA was first conducted twenty years ago by Mazarella et al. in an attempt to analyze its efficacy and safety.10 In the past five years, emerging evidence suggests that topical FNS may be a promising treatment with a less severe side effect profile compared to systemic therapy. This review will provide a summary of past and current clinical studies investigating topical FNS therapy for AGA.

A primary literature search was conducted using PubMed/MEDLINE, Embase, PsycINFO, TRIP Cochrane Library, and Cochrane Skin databases with search terms[topical finasteride], [finasteride solution], [finasteride liquid], [finasteride foam], and [finasteride cream]. Given the focus of this article is the clinical application of topical FNS in humans, only studies regarding human in vivo topical FNS treatment efficacy were reviewed for inclusion; clinically relevant systematic reviews, randomized controlled trials, and open studies were considered. Inclusion criteria were studies involving at least one treatment group with topical FNS, inclusion of results regarding efficacy of topical FNS, and the use of in vivo treatment only. Excluded studies included those that were not written in English, involved treatment with oral FNS only, and those that addressed only the mechanism or pharmacodynamics of the topical FNS. Included studies were graded using the Oxford Center for Evidence-Based Medicine 2011 Levels of Evidence.

119 articles were found using the methodology outlined above. Of these, 67 records were identified by title, and further narrowed to seven records after inclusion criteria were applied and duplicates were removed. Of the reviewed articles, six were published in the last eight years, while one was published 20 years ago, and include five RCTs and two prospective studies. Three studies compare topical to oral FNS, two compare topical MNX to a topical combination of MNX and FNS, one compares combination topical treatments containing FNS, and one compares varying doses and frequencies of topical FNS application. A total of 256 (24 female, 232 male) human subjects were studied (, ).

Selecting clinically relevant articles on the use of topical FNS in human subjects with AGA.

Summarizing the use of topical FNS in animal models.

The first study on topical finasteride in humans was completed in 1997 by Mazarella et al.as a single-blind, placebo-controlled study, including 28 males and 24 females patients with AGA. Subjects were randomized to receive either 1.0 mL topical FNS 0.005% solution or placebo twice daily to the affected scalp for 16 months. Pharmacodynamic data revealed no significant change in plasma levels of total testosterone, free testosterone, and DHT between the groups. At sixth months, researchers observed a significant decrease in the rate of hair loss in the topical FNS compared to the placebo group. Patients opinion on the effectiveness of treatment was generally positive among the FNS group, with 73% of treated patients reporting high effectiveness, compared to 60% of placebo patients reporting no effect.10

Five years later, a double-blind, randomized clinical trial with 45 AGA male patients compared topical FNS gel 1% to the scalp twice daily with oral placebo tablets to oral FNS 1 mg daily with a control vehicle applied to the scalp twice daily. In A group (FNS gel and placebo tablet), increased terminal hair counts were observed at the third month of treatment (p = 0.001); however, increased hair counts were noted one month earlier in the B group (FNS tablet and placebo gel). During the therapeutic period, the size of alopecia area(s) was not significantly altered in group A, but in group B the change in alopecia area was significant at the fourth month of treatment and both groups demonstrated increased hair counts with moderate therapeutic response with no difference noted between treatment groups. 11

Studies comparing topical FNS 0.25% (2.275 mg/mL) (P-3074) to systemic FNS 1 mg tablets for AGA therapy have shown that both therapies significantly suppress plasma DHT levels. Caserini et al. randomized 24 male patients in a single-center, open-label, parallel-group, exploratory study with subjects either applying topical solution to their shaved scalp twice daily, or taking a tablet once daily for seven days. Although there is decreased absorption of topical FNS compared to oral, the authors noted a decrease in plasma DHT levels after one week of treatment with either topical or oral formulations. This study provides the first evidence that topical FNS slows AGA-associated hair loss by modulating DHT levels, while also reducing systemic exposure to the medication.12

A follow-up study also by Caserini et al. further examined the dose-dependent effects of topical FNS using a randomized, parallel-group design. The first part of this study examined 18 male patients applying 1 mL of topical FNS 0.25% solution to the scalp once or twice daily, versus administration of oral FNS 1 mg tablet once daily for seven days. There were an increase in alanine aminotransferase, pollakiuria, and testicular pain reported in two participants. In the second part, a group of 32 men received either placebo, or 100 L (0.2275mg), 200 L (0.455 mg), 300 L (0.6285 mg) or 400 L (0.91 mg) topical FNS 0.25% solution to apply to the scalp once daily for seven days. Interestingly, the results suggest that once daily application of topical FNS is more efficacious at decreasing scalp and plasma DHT levels than twice daily application, and is non-inferior to oral FNS administration. There was no significant differences noted between the varying concentrations of topical FNS, however 300 and 400 L doses are associated with higher plasma concentrations of FNS, and therefore at greater risk for systemic side effects. Presyncope, conjunctivitis, headache, and oropharyngeal pain were rarely reported. The authors concluded that 100 and 200 L doses of topical FNS applied daily may be the most effective treatment regimen for AGA.13

Research has also been completed to demonstrate the efficacy of topical FNS for AGA in comparison to topical combination therapies. A novel combination topical treatment by the name NuH Hair [topical FNS, dutasteride and minoxidil (MNX)], was formulated by Rafi and Katz (2011). 15 male patients were asked to apply the solution daily for nine months and were given the option of adding three further components to their treatment protocol: 1) oral FNS 1 mg daily 2) topical MNX 5% foam applied at least once per day, and/or 3) topical ketoconazole 2% shampoo applied 23 times per week. Eight subjects chose aggressive treatment with all four treatment modalities simultaneously. While all 15 patients demonstrated significant growth of hair by the end of the treatment period, the eight patients who utilized all four treatment options experienced significant growth in as little as 30 days; for the patients using topical FNS/dutasteride/MNX alone, significant hair growth was experienced after three months. The topical FNS/dutasteride/MNX was formulated as a hypoallergenic lotion and found to be safe even in subjects with atopy.14

A randomized, double-blind, comparative study assessed the efficacy and safety of twice daily topical MNX 3% versus topical combined MNX 3%/FNS 0.1% in 40 men with AGA for 24 weeks. Both groups demonstrated increased hair counts from baseline with the MNX 3%/FNS 0.1% group showed statically superior improvement compared to the MNX group.15 Further studies with retrospective assessment and prospective cohort tested a higher concentration of topical MNX 5%/FNS 0.1% for one year on 50 AGA men who were previously treated with oral FNS 1 mg daily and topical MNX 5% twice a day for two years. Approximately 80% of patients either maintained or improved their baseline hair density using topical combination therapy.16

Topical application of FNS in the treatment of AGA is an area of research in its infancy and limited to a small number of randomized-controlled trials, prospective studies, and retrospective medical record review. Overall data from the studies on investigating the efficacy and safety of topical FNS in the AGA show promising results and non-inferiority compared to systemic delivery.

Although preliminary results on the use of topical FNS are limited, the studies reviewed demonstrate that topical FNS may be safe for use in patients wishing to avoid systemic side effects. This may be especially important for the AGA population in female, in which systemic FNS is not approved due to hormonal suppression, considering that it is a category X drug during pregnancy.8 It is possible that topical FNS will follow the same path as topical retinoid derivatives (category C)17 and their parent systemic drug isotretinoin (category X),18 with the topical formulation of FNS considered relatively safe for use in pregnant females if the benefits outweigh the risk.

With consistent inhibitory effects on scalp DHT levels while minimizing the systemic effects on serum DHT, doses of 100 L (0.2275mg) and 200 L (0.455 mg) topical FNS 0.25% solution applied daily appears to be the most efficacious concentration and frequency at this time.13 The use of topical FNS has not resulted in the report of serious side effects; however, there are reports of scalp irritation manifesting as erythema and contact dermatitis, as well as cases of increased liver enzymes, bed-wetting, testicular pain, headaches, presyncope and oropharyngeal pain ().11,13,15 Although current evidence suggests that patients are satisfied and that the drug is well-tolerated, we believe large cohort studies examining the potential adverse effect profile of the drug are warranted.

Several challenges arise from the available studies on topical FNS including the vehicle, concentration, as well as application regimen and frequency. The delivery of topical pharmacologic drug to any dermatologic disease state is a heavily studied and debated subject; pharmacokinetic and -dynamic properties, solubility, concentration, potency, drug-drug interactions, absorption, and degradation are dependent on the exact formulation of the vehicle. For the treatment of AGA, the variable efficacy of topical FNS formulations likely depends on the composition of the vehicle.19 Currently, topical formulations of FNS have been tested as gels and solutions at varying concentrations; all of which have resulted in improved hair growth.10, 11, 12, 13, 14, 15, 16

There is no study comparing vehicle delivery (gel vs. solution), and it is unknown which formulation is the most effective at penetrating the scalp, stabilizing FNS over a period of time (i.e. prolonging shelf-life), delivering drug and producing hair regrowth. Combining topical FNS with MNX and/or dutasteride has shown greater efficacy at hair regrowth than topical MNX alone14 and also allowed for the maintenance of hair density. Researchers have optimized the penetration of FNS into the dermis by modulating the type and size of particles transporting the medication across the skin. Studies evaluating the efficacy of nanoparticle delivery have shown enhanced absorption of FNS with smaller particles, particularly with the liquid crystalline variation.20,21 Liposomes and microplated films are also successful delivery methods, as well as the use of absorption enhancers, such as ethanol and propylene glycol.22,23,24A head-to-head comparison of compounds used to deliver nanoparticles has yet to be done, and no conclusions can be drawn at this time regarding which will be most efficacious, with the least amount of adverse events, and the most cost-effective. Although most studies apply topical solution twice daily, once daily application of topical FNS is more effective at decreasing scalp DHT levels. 13 Other studies revealed that combination of topical medications such as MNX 5% with FNS 0.1% may have synergistic and additive effects compared to single agent usage.14, 15, 16

In the future, further research clarifying an optimal drug-delivery system, ideal concentration and frequency of the drug application, the adverse effect profile, as well as use in other hair loss disorders is required to determine the full extent to which topical FNS may be used.

AGA is a debilitating chronic condition, causing a great deal of psychological patient morbidity and decreased patient quality of life. Preliminary results regarding the application of topical FNS for the treatment of AGA are promising. Current data suggests that there may be a therapeutic potential for topical FNS in the treatment of AGA, while minimizing unwanted systemic side effects associated with oral use. Topical FNS appears to be non-inferior for hair regrowth when compared to systemic FNS. Combination therapies including topical FNS, as well as MNX or dutasteride, may be more effective than topical FNS alone. Topical FNS is not widely used despite its proven efficacy and lack of side effects, most likely due to the lack of evidence-based research. At this time it is unknown whether the cost of compounding topical FNS is a barrier to treatment. Given the benefits of topical FNS in both male and female AGA patients, further studies are warranted to determine the efficacy of long-term hair regrowth, therapeutic safety, cost-effectiveness, patient tolerability and satisfaction.

Summarizing the results of studies demonstrating the use of topical FNS for the treatment of AGA.

SubjectAssessments:Subjective four-point scale of effectiveness (0 to 3, with 0 being no effect, and 3 being high effectiveness)

Adverse Events:30% subjects withdrew from the placebo group due to treatment non-efficacy.No reported local or systemic effects in treatment or placebo groups.

Adverse Events:Erythema of scalp after application of topical FNS (n = 1).Decreased libido with use of systemic FNS (n= 1).

Adverse Events:No report of contact or irritant dermatitis were reported with the use of NuH Hair.

Adverse Events:Contact dermatitis experienced in MNX group n = 6 (38%), MFX group n = 4 (24%).

Adverse Events:No clinically significant adverse events occurred.

Study 2:Placebo vs topical FNS 0.25% twice daily in varying quantities 100 l vs. 200 l vs. 300 l vs. 400 l for 7 days

Study 2:Scalp DHT reduction was decreased by 4752% using 100 l and 200 l of topical FNS, which was similar to the 37% and 54% reduction seen with 300 l and 400 l respectively.Serum DHT was reduced by 24%, 26%, 44%, and 48% by 100 l, 200 l, 300 l, and 400 l respectively.No significant changed occurred in serum testosterone levels.

Adverse Events:Study 1: Increased alanine aminotransferase, pollakiuria and testicular pain (n = 2, 11.1%)Study 2: Presyncope, conjunctivitis, headache, oropharyngeal pain (n = 5, 15.6%)

Adverse Events:No adverse events were reported with either treatment.Patient compliance was good with topical finasteride.

The authors received no financial support for this research.

Disclosure:

The authors have no conflicts of interest to disclose.

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A Systematic Review of Topical Finasteride in the ...

Clinical trial design: When age is more than just a number – Healthcare Global – Healthcare News, Magazine and Website

Posted: at 1:56 am


Dr Gen Li, CEO and Founder of Phesi, discusses the impact of Covid-19 on clinical trials - and the significance of age

Perception-led rather than data-led clinical trial design still lies at the core of many challenges in clinical development. Moreover, the challenge of clinical trial design does not discriminate between the smallest biotech startups and the largest pharmaceutical companies. All organisations in the clinical development sector suffer from similar challenges. We can confidently say that there is no perfectly designed clinical trial. But even for those trials that complete successfully, there are still design elements that could have been improved reducing patient burden and operational cost, and accelerating time to commercialization or a stop decision. And the breaking news? Many if not most of these outcomes could have been predicted.

Numerous existing problems in trial design have been exacerbated by the COVID-19 pandemic, but not caused by it.

Throughout the past 18 months, we have seen several examples of trials thought to be at risk of failure because of the impact of the pandemic. On closer review, the reality is that these trials were already at risk because of factors rooted in design issues. When a trial ran into problems and needed rescue, it was typically because investigator sites were not recruiting patients at the speed they should be.

To solve this problem, the easiest solution appears to be adding more investigator sites and hoping that those sites recruit more successfully. However, simply adding more sites does not solve the problem, in fact it adds unnecessarily high costs to a study and compounds the trial performance issue. More often than not, investigator site enrollment performance is the symptom, while the root cause is the trial design itself. Successful trial design relies on identifying variables and trends in the patient population and using structured and integrated global data to do this. One such variable is patient age distribution.

There is a wealth of historical trial and patient data available that can be employed in study design. In analysing 4,000+ human diseases, it becomes clear that each disease has a distinct pattern in patient age distribution. This pattern is dynamic. It is also predictable. It can be positively impacted by medical innovations and varies geographically as socio-economic factors differ. Age should always be an integrated part of trial design. However, many organisations lack access to sufficient volume of relevant data, and so create patient age eligibility parameters which are inaccurate.

This typically results in numerous protocol amendments being made while implementing the trial, with concomitant and significant financial costs, and prolonged cycle times and even the potential failure of a trial. Recent analysis by Phesi of Phase III trials showed that 9% of undergo protocol amendments to modify patient age eligibility. This figure is 8.9% for Phase II trials. Given that Phase III trials are defined as confirmatory, this similarity is alarming. Applying insights from data can optimise clinical trial design relating to patient age eligibility and potentially avoid such protocol amendments. The following example using protocols for a neurological disease clinical trial demonstrates how.

Synthesised patient characteristics from 69,495 patients with this neurological disease show the average age of patients was 60.9 years old, with standard deviation of 9.5 years (fig.1.). Among these patients, 31% were over 65 years old. The average disease duration was seven years. There were very few patients under 40, ranging between 0.4% and 3.5%. For the combined cohorts, 1.5% patients were under 40 years old (37 out of 2,384) (fig.3.).

Unsurprisingly, most of the clinical trials for this neurological disease included patients 40 years and older (105/198) (fig.3.). Indeed, 40 years old is the modal age value (i.e., the data value that appears most often in historical trial data and so helps to identify potential anomalies that may cause failure or delay).

However, despite the modal value, 16% of protocols included patients 18 years and older (32/198). This is a design element risk. Typically, where design elements are outside of modal values, we subsequently see protocol amendments implemented to bring the ranges back in line. This proved to be the case in this example, with multiple amendments for age eligibility made (fig.4.).

From analysing synthesised patient profiles in this neurological disease, it becomes immediately clear there are few patients between ages 18 years and 40 years. Furthermore, reviewing historical protocol amendments data shows us that protocols are eventually amended to conform with the modal value of 40. Had the trial sponsors in these 198 protocols accessed this data, many protocol amendments could have been avoided.

Making use of modal values requires significantly large pools of historical and current trial data to find the most commonly used protocol elements including:

These data points are then used to apply modal value-based design. Such a data-driven approach will reduce the number of amendments; reduce the cost of trials and reduce cycle times. Ultimately, it will accelerate the path of a treatment from development to market, assuming safety and efficacy milestones are met.

This requires a blend of data science and medical expertise. It also necessitates investment in digital analytics, with a combination of:

Although it may seem complex to implement, modal value-based trial design has the potential to revolutionise the ways in which we plan and implement clinical studies.

Whats more, today, the industry has access to large volumes of published data, publicly available data, and historical trial data that can now be analysed via predictive analytics to optimise trial design and make modal value guided design possible.

With such data at their fingertips, now is the time for sponsors to focus on how to employ it to their advantage and ultimately accelerate getting critical therapies to patients.

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Clinical trial design: When age is more than just a number - Healthcare Global - Healthcare News, Magazine and Website

Panel Discusses the Ongoing Evolution of Remote Patient Care – AJMC.com Managed Markets Network

Posted: at 1:56 am


Remote patient monitoring has gained ground but there are plenty of challenges, including finding a balance between reimbursement and payer provision of services, according to panelists who took part in a discussion during the first day of Patient-Centered Oncology Care (PCOC).

How would you define what technologies or services you would include under this rubric of remote patient monitoring? asked PCOC co-chair Joseph Alvarnas, MD, of City of Hope. This could include software, telehealth, and other devices, including wearables. We are in a new domain of remote patient monitoring.

Alvarnas moderated the panel discussion, Remote Patient Monitoring: Case Studies From the Front Lines, which explored real-world experiences with remote patient monitoringan area that has taken on greater heft as the COVID-19 pandemic continues to affect health care delivery. He was joined by several experts:

RAJINI KATIPAMULA-MALISETTI, MD, vice president, medical oncology, and quality medical director, Minnesota Oncology in Coon Rapids; STEVEN W. YATES, MD, medical director, oncology services, Intermountain Healthcare in Las Vegas, Nevada; ELIZABETH KWO, MD, MBA, MPH, deputy chief clinical officer, Anthem Blue Cross Blue Shield in Boston, Massachusetts; and GREGORY VIDAL, MD, PHD, director, Breast Cancer Research Group, West Cancer Center & Research, and associate professor, University of Tennessee West Cancer Center in Memphis.

It is not easy to shape a universal definition of what remote patient monitoring must include, the panelists agreed. And there was consensus that care and resource utilization management are important goals, particularly weighing its medical necessity to ensure that patients get the right care.

I consider multiple categories, from the medical devices, that occur, Kwo stated. Categories under the umbrella of remote patient monitoring include the small and lightweight wearables and biosensors to in-home resources, such as home care and setting up a medical home. Whats important, she emphasized, is never losing that doctorpatient connection, whether it be asynchronous (delayed delivery of patient data) or synchronous (in real time) or delivered through an app that connects the patient and their treating clinician via telehealth.

The potential of remote monitoring, too, isnt confined to benefiting the oncology space, as the diabetes and respiratory fields are already benefi ting from automated insulin delivery and smart inhalers, Kwo added. We can see how our patients are doing, thanks to the internet of things, she noted.

Katipamula-Malisetti acknowledged that some clinicians may question the ability to eff ectively monitor patient care on a remote basis or that patients truly reap benefi ts from remote care. Weve found huge differences in patient satisfaction, she said. And these are not just tangible, care-related worries, such as exposure to COVID-19, but also intangibles, such as not being able to make an appointment due to inclement weather.

Cancer care encompasses so much more than just addressing the patients disease, Katipamula-Malisetti added, which means that in addition to visits with their treating clinicians, patients may also consult with dieticians, the chemotherapy team, or genetic specialists. However, that doesnt mean all these appointments will be kept, and to that point, Katipamula-Malisetti emphasized the importance of caregiver support buttressing patient eff orts to continue getting the most out of an altered care path by reducingpatient no-shows.

Survivorship visits, nutritionist consults, even geneticists have all benefi ted from a second set of ears, because as a by-product of patients not having to come in for another visit, she said, there have been gains in both patient satisfaction and engagement, especially when they feel more confi dence in the presence of loved ones to ask questions related to their care. The no-show rate has improved significantly, Katipamula-Malisetti emphasized.

Yates highlighted the results he has seen among high-risk patients with comorbidities, high-fl iers, or those patients with comorbid conditions who are likely to end up in the hospital or emergency department [ED]. His perspective was infused by historical datafrom a clinical trial Intermountain initiated in 2000with results showing that daily remote monitoring helpedto reduce inpatient admissions by 67%, observation hospitalizations by 63%, and ED visits by 35%.

This extra attention, Yates stated, enabled providers to do a better job, even with advanced care planning, which was another area of improved patient engagement, which itself positively affected patients unnecessary use of service. We found that patients were better able to think through their processes, and they also had less utilization of hospital and ED visits, he said.

Vidal addressed the elephant in the room by noting that although remote patient monitoring has been shown to be of benefit to many, this may be a disproportionate result because not all patientsparticularly patients of colorhave access to the necessary technology to participate in virtual care, and that puts them at a care disadvantage.

This disparity, Alvarnas echoed, has potential to create digital haves and have-nots. This can include patients of color as well as those affected by social determinants of health. The geographic challenges presented by rural locations, for example, can adversely affect broadband internet access and limit the use of monitoring devices, thereby relegating individuals to a diff erent level of care based upon that lack of access.

Financial and educational challenges also present roadblocks, because even if a patient can afford the technology needed, the next patient may have a better smartphone with more data, someone else might be more digitally savvy, and yet others still prefer receiving in-person care.

Is it even possible, then, to have a best-case scenario for telemedicine? Are there patients for whom this method of care will never work? Alvarnas asked the panelists. What is the best approach to take?

Start with simple solutions, those assembled seemed to agree. Suggestions included collaborating more with rural physicians to establish remote monitoring centers for low-risk patients, which include exams performed by their primary care physicians and surveillance for those not needing chemotherapy; enabling inclusion in clinical studies by permitting remote capture of data at nearby clinical centers; designing user-friendly access solutions with seamless integration into daily routines; and equipping patients with easy-to-use electronics.

All of this is not possible, however, without the funds to fuel development. Alvarnas addressed this potential barrier from the payer perspective by asking if it was possible to achieve a balance between reimbursement and empowering greater technology use, especially in regard to saving patienttime by avoiding unnecessary in-person care or preventable admissions and focusing on what preventive services payers should cover.

Using technology to reduce total medical costs is top-of-mind, as is ongoing engagement with and monitoring of the patients with the most potential to generate very-high-cost claims, Kwo emphasized. Following claims reporting is another area, she noted, because that can inform if its possible to prevent higher-cost claims down the line with a certain patient monitoring device.

Katipamula-Malisetti added that she would like to see more services covered that dont directly involve the physiciansuch as visits with palliative care specialists, geneticists, and dietitiansas well as those that contribute to the big picture by keeping patients out of the hospital.

Knowing of the looming possibility that CMS might roll back some of the flexibility it has introduced since the start of the COVID-19 pandemic, especially in regard to Medicares hospital outpatient prospective payment system,1 Vidal said there needs to be improvement in billing practices, because billing is frequently based on what you can accomplish during a true physical exam. Compensation practices also need to be adopted that adequately compensate those who deal with the information overload that practices sometimes face from the glut of patient data produced from remote monitoring.

I think patients and payers and providers are going to revolt if we roll back too much, Yates added. I think COVID is here to stay, in the way that our world has changed, in the way that we deliver health care has changed. I dont think it will go back to what it was in the past few years.

Alvarnas echoed those sentiments, noting the changing tide in patient care. Its about seeing solutions that include a move toward greater patient centricity and leveraging technology to have a better understand of what patients and families seek as their goals of care and hopefully to find betterexperiences of care along the way, he said.

According to Kwo, the most important questions we need to be asking regarding the optimal benefits of remote patient monitoring and how to get the most out of a shared-savings model are: How do we best engage? What are actionable care plans? Have we really closed care gaps? Does this technology really enable a provider to better monitor patients between appointments?

The answers to these have the potential to affect cost reductions and reimbursement, Kwo concluded.

Reference

CMS-1753-P: Hospital outpatient prospective payment notice of proposedrulemaking (NPRM). CMS. Accessed October 18, 2021. https://www.cms.gov/medicaremedicare-fee-service-paymenthospitaloutpatientppshospitaloutpatient-regulations-and-notices/cms-1753-p

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Panel Discusses the Ongoing Evolution of Remote Patient Care - AJMC.com Managed Markets Network

Merck Announces Clinical Holds on Studies Evaluating Islatravir for the Treatment and Prevention of HIV-1 Infection – Yahoo Finance

Posted: at 1:56 am


KENILWORTH, N.J., December 13, 2021--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has placed clinical holds on the investigational new drug applications (INDs) for the oral and implant formulations of islatravir (MK-8591) for HIV-1 pre-exposure prophylaxis (PrEP); the injectable formulation of islatravir for HIV-1 treatment and prophylaxis; and the oral doravirine/islatravir (DOR/ISL) HIV-1 once-daily treatment. The FDAs clinical hold is based on previously announced observations of decreases in total lymphocyte and CD4+ T-cell counts in some participants receiving islatravir in clinical studies. As previously announced, Merck has stopped dosing in the Phase 2 IMAGINE-DR clinical trial of islatravir in combination with MK-8507 (MK-8591-013) and paused enrollment in the once-monthly Phase 3 PrEP studies, (MK-8591-022 and MK-8591-024) (see announcements here and here). With the FDAs clinical hold, no new studies may be initiated. Participants who are currently receiving islatravir as part of the studies for PrEP, including oral and implant formulations, as well as injectable islatravir for treatment and prophylaxis, will no longer receive the study drug; CD4+ T-cell and total lymphocyte counts will be monitored for recovery (full clinical hold). Participants in the PrEP studies will be offered approved, once-daily, oral PrEP. Additionally, participants in studies of DOR/ISL who were started on treatment will continue to receive study medication (partial clinical hold). No new participants will be screened or randomized in DOR/ISL studies for treatment during the partial clinical hold. Investigators have been informed of these actions.

"We are grateful to the participants and the study investigators for their ongoing contributions to this research," said Dr. Joan Butterton, vice president, infectious diseases, Global Clinical Development, Merck Research Laboratories. "Merck continues to investigate the potential of islatravir and nucleoside reverse transcriptase translocation inhibitors and remains committed to helping to address unmet needs in HIV treatment and prevention."

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The following studies have been placed on full clinical hold:

MK-8591-016 A Phase 2a PrEP study evaluating the safety and pharmacokinetics of oral islatravir once-monthly in participants at low risk of HIV-1 infection

MK-8591-022 (IMPOWER 22) A Phase 3 PrEP study evaluating oral islatravir once-monthly in cisgender women at high risk for HIV-1 infection

MK-8591-024 (IMPOWER 24) A Phase 3 PrEP study evaluating oral islatravir once-monthly in cisgender men and transgender women who have sex with men, and are at high risk for HIV-1 infection

MK-8591-034 A Phase 1 study evaluating injectable islatravir (dosing complete)

MK-8591-035 A Phase 2 PrEP study evaluating once-monthly oral islatravir in trans and gender diverse individuals (study had not yet opened enrollment)

MK-8591-043 A Phase 2a PrEP study evaluating islatravir implant once-yearly in individuals at low risk for HIV-1 infection (study had not yet opened enrollment)

The following studies have been placed on partial clinical hold:

MK-8591-011 A Phase 2 dose ranging study of oral DOR/ISL once-daily and lamivudine (3TC) in treatment-nave adult participants with HIV-1 infection (fully enrolled)

MK-8591A-017 (ILLUMINATE SWITCH A) A Phase 3 oral once-daily, open label study evaluating a switch from antiretroviral therapy (ART) to DOR/ISL in adults with HIV-1 who are virologically suppressed (fully enrolled)

MK-8591A-018 (ILLUMINATE SWITCH B) A Phase 3 oral once-daily study evaluating a switch from bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) to DOR/ISL in adults with HIV-1 who are virologically suppressed (fully enrolled)

MK-8591A-019 (ILLUMINATE HTE) A Phase 3 study evaluating oral islatravir and DOR/ISL once-daily in heavily treatment-experienced (HTE) participants with HIV-1 infection

MK-8591A-020 (ILLUMINATE NAIVE) A Phase 3 study evaluating oral islatravir and DOR/ISL once-daily in treatment-nave participants with HIV-1 infection

MK-8591A-028 (ILLUMINATE YOUTH) A Phase 2 open label study evaluating oral DOR/ISL once-daily for the treatment of HIV-1 infection in pediatric participants who are virologically suppressed on ART for 3 months or are treatment-naive

MK-8591A-033 A Phase 3 open label follow up of adult and pediatric participants with HIV-1 who were treated with oral DOR/ISL once-daily in earlier clinical studies

Additionally, Gilead and Merck have made the decision to stop all dosing of participants in the Phase 2 clinical study (NCT05052996) evaluating an oral-weekly combination treatment regimen of Mercks investigational islatravir and Gileads investigational lenacapavir in people living with HIV who are virologically suppressed on antiretroviral therapy. This decision follows the joint announcement on November 23 of a temporary hold on further enrollment and screening in the study, which commenced in October 2021. Following this decision to stop dosing in the study, participants in both treatment groups will stop taking study drug and restart their prior antiretroviral regimen, as the two companies assess whether a different dosing of islatravir in combination with lenacapavir may provide a once-weekly oral therapy option for people living with HIV. Gilead and Merck remain committed to the collaboration, which aims to develop long-acting new treatment options to address the unmet needs for people living with HIV.

About IMPOWER 22 (MK-8591-022) and IMPOWER 24 (MK-8591-024)

The IMPOWER 22 clinical trial is a Phase 3, randomized, active-controlled, double-blind clinical study to evaluate the efficacy and safety of oral islatravir once-monthly compared to once-daily emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as pre-exposure prophylaxis (PrEP) in cisgender women at high risk for HIV-1 Infection.

The IMPOWER 24 clinical trial is a Phase 3, randomized, active-controlled, double-blind clinical study to evaluate the efficacy and safety of oral islatravir once-monthly as PrEP compared to once-daily FTC/TDF or emtricitabine/tenofovir alafenamide (FTC/TAF) in cisgender men and transgender women who have sex with men, and are at high risk for HIV-1 infection.

About IMAGINE-DR

The IMAGINE-DR clinical trial was a Phase 2, randomized, controlled, double-blind, dose-ranging study, designed to evaluate a switch to MK-8507 and ISL in combination as a once-weekly oral treatment in adults with HIV-1 who have been virologically suppressed for greater than or equal to six months on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) once-daily. The study had been fully enrolled with 161 participants and was ongoing.

About ILLUMINATE SWITCH A (MK-8591A-017) and ILLUMINATE SWITCH B

The ILLUMINATE SWITCH A clinical trial is a Phase 3, randomized, active-controlled, open-label clinical trial to evaluate a switch from ART to DOR/ISL, in adults with HIV-1 who are virologically suppressed.

The ILLUMINATE SWITCH B clinical trial is a Phase 3, randomized, double-blind clinical trial to evaluate a switch from BIC/FTC/TAF to DOR/ISL in adults with HIV-1 who are virologically suppressed.

About Islatravir (MK-8591)

Islatravir (MK-8591) is Mercks investigational nucleoside reverse transcriptase translocation inhibitor under evaluation for the treatment and prevention of HIV-1.

About PIFELTRO and DELSTRIGO

PIFELTRO (doravirine, 100 mg) is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.

DELSTRIGO (doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO. DELSTRIGO contains a boxed warning regarding post-treatment acute exacerbations of hepatitis B (HBV) infection. See Selected Safety Information below.

Selected Safety Information about PIFELTRO and DELSTRIGO

Warning: Posttreatment Acute Exacerbation of Hepatitis B (HBV)

All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute exacerbations of HBV have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be monitored with both clinical and laboratory follow-up for at least several months after stopping DELSTRIGO. If appropriate, initiation of anti-HBV therapy may be warranted.

PIFELTRO and DELSTRIGO are contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers (including the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; and the herbal product St. Johns wort (Hypericum perforatum)), as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO and PIFELTRO.

DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.

Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (eg, high-dose or multiple NSAIDs). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in patients with risk factors for renal dysfunction who appeared stable on TDF.

Prior to or when initiating DELSTRIGO, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min.

In clinical trials in HIV-1 infected adults, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF.

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

Because DELSTRIGO is a complete regimen, co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

Co-administration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended.

If DELSTRIGO is co-administered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO.

If PIFELTRO is co-administered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart).

Consult the full Prescribing Information prior to and during treatment for more information on potential drug-drug interactions.

Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min.

The most common adverse reactions with DELSTRIGO (incidence 5%, all intensities) were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with PIFELTRO (incidence 5%, all intensities) were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%), and abnormal dreams (5%).

By Week 96 in DRIVE-FORWARD, 2% of adult subjects in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication.

By Week 96 in DRIVE-AHEAD, 3% of adult subjects in the DELSTRIGO group and 7% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication.

In DRIVE-FORWARD, mean changes from baseline at Week 48 in LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -4.6 mg/dL in the PIFELTRO group vs 9.5 mg/dL in the DRV+r group. Non-HDL-C: -5.4 mg/dL in the PIFELTRO group vs 13.7 mg/dL in the DRV+r group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-AHEAD, mean changes from baseline at Week 48 in LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -2.1 mg/dL in the DELSTRIGO group vs 8.3 mg/dL in the EFV/FTC/TDF group. Non-HDL-C: -4.1 mg/dL in the DELSTRIGO group vs 12.7 mg/dL in the EFV/FTC/TDF group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-SHIFT, mean changes from baseline at Week 48 in LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -16.3 mg/dL in the DELSTRIGO group vs -2.6 mg/dL in the PI + ritonavir group. Non-HDL-C: -24.8 mg/dL DELSTRIGO group vs -2.1 mg/dL in the PI + ritonavir group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-AHEAD, neuropsychiatric adverse events were reported in the three pre-specified categories of sleep disorders and disturbances, dizziness, and altered sensorium. Twelve percent of adult subjects in the DELSTRIGO group and 26% in the EFV/FTC/TDF group reported neuropsychiatric adverse events of sleep disorders and disturbances; 9% in the DELSTRIGO group and 37% in the EFV/FTC/TDF group reported dizziness; and 4% in the DELSTRIGO group and 8% in the EFV/FTC/TDF group reported altered sensorium.

The safety of DELSTRIGO in virologically-suppressed adults was based on Week 48 data from subjects in the DRIVE-SHIFT trial. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no ARV treatment history.

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO or DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Mothers infected with HIV-1 should be instructed not to breastfeed if they are receiving PIFELTRO or DELSTRIGO due to the potential for HIV-1 transmission.

Our Commitment to HIV

For more than 35 years, Merck has been committed to scientific research and discovery (R&D) in HIV. Today, we are developing a series of antiviral options designed to help people manage HIV and protect people from HIV, with the goal of reducing the growing burden of infection worldwide. We remain committed to working hand-in-hand with our partners in the global HIV community to address the complex challenges that impede progress toward ending the epidemic.

About Merck

For over 130 years, Merck, known as MSD outside the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the worlds most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit http://www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the "company") includes "forward-looking statements" within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the companys management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the companys ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the companys patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the companys 2020 Annual Report on Form 10-K and the companys other filings with the Securities and Exchange Commission (SEC) available at the SECs Internet site (www.sec.gov).

View source version on businesswire.com: https://www.businesswire.com/news/home/20211213005976/en/

Contacts

Media Contacts:Melissa Moody(215) 407-3536

Sienna Choi(908) 873-4311

Investor Contacts:Peter Dannenbaum(908) 740-1037

Raychel Kruper(908) 740-2107

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Merck Announces Clinical Holds on Studies Evaluating Islatravir for the Treatment and Prevention of HIV-1 Infection - Yahoo Finance

BeyondSpring Pharmaceuticals Announces New Clinical Data Confirming Plinabulin’s Fast Onset Mechanism of Action in the Prevention of…

Posted: at 1:56 am


NEW YORK, Dec. 15, 2021 (GLOBE NEWSWIRE) -- BeyondSpring Pharmaceuticals (the Company or BeyondSpring) (NASDAQ: BYSI), a global pharmaceutical company focused on the development of cancer therapeutics, today announced new data highlighting the mechanism of action of plinabulin in the prevention of chemotherapy-induced neutropenia (CIN) at the 63rdAmerican Society of Hematology (ASH) Annual Meeting and Exposition, held virtually and in person in Atlanta, Georgia from December 11-14, 2021. The data demonstrate that adding plinabulin to a myelosuppressive regimen rapidly reversed (within 24 hours) neutropenia and leukopenia in the PROTECTIVE-1 and -2 clinical studies by protecting progenitor stem cells in the bone marrow.

This clinical data provides evidence confirming the hypothesized progenitor stem cell protective mechanism of action for plinabulin, which further validates the positive Phase 3 data from the PROTECTIVE-2 clinicalprogram.These data also build upon the rapid effect seen in clinical trials to date and support the opportunity for enhanced CIN prevention care with plinabulin,said Dr. Douglas Blayney, professor of medicine at Stanford University Medical School and global principal investigator for the CIN studies.These data provide a strong rationale for combining plinabulin with pegfilgrastim, since the latter has a mechanism of action exerting CIN prevention in week 2 of the chemotherapy cycle while plinabulin shows a week 1 benefit. This early CIN benefit is critically important because these white blood cells are the bodys main source of defense against infection. If a cancer patient gets an infection due to CIN, it may affect their ability to finish chemotherapy for cancer treatment.

Dr. Ramon Mohanlal, executive vice president of research and development and chief medical officer at BeyondSpring Pharmaceuticals, added, This presentation at ASH provides mechanistic support for the observed benefit of plinabulin in the prevention of CIN, a condition that still has unmet medical need, despite the availability of the standard of care CIN prevention drug, G-CSF. In addition, the rapid onset of action is critical since week 1 of each chemotherapy cycle is when more than 75% of CIN cases occur, even with G-CSF.Investigating the nuances of how and when plinabulin works is a continuous part of our work in understanding this multifaceted therapy. We look forward to sharing more of these insights with the oncology community in future studies.

This poster was presented on Sunday, December 12, 2021 and is available on the ASH website.

Poster Title: Plinabulin Rapidly (within 24 Hours) Reverses Myelosuppression Induced by ChemotherapyAbstract Number: 2056Key Findings:

About PlinabulinPlinabulin,BeyondSpringslead asset, is a selective immunomodulating microtubule-binding agent (SIMBA), which is a potent antigen presenting cell (APC) inducer. It is a novel, intravenous infused, patent-protected asset forCIN prevention and a Phase 3 anti-cancer candidate for non-small cell lung cancer (NSCLC) with recently released positive topline data. Plinabulin triggers the release of the immune defense protein, GEF-H1, which leads to two distinct effects: first is a durable anticancer benefit due to the maturation of dendritic cells resulting in the activation of tumor antigen-specific T-cells to target cancer cells, and the second is early-onset of action in CIN prevention after chemotherapy by boosting the number of hematopoietic stem/progenitor cells (HSPCs). Plinabulin received Breakthrough Therapy designation from both U.S. and China FDA for the CIN prevention indication. As a pipeline in a drug, plinabulin is being broadly studied in combination with various immuno-oncology agents that could boost the effects of the PD-1/PD-L1 antibodies and re-sensitize PD-1/PD-L1 antibody-resistant patients.

AboutBeyondSpringPharmaceuticalsHeadquartered in New York City,BeyondSpringis a global biopharmaceutical company focused on developing innovative cancer therapies to improve clinical outcomes for patients who have high unmet medical needs.BeyondSpringsfirst-in-class lead asset, plinabulin, a selective immunomodulating microtubule-binding agent (SIMBA), is being developed as a pipeline in a drug in various cancer indications as a direct anti-cancer agent and to prevent chemotherapy-induced neutropenia (CIN). Inthe DUBLIN-3 study, a global, randomized, active controlled Phase 3 study, the plinabulin and docetaxel combination has met the primary endpoint of extending overall survival compared to docetaxel alone, in 2nd/3rdline NSCLC (EGFR wild type). Additionally, it is being broadly studied in combination with various immuno-oncology regimens that could boost the effects of PD-1 / PD-L1 antibodies in seven differentcancers. In addition to plinabulin,BeyondSpringsextensive pipeline includes three pre-clinical immuno-oncology assets and a subsidiary, SEED Therapeutics, which is leveraging a proprietary targeted protein degradation drug discovery platform.

Cautionary Note Regarding Forward-Looking StatementsThis press release includes forward-looking statements that are not historical facts. Words such as will, expect, anticipate, plan, believe, design, may, future, estimate, predict, objective, goal, or variations thereof and variations of such words and similar expressions are intended to identify such forward-looking statements. Forward-looking statements are based onBeyondSpringscurrent knowledge and its present beliefs and expectations regarding possible future events and are subject to risks, uncertainties and assumptions. Actual results and the timing of events could differ materially from those anticipated in these forward-looking statements as a result of several factors including, but not limited to, difficulties raising the anticipated amount needed to finance the Companys future operations on terms acceptable to the Company, if at all, unexpected results of clinical trials, delays or denial in regulatory approval process, results that do not meet our expectations regarding the potential safety, the ultimate efficacy or clinical utility of our product candidates, increased competition in the market, and other risks described inBeyondSpringsmost recent Form 20-F on file with the U.S. Securities and Exchange Commission. All forward-looking statements made herein speak only as of the date of this release andBeyondSpringundertakes no obligation to update publicly such forward-looking statements to reflect subsequent events or circumstances, except as otherwise required by law.

Investor Contact:Ashley R. RobinsonLifeSciAdvisors, LLC+1 617-430-7577arr@lifesciadvisors.com

Media Contact:Darren Opland, Ph.D.LifeSciCommunications+1 646-627-8387darren@lifescicomms.com

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BeyondSpring Pharmaceuticals Announces New Clinical Data Confirming Plinabulin's Fast Onset Mechanism of Action in the Prevention of...

LEO Pharma Initiates a Phase 2b Dose-Ranging Clinical Trial With an Oral H4R Antagonist in Adult Patients With Moderate-to-Severe Atopic Dermatitis…

Posted: at 1:56 am


BALLERUP, Denmark--(BUSINESS WIRE)--LEO Pharma A/S, a global leader in medical dermatology, today announced it has enrolled the first patient in a Phase 2b dose-ranging clinical trial with an investigational oral histamine receptor 4 (H4R) antagonist (LEO 152020) for the potential treatment of adults with moderate-to-severe atopic dermatitis (AD).

Histamine is a key mediator of allergic inflammation.i Unlike histamine receptors 1-3, H4R plays a role in itch response and triggers the migration of cells in the immune system toward inflammatory and allergic sites throughout the body.ii,iii,iv As an oral H4R antagonist, LEO 152020 has the potential to prevent histamine-induced initiation of inflammatory and itch mechanisms via the histamine 4 receptor.v

The primary objective for the randomized, triple-blind, placebo-controlled, multi-center Phase 2b dose-ranging clinical trial is to evaluate the efficacy of LEO 152020 compared with placebo in the treatment of adults with moderate-to-severe AD.vi The primary endpoint of the trial is change in Eczema Area and Severity Index (EASI) from baseline to Week 16.vi Additional exploratory endpoints will evaluate patient-reported symptoms such as itch and sleeplessness.vi The number of treatment-emergent adverse events per patient from baseline to Week 16 defines the key safety endpoint of the trial.vi

"Managing a skin disease such as atopic dermatitis with oral treatments is challenging because of limited available options for chronic use, said Prof. Dr. med. Thomas Werfel, Dept. Dermatology and Allergy, Hannover Medical School, Hannover, Germany, and lead investigator of the Phase 2b clinical trial. This trial will evaluate whether an alternative oral option can potentially offer a new choice for adult patients with moderate-to-severe AD.

AD is a chronic, inflammatory, skin disease characterized by intense itch and eczematous lesions.vii AD is the result of skin barrier dysfunction and immune dysregulation, leading to chronic inflammation.viii

We have been encouraged by results on itch in pre-clinical studies with this investigational medicine for patients who prefer oral treatment options, said Dr. Jrg Mller, Executive Vice President, Global Research & Development, LEO Pharma. We are committed to developing innovative therapies that may help improve the lives of patients who need a wider range of treatment options and routes of administration for skin diseases.

#ENDS#

About LEO 152020In 2018, LEO Pharma A/S and JW Pharmaceutical Corporation entered into a license agreement in which LEO Pharma gained exclusive rights to develop and commercialize LEO 152020 (LP0190/JW1601) for all non-ophthalmic indications worldwide, except in South Korea, where JW Pharmaceutical retains rights.

About LEO PharmaLEO Pharma helps people achieve healthy skin. The company is a leader in medical dermatology with a robust R&D pipeline, a wide range of therapies and a pioneering spirit. Founded in 1908 and owned by the LEO Foundation, LEO Pharma has devoted decades of research and development to advance the science of dermatology, setting new standards of care for people with skin conditions. LEO Pharma is headquartered in Denmark with a global team of 6,000 people, serving 93 million patients in 130 countries. In 2020, the company generated net sales of DKK 10,133 billion.For more information, please visit http://www.LEO-Pharma.com.

References

i Jemima EA, et al. Mol Immunol. 2014;62:19-28.

ii Thurmond RL. Frontiers Pharmacol. 2015;6:65.

iii SchaperGerhardt K, et al. Br J Pharmacol. 2020;177:490-502.

iv Damaj BB, et al. J Immunol. 2007;179:7907-15.

v de Esch IJ et al. Trends Pharmacol Sci 2005;26:462-469.

vi ClinicalTrials.Gov: https://clinicaltrials.gov/ct2/show/NCT05117060 (Accessed November 2021).

vii Weidinger S, et al. Lancet. 2016; 387:1109-1122.

viii Boguniewicz M, et al. Immunol Rev. 2011;242(1):233-46.

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LEO Pharma Initiates a Phase 2b Dose-Ranging Clinical Trial With an Oral H4R Antagonist in Adult Patients With Moderate-to-Severe Atopic Dermatitis...

Clinical outcomes and quality of vision correcting IOL | OPTH – Dove Medical Press

Posted: at 1:56 am


Plain Language Summary

Many patients who have cataract surgery are interested in being less dependent on their glasses afterwards. Some intraocular lenses (multifocal IOLs) create several distinct focal points for far, intermediate and/or near viewing, to provide better vision at these working distances. Other lenses can extend a single focal point to help increase the range of vision. There are limits to this technology, so distance vision and computer work are generally good but near vision may not be as good as can be obtained with a multifocal IOL. However, the level of visual disturbances may be relatively lower with the extended focus IOL. The current study was designed to evaluate the clinical results obtained for patients who had a new extended range of vision IOL implanted in both eyes. The study showed that this IOL provided very good distance and intermediate vision and good near vision. Visual disturbances such as hazy vision and blurred vision were the most common reported, with low reports of glare, halos, or starbursts.

With modern intraocular lens (IOL) power calculation formulas, cataract surgery is justifiably considered a refractive procedure, with a high likelihood that patients will not need spectacles for distance vision when a monofocal IOL is implanted. For subjects interested in reducing their dependence on spectacles for intermediate (computer) or near (reading) vision, multifocal or extended depth of focus (EDOF) IOLs may be considered. It has been demonstrated that trifocal IOLs are most likely to provide spectacle independence at all distances.13 Limitations in how far the depth of focus can be extended prevent EDOF lenses from providing the same level of near vision as can be achieved with a multifocal, but they generally provide good vision at distance and intermediate. A purported advantage of EDOF IOLs is the expectation that visual disturbances will be lower, as light is not split to provide several distinct foci.3 However, some studies have shown that visual disturbances with a diffractive EDOF lens (Symfony, Johnson & Johnson Vision, Santa Ana, CA) are not significantly reduced relative to a trifocal IOL.46 It is recognized, though, that patients implanted with monofocal IOLs tend to have a lower incidence and severity of visual disturbances, such as glare and halos, relative to either multifocal or traditional EDOF lenses.4,5

There are several different approaches that have been used to create EDOF lenses.7 One involves manipulating spherical aberration (SA), with one IOL designed with alternating annular zones of positive and negative SA in the IOL to increase the depth of focus.8,9 Challenges with this approach are the variability in the existing SA in each eye (making it more difficult to obtain a predictable effect) and the limits to which SA can be modified before the quality of vision degrades. Another is the use of diffractive elements to produce the EDOF effect, but as noted above the advantages of such an IOL relative to a diffractive multifocal have been questioned. A third involves the use of a limiting aperture to extend the depth of focus, a method commonly used in photography.10 The challenge with this method is that the amount of light entering the eye may be significantly reduced; as a result, this approach typically involves only monocular implantation.

The AcrySof IQ Vivity IOL is based on a new optical design principle. It does not incorporate diffractive elements, nor does it target SA changes or aperture limiting technology to achieve a better range of vision. This novel presbyopia correcting IOL from Alcon (Fort Worth, TX) incorporates proprietary wavefront shaping (X-WAVE) technology to produce an extended focal length that channels almost all the incoming light through the IOL in that specific range.11 The low amount of unused light is expected to reduce the potential for visual disturbances, because out-of-focus light is generally the root cause of disturbances such as halos and glare. In several clinical studies the reported visual disturbances with this IOL were not different from those observed with a monofocal IOL, but intermediate and near vision were better than can be achieved with a monofocal IOL.12,13 The lens is a 1-piece, hydrophobic aspheric posterior chamber IOL with ultraviolet protection and a blue-light filter. It has a 6 mm optical zone with a modified central 2.2 mm region to create the stretched wavefront.

The purpose of the current study was to provide objective and subjective normative clinical outcomes data for patients who have the Vivity IOL bilaterally implanted.

This study was a non-interventional single-arm study of visual outcomes and quality of vision after successful bilateral implantation of the Vivity IOL. A regional ethics committee (REK, Norway) approved the study, and enrolled subjects signed an appropriate informed consent document. As a non-interventional study, there was no clinical trial registration requirement. The study was conducted in accordance with good clinical practice (GCP) and the tenets of the Declaration of Helsinki were observed. Data are not available for sharing.

Eligible patients had to have had previous uncomplicated bilateral cataract surgery with binocular implantation of the Vivity lens more than 3 months but less than a year prior to their enrollment. They had to have a best-corrected monocular and binocular distance visual acuity (VA) of 20/40 (0.3 logMAR) or better. Subjects with previous corneal surgery, ocular pathology, or significant posterior capsular opacity (PCO) were excluded. One surgeon (KGG) had performed all surgeries. Eyes with both toric and non-toric versions of the Vivity IOL were included. To be enrolled, the inclusion and exclusion criteria had to be met in both eyes of any potential subject.

Potential participants were identified from the clinical records of the site and screened to establish their eligibility, based on the inclusion and exclusion criteria above. If eligible, they were asked to participate in two postoperative diagnostic visits (one to three weeks apart); this was to reduce potential fatigue related to testing multiple defocus curves. Clinical evaluations included a manifest refraction, uncorrected and distance corrected VA at near (40 cm and 50 cm) intermediate (66 cm), and distance (4 m). Uncorrected photopic low contrast (25%) VA at 4 m was also tested, with and without a glare source. VA data were collected using the M&S Technologies Clinical Trial Suite (Niles, IL, USA). A patient reported outcome questionnaire related to quality of vision was also administered (the Quality of Vision questionnaire, or Q of V).14 This Rasch-scored questionnaire measures the reported Frequency, Severity and Degree of Bother associated with 10 distinct visual disturbances, such as glare, halos, starbursts, and blurred vision. In addition to the above, four binocular defocus curves were collected for each subject based on different levels of simulated monovision. Defocus curve results are reported in a separate publication.15

Demographic and surgical planning data were obtained from the subjects clinical records. Surgeries were performed bilaterally on the same day, with one eye targeted for the least-plus sphere from the surgery planning results and the contralateral eye targeted for the least-minus sphere. Toric planning was based on software that included consideration of posterior corneal astigmatism. One optometrist conducted all diagnostic visits. Detailed statistical analyses were performed using STATISTICA, version 12 (TIBCO Software Inc., Palo Alto, CA, USA).

Forty subjects were recruited for the study and completed the two diagnostic visits. A summary of the relevant demographic, preoperative and postoperative data is contained in Table 1. No subject had any adverse events identified at either diagnostic visit. Fifteen percent (12/80) of eyes had a toric IOL implanted. There was no statistically significant difference in either the postoperative spherical equivalent refraction (p = 0.51) or the refractive cylinder (p = 0.57) between the non-toric and toric eyes. Overall, 90% of eyes had a spherical equivalent refraction within 0.50D of plano and 83% had 0.50 D of refractive cylinder. Only one eye was more than 0.50D hyperopic. Three quarters of all eyes (60/80) had a residual spherical equivalent refraction within 0.50D of plano with 0.50 D of refractive cylinder. Figure 1 shows the distribution of residual refractive error. YAG capsulotomies were performed in 9% (7/80) of eyes, all prior to their study visit.

Table 1 Subject (n = 40) Demographics and Refractive Data (80 Eyes)

Figure 1 Postoperative MRSE and refractive cylinder magnitude.

Abbreviations: MRSE, mean refraction spherical equivalent; D, diopter.

Figure 2 shows the uncorrected and distance corrected binocular visual acuity at all test distances. There was no statistically significant difference between the uncorrected and distance corrected VA at any distance. A repeated measures ANOVA showed that the VA at the different test distances was statistically significantly different but post-hoc testing showed there was no statistically significant difference between 66 cm and 50 cm for either the uncorrected (p = 0.6) or distance corrected (p = 0.9) condition.

Figure 2 Uncorrected and distance corrected binocular visual acuity at various test distances.

Abbreviation: logMAR, log of the minimum angle of resolution.

The binocular mesopic uncorrected and distance corrected near VA at 40 cm and 50 cm was measured. There was no statistically significant difference between the uncorrected and corrected states at either distance. The mean binocular mesopic uncorrected VA was about 0.1 0.10 in both cases at both distances.

Figure 3 shows the distribution of the uncorrected binocular photopic low contrast VA with and without glare at 4 m. There was a statistically significant difference between the no glare and glare conditions (0.09 0.10 with no glare vs 0.44 0.21 with glare, p < 0.01). The low contrast acuity in no glare conditions was about 2 lines worse than the high contrast BDVA reported above.

Figure 3 Uncorrected photopic low contrast binocular visual acuity at 4 m.

Abbreviation: logMAR, log of the minimum angle of resolution.

Figure 4 shows a box-whisker plot of the distributions of the Rasch-scored results of the Quality of Vision questionnaire, showing summary data for the Frequency, Severity and Degree of Bother of visual disturbances with this IOL. There was no correlation between the Q of V scores and the follow-up time. There was also no apparent correlation between the Q of V scores and the refractive status or visual acuity results. Figure 5 shows the average responses related to each of the specific visual disturbances included in the questionnaire. For glare, halos and starbursts, three of the visual disturbances most often reported with multifocal and EDOF IOLs, 93% or more of subjects reported a frequency of never or occasionally, 90% a severity of not at all or mild and 95% a degree of bother of not at all or a little. The most frequently reported visual disturbances in the current study were hazy vision, blurred vision and focusing difficulties.

Figure 4 Distribution of aggregate results for the Quality of Vision questionnaire.

Figure 5 Detailed Quality of Vision questionnaire responses, with scoring on a 03 ordinal scale (lower is better). (A) Frequency, (B) severity, (C) degree of bother.

These results are among the first reported for this IOL in a clinical setting. As noted earlier, defocus curve results are reported in a separate publication. The distance corrected and uncorrected VA results at all tested distances were slightly better than those reported in the Vivity FDA Summary of Safety and Effectiveness document.12 They were also slightly better than the results reported by Bala et al13 and Arrigo.16

The Vivity lens also seemed to provide intermediate VA results that were better than those reported for several other EDOF lenses,17,18 and a monofocal IOL enhanced to improve intermediate vision.19 The combined use of a small aperture IOL (IC-8, Acufocus) and the Symfony diffractive EDOF lens appeared to provide similar intermediate vision to that obtained with the Vivity lens in the current study,20 as did one other EDOF lens (Mini Well, SiFi Medtec, Catania, Italy).9 In all the studies mentioned above the binocular distance vision appeared comparable, though the mean binocular near vision measured in the current study (0.07 logMAR) was almost 1 line to more than two lines better than results from the different EDOF IOLs in these other studies. As always, comparisons between different clinical studies must be evaluated with due consideration for different testing conditions, test distances (eg, intermediate), inclusion/exclusion criteria and follow-up time.

Mesopic VA at 50 cm was similar to the photopic VA measured at the same distance and was about a line better than mesopic VA at 40 cm. No specific luminance was recorded for these measures, so it is possible the level of room illumination was not dimmed sufficiently to result in a measurable difference.

Low contrast visual acuity at distance was reduced by about 2 lines in the no glare condition and about 5 lines with added glare. These results were slightly better than recorded for an EDOF lens and a trifocal IOL at the same practice, though the testing methodology was slightly different for both studies.21

The overall Quality of Vision scores were somewhat higher than expected, though visual disturbances such as glare, halos and starbursts were reported infrequently and were classified as of little or no bother. The frequency, severity and degree of bother related to glare, halos and starbursts reported here are lower than those reported by Bala et al13 and Arrigo et al15 for the same lens using the same questionnaire; subjects were evaluated at 3 months postoperative in these two studies.13 In the current study, hazy vision and blurred vision were reported most often. In contrast to this, raw scores from Arrigo et al indicated that blurred vision and trouble focusing were of most concern to subjects (after glare and halos), but hazy vision and fluctuating vision were never, or only rarely, reported. While a different questionnaire was used for the Vivity trial to obtain FDA approval, the questions were very similar; the level of hazy vision reported here appears higher than was reported in that previous trial.12 It is unclear whether the questionnaire results obtained in the current study were related to patient expectations, patient instructions related to the questionnaire or regional differences in responses; the latter issue has been noted in the past.22 Residual refractive error is also a possible contributing factor, though we found no correlation. Ocular surface disease may be another contributing factor. Further studies would be helpful in determining if the results at this site were anomalous. Aggregate raw scores appeared lower (better) than those previously reported for an EDOF lens and bifocal lens using the same questionnaire.23

There are limitations to the current study. It was at a single center and the number of subjects was limited. Subjects were recruited from patients in the practice who had already been binocularly implanted with the Vivity IOL, so there was a relatively wide range of follow-up. Mesopic vision illumination levels were not recorded. The range of postoperative follow-up was also relatively high (91 to 413 days), which might be a concern related to different levels of neuroadaptation. However, we found no correlation between quality of vision scores and follow-up time; recent research has suggested that neuroadaptation occurs within 3 months of implantation of either a monofocal or multifocal IOL.24

In conclusion, the Vivity IOL provided patients with good distance and intermediate vision, and functional near vision; with most subjects reporting little or no bother from glare, halos, or starbursts.

Steffen stenstad, MSc, of IFocus yeklinikk AS assisted with diagnostic testing and data collection/checking. This work was supported by as an investigator-initiated study grant funded by Alcon (IIT#61478839). Preliminary results from this study were presented at the 2021 American Society of Cataract and Refractive Surgery conference (Las Vegas, USA, July 2327, 2021) and the 2021 European Society of Cataract and Refractive Surgery (Amsterdam, NL, October 811, 2021) in conference lectures.

Drs. Gundersen and Potvin are consultants to Alcon. Dr Potvin reports personal fees from Alcon and Carl Zeiss Meditec, outside the submitted work. The authors report no other conflicts of interest in this work.

1. Rodov L, Reitblat O, Levy A, Assia EI, Kleinmann G. Visual outcomes and patient satisfaction for trifocal, extended depth of focus and monofocal intraocular lenses. J Refract Surg. 2019;35(7):434440. doi:10.3928/1081597X-20190618-01

2. Pedrotti E, Carones F, Talli P, et al. Comparative analysis of objective and subjective outcomes of two different intraocular lenses: trifocal and extended range of vision. BMJ Open Ophthalmol. 2020;5:e000497. doi:10.1136/bmjophth-2020-000497

3. Hovanesian JA, Jones M, Allen Q. The PanOptix trifocal IOL vs the ReSTOR 2.5 active focus and ReSTOR 3.0-add multifocal lenses: a study of patient satisfaction, visual disturbances, and uncorrected visual performance. Clin Ophthalmol. 2021;15:983990. doi:10.2147/OPTH.S285628

4. Monaco G, Gari M, Di Censo F, Poscia A, Ruggi G, Scialdone A. Visual performance after bilateral implantation of 2 new presbyopia-correcting intraocular lenses: trifocal versus extended range of vision. J Cataract Refract Surg. 2017;43(6):737747. doi:10.1016/j.jcrs.2017.03.037

5. Cochener B, Boutillier G, Lamard M, Auberger-Zagnoli C. A comparative evaluation of a new generation of diffractive trifocal and extended depth of focus intraocular lenses. J Refract Surg. 2018;34(8):507514. doi:10.3928/1081597X-20180530-02

6. Singh B, Sharma S, Dadia S, Bharti N, Bharti S. comparative evaluation of visual outcomes after bilateral implantation of a diffractive trifocal intraocular lens and an extended depth of focus intraocular lens, eye & contact lens. Sci Clin Pract. 2020;46(5):314318. doi:10.1097/ICL.0000000000000637

7. Kohnen T, Suryakumar R. Extended depth-of-focus technology in intraocular lenses. J Cataract Refract Surg. 2020;46(2):298304. doi:10.1097/j.jcrs.0000000000000109

8. Ruiz-Mesa R, Blanch-Ruiz J, Ruiz-Santos M, Monts-Mic R. Optical and visual quality assessment of an extended depth-of-focus intraocular lens based on spherical aberration of different sign. Int Ophthalmol. 2021;41(3):10191032. doi:10.1007/s10792-020-01659-z

9. Savini G, Balducci N, Carbonara C, et al. Functional assessment of a new extended depth-of-focus intraocular lens. Eye (Lond). 2019;33(3):404410. doi:10.1038/s41433-018-0221-1

10. Hooshmand J, Allen P, Huynh T, et al. Small aperture IC-8 intraocular lens in cataract patients: achieving extended depth of focus through small aperture optics. Eye (Lond). 2019;33(7):10961103. doi:10.1038/s41433-019-0363-9

11. Kohnen T. Nondiffractive wavefront-shaping extended range-of-vision intraocular lens. J Cataract Refract Surg. 2020;46(9):13121313. doi:10.1097/j.jcrs.0000000000000247

12. US FDA. AcrySof IQ Vivity extended vision intraocular lens (IOL): summary of safety and effectiveness data. Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf/P930014S126B.pdf. Accessed March 7, 2021.

13. Bala C, Poyales F, Guarro M, et al. Multi-country clinical outcomes of a new nondiffractive presbyopia-correcting intraocular lens. J Cataract Refract Surg. 2021;Publish Ahead of Print. doi:10.1097/j.jcrs.0000000000000712.

14. McAlinden C, Pesudovs K, Moore JE. The development of an instrument to measure quality of vision: the Quality of Vision (QoV) questionnaire. Invest Ophthalmol Vis Sci. 2010;51(11):55375545. doi:10.1167/iovs.10-5341

15. Gundersen KG, Potvin R. The effect of spectacle-induced low myopia in the non-dominant eye on the binocular defocus curve with a non-diffractive extended vision intraocular lens. Clin Ophthalmol. 2021;15:35413547. doi:10.2147/OPTH.S329922

16. Arrigo A, Gambaro G, Fasce F, Aragona E, Figini I, Bandello F. Extended depth-of-focus (EDOF) AcrySof IQ Vivity intraocular lens implant: a real-life experience. Graefes Arch Clin Exp Ophthalmol. 2021;259:27172722. doi:10.1007/s00417-021-05245-6

17. Iradier MT, Cruz V, Gentile N, Cedano P, Piero DP. Clinical outcomes with a novel extended depth of focus presbyopia-correcting intraocular lens: pilot study. Clin Ophthalmol. 2021;15:12151221. doi:10.2147/OPTH.S297985

18. Reinhard T, Maier P, Bhringer D, et al. Comparison of two extended depth of focus intraocular lenses with a monofocal lens: a multi-centre randomised trial. Graefes Arch Clin Exp Ophthalmol. 2021;259(2):431442. doi:10.1007/s00417-020-04868-5

19. Mencucci R, Cennamo M, Venturi D, Vignapiano R, Favuzza E. Visual outcome, optical quality, and patient satisfaction with a new monofocal IOL, enhanced for intermediate vision: preliminary results. J Cataract Refract Surg. 2020;46(3):378387. doi:10.1097/j.jcrs.0000000000000061

20. Schojai M, Schultz T, Jerke C, Bcker J, Dick HB. Visual performance comparison of 2 extended depth-of-focus intraocular lenses. J Cataract Refract Surg. 2020;46(3):388393. doi:10.1097/j.jcrs.0000000000000068

21. Gundersen KG, Potvin R. Comparing visual acuity, low contrast acuity and contrast sensitivity after trifocal toric and extended depth of focus toric intraocular lens implantation. Clin Ophthalmol. 2020;14:10711078. doi:10.2147/OPTH.S253250

22. Tran DB, Owyang A, Hwang J, Potvin R. Visual acuity, quality of vision, and patient-reported outcomes after bilateral implantation with a trifocal or extended depth of focus intraocular lens. Clin Ophthalmol. 2021;15:403412. doi:10.2147/OPTH.S295503

23. Liu X, Song X, Wang W, et al. Comparison of the clinical outcomes between echelette extended range of vision and diffractive bifocal intraocular lenses. J Ophthalmol. 2019;2019:5815040. doi:10.1155/2019/5815040

24. Zhang L, Lin D, Wang Y, et al. Comparison of visual neuroadaptations after multifocal and monofocal intraocular lens implantation. Front Neurosci. 2021;15:648863. doi:10.3389/fnins.2021.648863

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Clinical outcomes and quality of vision correcting IOL | OPTH - Dove Medical Press

Equillium Announces Additional Patient Data at ASH 2021 Demonstrating Continued Positive and Durable Clinical Responses in Acute Graft-Versus-Host…

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Data from EQUATE study continues to show rapid and durable complete responses, resulting in clinically meaningful reduction in corticosteroid use

79% of responders maintained or achieved a complete response at six months

Pivotal study in aGVHD to commence in early 2022

LA JOLLA, Calif.--(BUSINESS WIRE)-- Equillium, Inc.(Nasdaq: EQ), a clinical-stage biotechnology company developing itolizumab to treat severe autoimmune and inflammatory disorders with high unmet medical need, today announced two poster presentations at the 63rd Annual Meeting of the American Society of Hematology (ASH), including additional patient data from EQUATE Phase 1b study in acute graft-versus-host disease (aGVHD) demonstrating a continued positive clinical impact on patients treated with itolizumab. Data collected at six months, at least four months after each patients last dose of itolizumab, showed that 79% (11 of 14) of patients who achieved any response (CR, VGPR or PR) at Day 29 maintained that response and were evaluated as having a complete response (CR) at six months (Day 169). These patients also experienced a clinically meaningful reduction in steroid administration during the evaluation period. Data were presented by John Koreth, M.D., associate professor of medicine, Dana Farber Cancer Institute, Harvard Medical School. The ongoing EQUATE study is evaluating itolizumab as a first-line treatment in severe aGVHD patients where there are no approved treatments for this severe, life-threatening disease.

The six-month data, which includes five additional patients all dosed at 0.8 mg/kg continues to demonstrate the potential clinical value of itolizumab in this patient population who have no alternatives to steroids. I am encouraged to see that the early complete response rates seen in these extremely sick, high-risk aGVHD patients are maintained, as well as the concomitant reduction in systemic corticosteroid use, even after cessation of treatment for over four months, said Dr. Koreth.

Data from 25 patients treated with itolizumab (0.4, 0.8 or 1.6 mg/kg) were presented. In patients treated within 3 days of first steroid administration (n=18), Day 29 complete response rates were 61% (11 of 18). Among all patients that have been evaluated at Day 169, outcomes were notable for durability of responses with 50% (11 of 22) of patients achieving a CR and overall survival rate of 64% (14 of 22), with a total of 12 of 14 (86%) responders alive at Day 169 compared to 2 of 8 (25%) non-responders. Responders also experienced a clinically meaningful mean reduction in steroid administration during the evaluation period. Itolizumab treatment was well tolerated across all doses, with reported adverse events consistent with a hospitalized severe aGVHD population, with 2 of 25 subjects (8%) reporting treatment-related serious adverse events (SAEs). Itolizumab treatment resulted in a dose-dependent reduction of CD6 expression on CD4+ T cells and an increase in the regulatory to effector T cell ratio in patients, consistent with the drugs mechanism of action.

As we collect additional data from the EQUATE study, we are encouraged by the continued promising impact that itolizumab has on the lives of patients with high-risk aGVHD, said Dolca Thomas, executive vice president of research and development and chief medical officer of Equillium. There is significant unmet need in this patient population for an effective treatment that resolves severe disease while reducing corticosteroid use. The data presented at ASH provides further validation for targeting CD6 to treat aGVHD. Feedback from hematologists and transplantation specialists is that the EQUATE study results are encouraging as a new potential therapeutic and we are optimistic as we advance itolizumab into a pivotal study in first-line treatment of aGVHD patients.

Details of Itolizumab Data Presented at ASH 2021

Title: Itolizumab, a Novel Targeted Anti-CD6 Therapy, in Combination with Corticosteroids, Is Well-Tolerated, with Rapid Pharmacodynamic and Clinical Response in Newly Diagnosed Acute Graft-Versus-Host DiseaseFirst Author: Dr. John Koreth, associate professor of medicine, Dana Farber Cancer Institute, Harvard Medical SchoolSession Name: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster IIPublication Number: 2891

Title: Antigenic Modulation of CD6 By Itolizumab Is a New Mechanism for Effector T Cell InhibitionFirst Author: Dalena Chu, Senior Research Associate, Equillium, Inc.,Session Name: 203. Lymphocytes and Acquired or Congenital Immunodeficiency Disorders: Poster IPublication Number: 995

In addition to these presentations, abstracts were published online in the November supplemental issue of Blood. To view the poster presentations, visit the Publications & Presentations page of Equilliums website: https://www.equilliumbio.com/technology/publications-presentations/default.aspx.

About Graft-Versus-Host Disease (GVHD)

GVHD is a multisystem disorder that is a common complication of allogeneic hematopoietic stem cell transplants (allo-HSCT) caused by the transplanted immune system recognizing and attacking the recipients body. Symptoms of GVHD include rash, itching, skin discoloration, nausea, vomiting, diarrhea, and jaundice, as well as eye dryness and irritation.

GVHD is the leading cause of non-relapse mortality in cancer patients receiving allo-HSCT, and its risk limits the number and type of patients receiving HSCT. GVHD results in high morbidity and mortality, with five-year survival of approximately 53% in patients who respond to steroid treatment and mortality as high as 95% in patients who do not respond to steroids. There are no approved treatments for first-line aGVHD. Published literature (MacMillan et al., 2015) describes background response rates to high-dose steroid administration in severe high-risk patients as 43% overall response and 27% complete response.

About the EQUATE Study

The EQUATE study is a Phase 1b/2 trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity of itolizumab for first-line treatment in patients who present with aGVHD (NCT 03763318). The Phase 1b part of the trial is an open-label dose escalation study in adult patients who present with high-risk aGVHD and typically respond poorly to steroids. The Phase 1b data will inform selection of the dose to be used in the next phase of development for the program.

About Itolizumab

Itolizumab is a clinical-stage, first-in-class anti-CD6 monoclonal antibody that selectively targets the CD6-ALCAM signaling pathway to selectively downregulate pathogenic T effector cells while preserving T regulatory cells critical for maintaining a balanced immune response. This pathway plays a central role in modulating the activity and trafficking of T cells that drive a number of immuno-inflammatory diseases. Equillium acquired rights to itolizumab through an exclusive partnership with Biocon Limited.

About Equillium

Equillium is a clinical-stage biotechnology company leveraging deep understanding of immunobiology to develop novel products to treat severe autoimmune and inflammatory disorders with high unmet medical need. Equillium is developing itolizumab for multiple severe immuno-inflammatory diseases, including acute graft-versus-host-disease (aGVHD), lupus/lupus nephritis and uncontrolled asthma.

For more information, visit http://www.equilliumbio.com.

Forward Looking Statements

Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, many of which are outside of the Companys control, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to statements regarding the potential benefit of treating patients with aGVHD, uncontrolled asthma, or lupus/lupus nephritis with itolizumab, Equilliums plans and expected timing for developing itolizumab including the expected timing of initiating, completing and announcing further results from the EQUATE, EQUIP, and EQUALISE studies, the potential for any of Equilliums ongoing or planned clinical studies to show safety or efficacy, statements regarding the impact of new leadership team members, Equilliums anticipated timing of regulatory review and feedback, Equilliums cash runway, and Equilliums plans and expected timing for developing itolizumab and potential benefits of itolizumab. Risks that contribute to the uncertain nature of the forward-looking statements include: uncertainties related to the abilities of the leadership team to perform as expected; Equilliums ability to execute its plans and strategies; risks related to performing clinical studies; the risk that interim results of a clinical study do not necessarily predict final results and that one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data, and as more patient data become available; potential delays in the commencement, enrollment and completion of clinical studies and the reporting of data therefrom; the risk that studies will not be completed as planned; Equilliums plans and product development, including the initiation and completion of clinical studies and the reporting of data therefrom; whether the results from clinical studies will validate and support the safety and efficacy of itolizumab; changes in the competitive landscape; uncertainties related to Equilliums capital requirements; and having to use cash in ways or on timing other than expected and the impact of market volatility on cash reserves. These and other risks and uncertainties are described more fully under the caption "Risk Factors" and elsewhere in Equillium's filings and reports with the SEC. Investors should take such risks into account and should not rely on forward-looking statements when making investment decisions. All forward-looking statements contained in this press release speak only as of the date on which they were made. Equillium undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

View source version on businesswire.com: https://www.businesswire.com/news/home/20211213005294/en/

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Equillium Announces Additional Patient Data at ASH 2021 Demonstrating Continued Positive and Durable Clinical Responses in Acute Graft-Versus-Host...

Diabetic Foot Ulcers Clinical and Non-Clinical Studies, Therapeutic Assessment, Emerging Therapies, and Treatment Algorithm | Key Companies Origin,…

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Diabetic Foot Ulcers Pipeline Insight, 2021 report by DelveInsight outlines comprehensive insights of present clinical development scenario and growth prospects across the Diabetic Foot Ulcers Market.

The Diabetic Foot Ulcers Pipeline report embraces in-depth commercial and clinical assessment of the Diabetic Foot Ulcers pipeline products from the pre-clinical developmental phase to the marketed phase.

The report covers a detailed description of the drug including mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, Diabetic Foot Ulcers collaborations, mergers, acquisition, funding, designations, and other product-related details.

Diabetic Foot Ulcers Pipeline Analysis

The report provides insights into:

The report provides detailed insights about companies that are developing therapies for the treatment of Diabetic Foot Ulcers with aggregate therapies developed by each company for the same.

It accesses the Different therapeutic candidates segmented into early-stage, mid-stage, and late-stage of development for the Diabetic Foot Ulcers Treatment.

Diabetic Foot Ulcers key companies involved in targeted therapeutics development with respective active and inactive (dormant or discontinued) projects.

Diabetic Foot Ulcers Drugs under development based on the stage of development, route of administration, target receptor, monotherapy or combination therapy, a different mechanism of action, and molecular type.

Detailed analysis of collaborations (company-company collaborations and company-academia collaborations), licensing agreement, and financing details for future advancement of the Diabetic Foot Ulcers market.

The report is built using data and information traced from the researchers proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations, and featured press releases from company/university websites and industry-specific third-party sources, etc.

Diabetic Foot Ulcers Therapeutics Landscape

Key Companies in the Diabetic Foot Ulcers Market includes:

Origin, Inc.

Microbion Corporation

CytoTools AG

Venturis Therapeutics

Smith & Nephew

And many others.

Diabetic Foot Ulcers Therapies covered in the report include:

And many more.

Request for Sample Pages @ Diabetic Foot Ulcers Emerging Therapies and Key Companies

Table of Content

1. Report Introduction

2. Diabetic Foot Ulcers

3. Diabetic Foot Ulcers Current Treatment Patterns

4. Diabetic Foot Ulcers DelveInsights Analytical Perspective

5. Therapeutic Assessment

6. Diabetic Foot Ulcers Late Stage Products (Phase-III)

7. Diabetic Foot Ulcers Mid Stage Products (Phase-II)

8. Early Stage Products (Phase-I)

9. Pre-clinical Products and Discovery Stage Products

10. Inactive Products

11. Dormant Products

12. Diabetic Foot Ulcers Discontinued Products

13. Diabetic Foot Ulcers Product Profiles

14. Diabetic Foot Ulcers Key Companies

15. Diabetic Foot Ulcers Key Products

16. Dormant and Discontinued Products

17. Diabetic Foot Ulcers Unmet Needs

18. Diabetic Foot Ulcers Future Perspectives

19. Diabetic Foot Ulcers Analyst Review

20. Appendix

21. Report Methodology

*The table of contents is not exhaustive; the final content may vary.

Visit to get the sample report:https://www.delveinsight.com/sample-request/diabetic-foot-ulcers-pipeline-insight

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Diabetic Foot Ulcers Clinical and Non-Clinical Studies, Therapeutic Assessment, Emerging Therapies, and Treatment Algorithm | Key Companies Origin,...

Fred Hutchinson Cancer Research Center, in Partnership with Sutro Biopharma, to Present at ASH 2021 – Yahoo Finance

Posted: at 1:56 am


Nonclinical data for STRO-002 and STRO-001 are shared in two oral presentations at the 63rd American Society of Hematology Annual Meeting

SOUTH SAN FRANCISCO, Calif, Dec. 13, 2021 /PRNewswire/ -- Sutro Biopharma, Inc. (NASDAQ: STRO), a clinical-stage drug discovery, development and manufacturing company focused on the application of precise protein engineering and rational design to create next-generation cancer and autoimmune therapeutics, today announced that its research collaborators at the Fred Hutchinson Cancer Research Center presented nonclinical data of STRO-002 and STRO-001 in two oral presentations at the 63rd American Society of Hematology Annual Meeting (ASH 2021) in Atlanta, Georgia. The research was conducted by investigators from the laboratory of Soheil Meshinchi, M.D., Ph.D., Professor, Clinical Research Division at Fred Hutchinson Cancer Research Center and Professor, Division of Pediatric Hematology-Oncology at the University of Washington School of Medicine.

Dr. Meshinchi commented, "Using a computational approach, we have identified FOLR1, or FolR, as an actionable target for high-risk pediatric AML; and CD74 as an actionable target in adult and pediatric AML and ALL. We further demonstrated that STR0-002 effectively targets a high-risk AML subtype and STRO-001 effectively targets AML and ALL cells that express CD74, providing promising nonclinical data for possible treatment options."

Nonclinical data was presented by Quy Le, Ph.D., Staff Scientist, Meshinchi Lab, Fred Hutchinson Cancer Research Center on Sutro's folate receptor alpha (FOLR1 or FolR) -targeting antibody-drug conjugate (ADC), STRO-002, as a potential therapeutic in a rare pediatric acute myeloid leukemia (AML) subtype expressing FolR. RNA-sequencing data demonstrated that FOLR1 is uniquely expressed in CBFA2T3-GLIS2 fusion (CBF/GLIS) AML and absent in other AML subtypes and normal hematopoietic cell populations. Data from an AML cell line engineered to express FOLR1 and CBF/GLIS-transduced cord blood hematopoietic stem/progenitor cells (CB HSPCs) demonstrated high cytotoxicity of STRO-002. In FOLR1 positive and CBF/GLIS-transduced CB HSPCs xenograft models, STRO-002 demonstrated potent activity that led to complete leukemia clearance.

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Nonclinical data was also presented by Quy Le, Ph.D., Staff Scientist, Meshinchi Lab, Fred Hutchinson Cancer Research Center on Sutro's CD74-targeting ADC, STRO-001, as a potential therapeutic in AML and acute lymphoblastic leukemia (ALL). Data from AML and ALL cell lines, as well as from nonclinical xenograft models, demonstrated robust in vitro and in vivo cytotoxicity of STRO-001 on cells expressing high- to -moderate levels of CD74, with no cytotoxicity observed in cells without CD74 expression. Potent anti-leukemia activity was also demonstrated in three primary AML patient samples with varied CD74 expression levels.

Dr. Arturo Molina, Sutro's Chief Medical Officer added, "These nonclinical data presented by collaborators at Fred Hutchinson Cancer Research Center demonstrates the potential of targeted ADCs as therapeutics for AML and ALL. These data provide additional validation for an FolR- and CD74-antigen directed approach, as our clinical studies for STRO-002 in ovarian and endometrial cancers and STRO-001 in B cell malignancies, respectively, continue to enroll patients."

About Sutro BiopharmaSutro Biopharma, Inc., located in South San Francisco, is a clinical-stage drug discovery, development and manufacturing company. Using precise protein engineering and rational design, Sutro is advancing next-generation oncology therapeutics.

Sutro's proprietary and integrated cell-free protein synthesis platform XpressCF and site-specific conjugation platform XpressCF+ led to the discovery of STRO-001 and STRO-002, Sutro's first two internally-developed ADCs. STRO-001 is a CD74-targeting ADC currently under investigation in a Phase 1 clinical trial for patients with advanced B-cell malignancies and was granted Orphan Drug Designation by the FDA for multiple myeloma. STRO-002, a folate receptor alpha (FolR)-targeting ADC, is currently being investigated in a Phase 1 clinical trial for patients with ovarian and endometrial cancers and was granted Fast Track designation by the FDA for ovarian cancer. A third product candidate, CC-99712, a BCMA-targeting ADC, which is part of Sutro's collaboration with Bristol Myers Squibb, formerly Celgene Corporation, is enrolling patients for its Phase 1 clinical trial of patients with multiple myeloma and has received Orphan Drug Designation from the FDA. A fourth product candidate, M1231, a MUC1-EGFR, first-in-class bispecific ADC, which is part of Sutro's collaboration with Merck KGaA, Darmstadt, Germany, known as EMD Serono in the U.S. and Canada (EMD Serono), is enrolling patients for its Phase 1 clinical trial of patients with metastatic solid tumors, non-small cell lung cancer (NSCLC) and esophageal squamous cell carcinoma. These four product candidates resulted from Sutro's XpressCF and XpressCF+ technology platforms. Bristol Myers Squibb and EMD Serono have worldwide development and commercialization rights for CC-99712 and M1231, respectively, for which Sutro is entitled to milestone or contingent payments and tiered royalties.

Sutro is dedicated to transforming the lives of cancer patients by creating medicines with improved therapeutic profiles for areas of unmet need. To date, Sutro's platform has led to ADCs, bispecific antibodies, cytokine-based immuno-oncology therapies, and vaccines directed at precedented targets in clinical indications where the current standard of care is suboptimal.

The platform allows it to accelerate discovery and development of potential first-in-class and best-in-class molecules through rapid and systematic evaluation of protein structure-activity relationships to create optimized homogeneous product candidates. In addition to developing its own oncology pipeline, Sutro is collaborating with select pharmaceutical and biotechnology companies to discover and develop novel, next-generation therapeutics.

Follow Sutro on Twitter, @Sutrobio, and at http://www.sutrobio.com to learn more about our passion for changing the future of oncology.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated preclinical and clinical development activities, timing of announcements of clinical results, potential benefits of the Company's product candidates and platform, potential future milestone and royalty payments, and potential market opportunities for the Company's product candidates. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Although the Company believes that the expectations reflected in such forward-looking statements are reasonable, the Company cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval is inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause the Company's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to the Company's ability to advance its product candidates, the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates, the impact of the COVID-19 pandemic on the Company's business, clinical trial sites, supply chain and manufacturing facilities, the Company's ability to maintain and recognize the benefits of certain designations received by product candidates, the timing and results of preclinical and clinical trials, the Company's ability to fund development activities and achieve development goals, the Company's ability to protect intellectual property, the value of the Company's holdings of Vaxcyte common stock, and the Company's commercial collaborations with third parties and other risks and uncertainties described under the heading "Risk Factors" in documents the Company files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and the Company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof.

Investor Contact

Annie J. ChangSutro Biopharma(650) 801-5728ajchang@sutrobio.com

Media ContactMaggie Beller

Russo Partners(646) 942-5631Maggie.beller@russopartnersllc.com

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Fred Hutchinson Cancer Research Center, in Partnership with Sutro Biopharma, to Present at ASH 2021 - Yahoo Finance

Nasal Polyposis Pipeline Insight, 2021 Clinical and Non-Clinical Studies, Emerging Therapies, and Treatment Algorithm | Key Companies Novartis, GSK,…

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Nasal Polyposis Pipeline Insight, 2021 report by DelveInsight outlines comprehensive insights of present clinical development activities and growth prospects across the Nasal Polyposis Market.

The Nasal Polyposis Pipeline report embraces in-depth commercial and clinical assessment of the Nasal Polyposis pipeline products from the pre-clinical developmental phase to the marketed phase.

The report covers a detailed description of the drug including mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, Nasal Polyposis collaborations, mergers, acquisition, funding, designations, and other product-related details.

Nasal Polyposis Pipeline Analysis

The report provides insights into:

The report provides detailed insights about companies that are developing therapies for the treatment of Nasal Polyposis with aggregate therapies developed by each company for the same.

It accesses the Different therapeutic candidates segmented into early-stage, mid-stage, and late-stage of development for the Nasal Polyposis Treatment.

Nasal Polyposis key companies involved in targeted therapeutics development with respective active and inactive (dormant or discontinued) projects.

Nasal Polyposis Drugs under development based on the stage of development, route of administration, target receptor, monotherapy or combination therapy, a different mechanism of action, and molecular type.

Detailed analysis of collaborations (company-company collaborations and company-academia collaborations), licensing agreement, and financing details for future advancement of the Nasal Polyposis market.

The report is built using data and information traced from the researchers proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations, and featured press releases from company/university websites and industry-specific third-party sources, etc.

Nasal Polyposis Therapeutics Landscape

The dynamics of the Nasal Polyposis Market is anticipated to change in the coming years owing to the improvement in the diagnosis methodologies, raising awareness of the diseases, incremental healthcare spending across the world, and also expects the launch of emerging therapies. Companies across the globe are thoroughly working toward the development of new treatment therapies for nasal polyps. The launch of the emerging therapies is expected to transform the treatment dynamics.

Some of the key companies in the therapeutic market of Nasal Polyposis at a global level include:

Novartis

GlaxoSmithKline

AstraZeneca

Idorsia Pharmaceuticals

AnapstysBio

And many others

Nasal Polyposis Therapies covered in the report include:

Xolair

Mepolizumab

Fasenra OSTRO

ACT-774312

Etokimab

And many more.

Request for Sample Pages @ Nasal Polyposis Emerging Therapies and Key Companies

Table of Content

1. Report Introduction

2. Nasal Polyposis

3. Nasal Polyposis Current Treatment Patterns

4. Nasal Polyposis DelveInsights Analytical Perspective

5. Therapeutic Assessment

6. Nasal Polyposis Late Stage Products (Phase-III)

7. Nasal Polyposis Mid Stage Products (Phase-II)

8. Early Stage Products (Phase-I)

9. Pre-clinical Products and Discovery Stage Products

10. Inactive Products

11. Dormant Products

12. Nasal Polyposis Discontinued Products

13. Nasal Polyposis Product Profiles

14. Nasal Polyposis Key Companies

15. Nasal Polyposis Key Products

16. Dormant and Discontinued Products

17. Nasal Polyposis Unmet Needs

18. Nasal Polyposis Future Perspectives

19. Nasal Polyposis Analyst Review

20. Appendix

21. Report Methodology

*The table of contents is not exhaustive; the final content may vary.

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Clinical and Therapeutic Factors Vary by Prognosis in Patients with Pa | CMAR – Dove Medical Press

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Introduction

Neoadjuvant chemotherapy has gradually become popular in breast cancer, and achieving pathological complete response (pCR) (ypT0/is, ypN0) in high-risk breast cancer has been associated with a relatively good prognosis.13 The effects of neoadjuvant chemotherapy may be used as an external proxy of in vivo drug sensitivity. Prognostic information can be more accurately provided to patients via the objective evaluation of postoperative pathological findings, which constitutes an important advancement towards individualised medicine.4,5 Meta-analyses have indicated that pCR has a better prognostic value than that of other pathological findings.3,6 Therefore, achieving pCR via treatment has become a surrogate endpoint for a large proportion of neoadjuvant chemotherapy clinical study designs and serves as a neoadjuvant treatment goal for high-risk types of breast cancer, such as human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast cancer. Nevertheless, evidence suggests that achievement of pCR after treatment does not preclude the risk of recurrence or metastasis.7 Therefore, clarifying the clinicopathological factors associated with these risks in patients with pCR is crucial for the postoperative treatment of neoadjuvant patients and screening of populations enrolled in neoadjuvant clinical studies.8

Currently, various criteria for pCR evaluation after neoadjuvant chemotherapy exist, including the American Joint Committee on Cancers post-neoadjuvant staging system, the net reclassification improvement, Miller and Payne system, Residual Cancer Burden, and Neo-Bioscore. These methods provide an approximate indication of differential patient prognoses based on residual pathology after neoadjuvant chemotherapy, thereby facilitating the provision of distinct treatment methods for patients during adjuvant therapy.911 However, the majority of these methods have not elucidated the key factors influencing the prognosis of patients with pCR.7,12,13 Although relevant factors that affect prognosis, such as hormone receptor (HR) expression, HER2 status, and clinical stage (cStage), are listed in the Neo-Bioscore, this evaluation system is too generalized. Notably, based on current treatment approaches, distinct treatment modalities are required for different subtypes of breast cancer, and prognoses are inconsistent. Therefore, the stratification of prognoses for all breast cancer types according to uniform standards is a major issue that contributes to inaccuracy.6,14,15 In addition, several studies have explored prognostic factors that affect patients with pCR. However, data have been unreliable owing to outdated, retrospective nature of the studies, inconsistent definitions or treatments for pCR, and lack of classification and refinement.1618

To address these gaps in the literature, we performed a retrospective analysis of patients with different types of breast cancer in the context of corresponding standard neoadjuvant chemotherapy. We aimed to determine the prognosis of patients with different subtypes of breast cancer who achieved pCR and elucidate the relevant clinicopathological factors influencing their prognosis.

This study retrospectively analysed patients who received neoadjuvant chemotherapy and achieved pCR at Harbin Medical University Cancer Hospital between June 2012 and May 2019. Patients who were initially diagnosed with metastatic breast cancer, underwent neoadjuvant chemotherapy without surgery, presented with inflammatory breast cancer, had incomplete follow-up data, and/or underwent surgery or chemotherapy at other institutions were excluded. The initial cStage of all patients was reviewed based on the American Joint Committee on Cancer staging system (seventh edition). Patients were classified into three groups according to cStage: group I (IIaIIb), group II (IIIa), and group III (IIIbIIIc). Electronic medical records were reviewed to obtain information on age, tumour characteristics, initial cStage, type of neoadjuvant chemotherapy received, recurrence, and survival. All procedures performed in this study complied with the ethical standards of the institution and/or the National Research Council, as well as the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. The retrospective study design was approved by the Ethics Committee of Harbin Medical University Cancer Hospital. Written informed consent was obtained from each patient.

Professional pathologists reviewed pathological specimens from diagnostic core biopsies from each patient to determine the HR and HER2 status, which was recorded by specialised breast doctors. HR status was assessed by immunohistochemistry. Specimens were classified as HR+ when more than 1% of cancer cells stained positive. HER2 positivity was defined according to the American Society of Clinical Oncology/American Society of Pathologists guidelines.19 If the immunohistochemical score of the tumour was 3+, or the immunohistochemical score was 2+ and the fluorescence in situ hybridisation test was positive, the specimen was classified as HER2+. Based on HR and HER2 status, intrinsic subtypes were classified as HER2+, HR+ (HR+/HER2), or triple-negative breast cancer. pCR was defined as the absence of any invasive disease in the breast and no micro-/macro-metastases in the ipsilateral axillary lymph nodes. All patients received at least four cycles of anthracycline- or taxane-based neoadjuvant chemotherapy. Trastuzumab was recommended for patients who were HER2+. After completing neoadjuvant chemotherapy, patients underwent radical breast surgery, axillary lymph node dissection, or sentinel lymph node dissection. The decision to undergo breast-conserving surgery was made via consensus between the patient and surgeon. For all patients with metastatic cancer in the axillary region at the diagnostic core biopsy, axillary lymph node dissection was used after the completion of neoadjuvant chemotherapy. If there was no lymph node involvement, lymph node dissection or sentinel lymph node biopsy was performed according to the patients wishes. If the patient had undergone breast-conserving surgery or had locally advanced disease at the time of consultation, postoperative radiotherapy was performed. Fifty Gy in 25 fractions was prescribed for these patients; radiotherapy regimens included whole breast, chest wall, and regional nodal radiation. Patients with HR+ breast cancer were offered adjuvant endocrine therapy for 5 years.

The primary endpoint was disease-free survival (DFS), defined as the time from disease diagnosis to the first documentation of cancer recurrence or last follow-up. The secondary endpoint was overall survival (OS), defined as the time from disease diagnosis to death from any cause or last follow-up. Survival curves were plotted using the KaplanMeier method and compared using the Log rank test. The 2 test or Fishers exact test was used to determine the factors that could predict recurrence and evaluate the impact of cStage on recurrence in each subgroup.

Univariate and multivariate analyses combined with Cox proportional hazards regression models were used to identify high-risk factors associated with survival. Known determinants in the logistic regression model were adjusted, including age, cStage, primary tumour size, lymph node status, HER2 status, HR status, administration of chemotherapy regimens, and Ki-67 labelling index. All tests were two-tailed. P < 0.05 was considered statistically significant. All statistical analyses were conducted using SPSS software version 22 (IBM Corp., Armonk, NY, USA).

From 2012 to 2019, a total of 2359 patients received neoadjuvant therapy. 285 patients achieved pCR and were included in the survival analysis. In total, 147 (51.6%), 77 (27.0%), and 61 (21.4%) patients were classified into cStage groups I, II, and III, respectively. All 285 patients underwent surgery. Detailed patient characteristics are summarised in Table 1. Among cStages based on clinical tumour (cT) size, cT2 accounted for the largest proportion (68.4%), while clinical lymph node metastasis constituted the highest proportion (71.6%) of the overall population. Among tumour subtypes, HER2+, triple-negative, and HR+ breast cancer accounted for 58.9%, 26.3%, and 15.8% of the population, respectively. The immunohistochemical results of one patient were unidentifiable.

Table 1 Patient Characteristics of the Final Cohort

Regimens for the majority of patients treated with neoadjuvant chemotherapy included anthracyclines and taxane (85.9%). In addition, 168 (58.9%) patients completed the standard treatment cycle preoperatively, while the remaining patients did not complete the standard treatment cycle before surgery and did not undergo postoperative adjuvant chemotherapy. The majority of patients in the HER2+ subgroup (80.9%) received preoperative chemotherapy with anthracyclines and taxane (Supplementary Table S1), and the recurrence rate was 16.9%, which was numerically higher than that in patients who received taxane or anthracyclines alone, although the difference was not statistically significant (P = 0.584). A numerical difference in the recurrence rate was also observed between patients treated with platinum and not statistically significant (4.2% vs 17.4%, respectively; P = 0.132). Fifty-eight patients (34.5%) were treated with combined targeted therapy during neoadjuvant chemotherapy, whereas the majority of patients (n=110, 65.5%) did not receive targeted therapy. The risk of recurrence was significantly higher in patients without targeted therapy compared to those who received targeted therapy (20.0% vs 6.9%, respectively; P = 0.026). We further classified the HER2+ group into HER2+/HR+ and HER2+/HR subgroups and evaluated the correlation between clinical factors of targeted therapy and recurrence. In the HER2+/HR+ subgroup, the risk of recurrence was significantly higher in patients who did not receive targeted therapy than in those who received targeted therapy (21.4% vs 0.0%, respectively; P = 0.048) (Supplementary Table S3). This difference was not observed in the HER2+/HR subgroup. One hundred and four patients (61.9%) completed standard treatment cycles before surgery. The risk of recurrence was higher in patients who did not complete the standard treatment cycle than in those who completed the standard treatment cycle, although it was not statistically significant (17.2% vs 14.4%, respectively; P = 0.458). In the triple-negative subgroup, the majority of patients (91.4%) received a combination of anthracyclines and taxane before surgery (Supplementary Table S2). More than half of the patients (51.7%) completed the standard treatment cycle of neoadjuvant therapy; the remaining patients did not complete the standard treatment cycle owing to pCR. The risk of recurrence between the group that did not complete the standard treatment cycle and the group that completed the standard treatment cycle was 13.2% vs 18.9%, respectively (P = 0.544). Three patients (4%) received platinum in addition to the neoadjuvant treatment regimen. The characteristics of the HR+ group are summarised in Supplementary Table S4.

The median time to recurrence was 31 (range, 299) months. The mean follow-up time was 39.7 months. In total, 42 end-point events related to recurrence or death occurred in patients with recurrence, of whom 12 (28.6%) presented with local recurrence and 30 (71.4%) developed distant metastases. Of these, 10 (23.8%) presented with liver metastases, 7 (16.7%) with brain metastases, and 4 (9.5%) with lung metastases (Table 2).

Table 2 Details of the First Site of Cancer Recurrence for the Final Cohort and Three Cancer Subtypes

Among patients with different tumour subtypes, 26 recurrence-related events were observed in the HER2+ subgroup. Eight (30.1%) patients presented with local recurrence and 18 (69.9%) with distant metastases. Most patients presented with brain (n=5, 19.2%) and liver metastases (n=5, 19.2%). Lung and bone metastases were identified in three patients (11.5%). In the triple-negative subgroup, 12 recurrence-related events were observed. Three patients presented with local recurrence and nine with distant metastases, while most patients presented with liver metastases (n=4, 30.0%). In the HR+ subgroup, four recurrence-related events were observed. One patient (25.0%) presented with local recurrence, and three (75.0%) with distant metastases.

Local recurrence and distant metastasis events were distinguished based on primary tumour size and lymph node status (Figure 1). T2 and N3 accounted for the largest proportion of local recurrence events. For distant metastatic events, T2 and N12 accounted for the largest proportion. T4 recurrence events were local recurrence events without distant metastasis.

Figure 1 Cancer recurrence stratified by (A) clinical tumour size and (B) lymph node status.

The 3-year DFS rates were 92.7%, 87.8%, and 66.7% in groups I, II, and III, respectively, with significant differences observed among groups (Log rank test, P < 0.01) (Figure 2A). The 3-year OS rates were 98.6%, 98.3%, and 90.6% in groups I, II, and III, respectively, with no significant differences observed among groups (Log rank test, P = 0.370) (Figure 2B). Clinical tumour size was not significantly correlated with DFS (Log rank test, P = 0.096) or OS (Log rank test, P = 0.087) (Figure 2C and D). Lymph node status was significantly correlated with DFS (Log rank test, P < 0.01) (Figure 2E), but not OS (Log rank test, P = 0.319) (Figure 2F).

Figure 2 (A) DFS and (B) OS among the three clinical stages in the final cohort. (C) DFS and (D) OS among patients stratified by clinical tumour size in the final cohort. (E) DFS and (F) OS among patients stratified by lymph node status in the final cohort.

Abbreviations: DFS, disease-free survival; OS, overall survival.

Cox regression analysis of factors predicting recurrence revealed that cStage III (hazard ratio: 3.2, 95% confidence interval [CI]: 1.66.3; P < 0.01) was associated with a higher risk of recurrence than cStage III (Table 3). The analysis of primary clinical tumour size- and lymph node involvement-related factors revealed that the risk of recurrence was significantly higher in patients with cT4 than in those with cT13 (hazard ratio: 4.4, 95% CI: 1.115.6; P = 0.03). The risk of recurrence was significantly higher in cN3 patients than in cN02 patients (hazard ratio: 13.3, 95% CI: 2.616.6; P < 0.01).

Table 3 Cox Proportional Hazard Model of Predictors of Cancer Recurrence in Patients Who Achieved pCR

In the correlation analysis, age at diagnosis (<50 vs 50 years), HER2 status (HER2 vs HER+), HR status (HR vs HR+), chemotherapy regimen (1 vs 3 weeks), Ki-67 level (<20% vs 20%), axillary surgical approach (sentinel lymph node biopsy versus axillary lymph node dissection), and treatment cycle (completion vs non-completion) were not significantly associated with recurrence. In the multivariate analyses, lymph node status was the only independent factor predicting recurrence in patients with pCR (hazard ratio: 2.2, 95% CI: 1.14.4; P = 0.03).

Based on the correlation analysis results for recurrence factors, we analysed different tumour types. In the HER2+ subgroup, significant differences were observed in DFS rates (Log rank test, P < 0.01) (Figure 3A) and lymph node status (Log rank test, P < 0.01) (Figure 3B), but not tumour size (Log rank test, P = 0.191) (Supplementary Figure S1A), among the three cStage groups. Separate analyses revealed that DFS was significantly different between patients with cT4 and those with cT13 (Log rank test, P = 0.037) (Figure 3C). In the HR+ subgroups, cStage, lymph node status, and tumour size were not significantly correlated with DFS (Supplementary Figure S1BD). However, the Log rank test P-values in the KaplanMeier analyses were significant for DFS for cStage III vs cStage III (Log rank test, P = 0.049) (Figure 4A) and cN02 vs cN3 (Log rank test, P = 0.037) (Figure 4B). No significant correlations with DFS were observed in the triple-negative subgroup, irrespective of cStage, clinical tumour size, or lymph node status (Supplementary Figure S1EG).

Figure 3 DFS in the HER2+ subgroup among (A) the three cStages and (B) patients stratified by lymph node status. (C) DFS in the HER2+ subgroup according to clinical tumour size (cT13 vs cT4).

Abbreviations: DFS, disease-free survival; HER2, human epidermal growth factor receptor 2.

Figure 4 DFS in the HR+ subgroup for (A) cStage III vs cStage III and (B) cN02 vs cN3.

Abbreviations: cStage, clinical stage; DFS, disease-free survival; HR, hormone receptor.

Increased research on the efficacy of neoadjuvant chemotherapy has contributed to an increase in its clinical implementation. Meta-analyses have indicated that the efficacy of neoadjuvant chemotherapy is comparable to that of adjuvant therapy for the same treatment regimen; however, the prognosis of patients with pCR is superior to that of patients without pCR.3,20 Moreover, studies of high-risk populations have revealed that the prognosis of pCR patients may be suboptimal, and the implications of pCR have been questioned.17,21 In this study, we examined the prognosis of patients with different breast cancer subtypes who achieved pCR and identified the clinicopathological factors relevant to their prognosis. We identified lymph node status as an independent risk factor for recurrence in patients with breast cancer who received neoadjuvant chemotherapy and achieved pCR. There was a trend in T4, although it was not statistically significant. We analysed the correlation of recurrence and metastasis in patients with pCR but did not identify any clear patterns. Recurrence events in the T4 population were all in situ; DFS exhibited the poorest performance while OS exhibited the best performance in this population. Based on these findings, caution should be exercised when formulating clinical decisions after neoadjuvant chemotherapy for patients with locally advanced or inoperable breast cancer. Clinical decisions should not be made solely based on references to previous criteria for neoadjuvant chemotherapy for operable breast cancer. Treatment options should instead be tailored according to advances in genetic mapping, as well as tumour and patient characteristics, following the achievement of pCR after neoadjuvant chemotherapy.

Our findings may differ from the results of previous retrospective studies because we included patients receiving neoadjuvant chemotherapy with cStage IIIII. As cStage I patients have a better prognosis, the patients in this study presented with a higher risk of recurrence and metastasis. In addition, our patient groups differed from those in previous studies. The use of tumour size and lymph node status to determine the included population may lead to considerable differences in the residual risk of recurrence. Based on the findings of Wei et al,21 we balanced the risk of recurrence in each group and classified patients as cStage IIaIIb, IIIa, or IIIbIIIc according to disease stage. Therefore, our results may more closely reflect the conditions observed in clinical practice. Notably, this is the first study to identify and analyse different immunohistochemical types based on cStage-, tumour size-, and lymph node-related prognoses to enable identification of prognostic risk and formulation of optimal clinical decisions.

We observed that a higher cStage, extensive lymph node involvement, and T4 were significantly associated with poor prognosis in the HER2+ population. For this group of patients, multimodal therapy (eg intensive drugs, including trastuzumab emtansine and tyrosine kinase inhibitors) is recommended, even if pCR is achieved. In the HR+ population, cStage III and N3 were key factors associated with poor prognosis. Compared to HER2+, which is a more aggressive tumour type, HR+ tumours grow more slowly. No HR+ patients with T4 primary tumours were identified in our study. HR+ patients have a lower probability of four or more lymph node metastases compared to HER2+ patients.22 Therefore, for HR+ patients, tumour size may not reflect disease duration, and a more accurate evaluation of axillary lymph nodes is required for disease diagnosis. In patients with severe lymph node involvement, early intensive treatment is required for cases with a high risk of recurrence, and, if necessary, continuous intensive endocrine therapy (eg cyclin-dependent kinase 4/6 inhibitors) should be considered. We were unable to differentiate the prognosis of patients with triple-negative breast cancer using the appropriate stratification owing to the small number of patients and single-treatment regimen used. Thus, the combination of traditional anthracyclines and taxane was commonly used, with the addition of platinum or taxane to neoadjuvant chemotherapy regimens accounting for only a small proportion.

A large proportion of HER2+ patients achieved pCR, despite not receiving targeted therapy during neoadjuvant chemotherapy. At follow-up, we observed that the risk of recurrence was higher in patients without targeted therapy than in those who received targeted therapy. Even though these patients achieved pCR without the support of targeted therapy, their prognosis was still affected by the absence of targeted therapy. However, for this population, the duration of targeted therapy is open to discussion since the application of short courses of targeted adjuvant therapy is a contradictory topic.2325 Although this study was a single-centre, retrospective analysis with a small sample, from the results, other studies had corroborated these findings, including a retrospective analysis by von Minckwitz et al,6 which demonstrated that patients with pCR after anti-HER2 treatment had better clinical outcomes compared to those who did not receive targeted therapy during neoadjuvant chemotherapy, especially with regard to OS (hazard ratio: 14.11, P = 0.009). For HR+ patients, as demonstrated in our study, potential synergy between signals may be key to improving the prognosis of HR+ and HER2+ patients. Further, long-term targeting and maintenance endocrine therapy are critical factors for improving prognosis, as supported by Exnet research.26 Collectively, these results suggest that targeted therapy for HER2+ breast cancer is crucial for achieving and maintaining good long-term survival. However, this needs to be confirmed by rigorous clinical studies in the future, given the discrepancies in the literature.27 Generally, no difference in long-term prognosis was observed, regardless of whether standard treatment cycles were completed or continued for three weeks during neoadjuvant pCR (including the replenishment of previously missing treatments after neoadjuvant chemotherapy). Notably, the effects of chemotherapy during the neoadjuvant period may affect long-term prognosis. Achievement of pCR may be employed to identify the optimal treatment plan for patients. Indeed, this issue has been investigated in several retrospective studies and clinical research, which may ultimately help to guide clinical treatment strategies.28,29

In our study, the recurrence of liver metastases accounted for a large proportion of patients. In a prospective study that included liver ultrasound and hepatic function tests, no significant differences in mortality were observed between intensive monitoring and minimal examination during follow-up.30 However, the optimal follow-up approach for patients with breast cancer who achieve pCR after treatment requires clarification. Notably, patients with brain metastases comprised a large proportion of patients with HER2+ breast cancer. In the KATHERINE study,11 a similar incidence of brain metastases was observed in the trastuzumab and T-DM1 groups. Of note, there is significant scope for improvement in the monitoring and prevention of recurrence. In the future, effective tyrosine kinase inhibitor drugs and monoclonal antibodies that can cross the blood-brain barrier should be included in neoadjuvant chemotherapy regimens to prevent brain metastases.31 Similarly, the National Comprehensive Cancer Network guidelines do not recommend magnetic resonance imaging of the head during follow-up of patients with breast cancer. Based on these issues, the present results clearly emphasise the need for systemic examination of patients with breast cancer who have achieved pCR after neoadjuvant chemotherapy. In this regard, it is necessary to develop clear methods and standards for the early detection of distant metastases in patients who have achieved pCR to improve prognosis and survival.

Our study had several limitations. The study was retrospective in nature, and was conducted in a single institution, thus limiting the generalisability of the results. In addition, the follow-up time was insufficient to identify the most relevant endpoints. Furthermore, tumour size was not uniformly distributed. One explanation for this is that the patients included in our study were diagnosed at an early stage and that Asian women typically have smaller breasts than European and American women. Further research should incorporate larger sample sizes and uniformly distributed tumour sizes.

In conclusion, our findings indicate that patients with breast cancer who achieve pCR after neoadjuvant chemotherapy have a good prognosis. However, patients with a late clinical stage before neoadjuvant chemotherapy remain at risk of recurrence after treatment. Therefore, close follow-up is warranted to improve survival rates and prevent recurrence and metastasis in this population.

The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

All procedures performed in this study complied with the ethical standards of the institution and/or the National Research Council, as well as the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. The retrospective study design was approved by the Ethics Committee of Harbin Medical University Cancer Hospital.

Written informed consent was obtained from each patient.

The authors affirm that all research participants provided written consent for the publication of their data in this study.

This study was supported by grants from the Hei Longjiang Postdoctoral Foundation (LBH-Z16120) and the Hai Yan Science Foundation of Harbin Medical University Cancer Hospital (JJZD2019-05).

All authors declare that they have no conflicts of interest.

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13. Campbell JI, Yau C, Krass P, et al. Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat. 2017;165(1):181191. doi:10.1007/s10549-017-4303-8

14. Bergquist JR, Murphy BL, Storlie CB, Habermann EB, Boughey JC. Incorporation of treatment response, tumor grade and receptor status improves staging quality in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2017;24(12):35103517. doi:10.1245/s10434-017-6010-4

15. Mittendorf EA, Vila J, Tucker SL, et al. The neo-bioscore update for staging breast cancer treated with neoadjuvant chemotherapy: incorporation of prognostic biologic factors into staging after treatment. JAMA Oncol. 2016;2(7):929936. doi:10.1001/jamaoncol.2015.6478

16. Ju NR, Jeffe DB, Keune J, Aft R. Patient and tumor characteristics associated with breast cancer recurrence after complete pathological response to neoadjuvant chemotherapy. Breast Cancer Res Treat. 2013;137(1):195201. doi:10.1007/s10549-012-2312-1

17. Gonzalez-Angulo AM, McGuire SE, Buchholz TA, et al. Factors predictive of distant metastases in patients with breast cancer who have a pathologic complete response after neoadjuvant chemotherapy. J Clin Oncol. 2005;23(28):70987104. doi:10.1200/JCO.2005.11.124

18. Asaoka M, Narui K, Suganuma N, et al. Clinical and pathological predictors of recurrence in breast cancer patients achieving pathological complete response to neoadjuvant chemotherapy. Eur J Surg Oncol. 2019;45(12):22892294. doi:10.1016/j.ejso.2019.08.001

19. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):39974013. doi:10.1200/JCO.2013.50.9984

20. Asselain B, Barlow W, Bartlett J. Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;19(1):2739. doi:10.1016/S1470-2045(17)30777-5

21. Wei W, Kurita T, Hess KR, et al. Comparison of residual risk-based eligibility vs tumor size and nodal status for power estimates in adjuvant trials of breast cancer therapies. JAMA Oncol. 2018;4(4):e175092. doi:10.1001/jamaoncol.2017.5092

22. Wiechmann L, Sampson M, Stempel M, et al. Presenting features of breast cancer differ by molecular subtype. Ann Surg Oncol. 2009;16(10):27052710. doi:10.1245/s10434-009-0606-2

23. Earl HM, Hiller L, Vallier AL, et al. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised Phase 3 non-inferiority trial. Lancet. 2019;393(10191):25992612. doi:10.1016/S0140-6736(19)30650-6

24. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013;14(8):741748. doi:10.1016/S1470-2045(13)70225-0

25. Joensuu H, Fraser J, Wildiers H, et al. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial. JAMA Oncol. 2018;4(9):11991206. doi:10.1001/jamaoncol.2018.1380

26. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):16881700. doi:10.1016/S1470-2045(17)30717-9

27. Tanioka M, Shimizu C, Yonemori K, et al. Predictors of recurrence in breast cancer patients with a pathologic complete response after neoadjuvant chemotherapy. Br J Cancer. 2010;103(3):297302. doi:10.1038/sj.bjc.6605769

28. Yan H, Xiao H, Zhu J, Zhang J, Liu Z. Association between the HER2 protein expression level and the efficacy of neoadjuvant chemotherapy in HER2-positive breast cancer. Cancer Manag Res. 2020;12:1271512722. doi:10.2147/CMAR.S278694

29. Spring LM, Fell G, Arfe A, et al. Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: a comprehensive meta-analysis. Clin Cancer Res. 2020;26(12):28382848. doi:10.1158/1078-0432.CCR-19-3492

30. von Minckwitz G, Untch M, Nesch E, et al. Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials. Breast Cancer Res Treat. 2011;125(1):145156. doi:10.1007/s10549-010-1228-x

31. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):26102619. doi:10.1200/JCO.20.00775

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Clinical and Therapeutic Factors Vary by Prognosis in Patients with Pa | CMAR - Dove Medical Press

The Impact of COVID-19 on Clinical Research in the Life Sciences Industry: Is there a Silver Lining? – JD Supra

Posted: December 7, 2021 at 1:51 am


Clinical research is one of the foundations of the Life Sciences industry as it involves the scientific investigation and treatment of diseases and other medical conditions in order to improve medical knowledge related to the diagnosis, treatment, and prevention of such diseases and medical conditions. Clinical research is the underlying process that results in the development of ground breaking new drugs and treatments that cure or treat diseases that improve all of our lives. One of the best and most recent examples of the importance of clinical research is the development of vaccines for the COVID-19 virus which to date has taken the lives of over 5 million people across the globe since early 2020.

The impact of the COVID-19 pandemic on the clinical research industry has been profound and in some respects may prove to be an inflection point for the Life Sciences industry.

The COVID-19 pandemic created massive disruption within the world of clinical research. In 2020, over 79% of ongoing clinical trials were disrupted in one way or another by COVID-19[1]. The disruptions ranged from stopping ongoing trials, pausing recruitment of ongoing trials and pausing the development of new clinical study sites[2]. Enrollment in clinical trials dropped dramatically during the early stages of the pandemic as potential participants were reluctant to make trips to hospitals or other research sites. In addition, many investigators, sub-investigators, and research staff had to shift focus to COVID related support instead of working on clinical research efforts.

Beyond the disruption to existing clinical research studies, however, COVID-19 has had other impacts on the clinical research industry that could have a potentially positive impact on how clinical research is conducted in the future.

COVID-19 Resulted in an Acceleration of the Clinical Research Process

When faced with the rapidly spreading COVID-19 virus, pharmaceutical companies and governments collaborated to accelerate the clinical research process in order to develop a vaccine that would work against COVID-19. Previously, the fastest a vaccine had been developed in the U.S. was four years when the vaccine for the mumps virus was developed in the 1960s[3]. In light of the global health emergency created by the COVID-19 pandemic, researchers were able to reduce the normal time to arrive at a vaccine by years. How was this done? One of the reasons for the rapid development of the COVID-19 vaccine was the years of prior research on vaccine development for other viruses, like HIV[4]. Researchers were also able to quickly determine the specific genetic makeup of the SARS-COV-2 virus by early 2020 and they used technology from RNA-based templates to develop a potential vaccine[5]. Another important factor in streamlining the development for the COVID-19 vaccine was the hundreds of thousands of people who volunteered to participate in the clinical studies for the vaccine development. In addition, the U.S. Government implemented Operation Warp Speed which provided very large government contracts and research grants to pharmaceutical companies to research and produce vaccines. The U.S. Government also had the FDA advance all COVID-19 vaccine clinical research studies to the front of the regulatory approval line through the use of emergency use authorizations (EUAs). This lead to the development of multiple COVID-19 vaccines that were ready for mass distribution within 1 year of the identification of the COVID-19 virus, which is a remarkable accomplishment. The FDA also used EUA to expedite other responses to COVID-19 by approving new testing and additional sources and types of personal protective equipment (PPE). The development and distribution of the vaccine was a groundbreaking accomplishment that reflected the resilience and innovation of the clinical research industry. According to some clinical researchers, the rapid creation of COVID-19 vaccines is a sea change in how to develop vaccines in the future[6].

As we continue to work through the COVID-19 pandemic, it remains to be seen how much faster future clinical research studies will be accelerated in the future based on our COVID-19 clinical research experience. The FDA is under both political and media pressure to accelerate its approval process because of the COVID-19 experience and the clinical research industry is looking at its normal processes to determine if things can and should be done in a different way in order to streamline and accelerate the overall process while at the same time maintaining safety and scientific integrity.

A New Focus on the Clinical Research Participant

Another potential change in clinical research that was caused in part by COVID-19 is an effort by clinical trial sponsors to focus more on the clinical trial participant and their experience during the clinical trial. This includes trying to reduce the administrative burden on clinical trial participants and making the process simpler and easier for participants to navigate. Clinical trial sponsors are also evaluating trials with more of a focus on quality of life for the participants and increasing the use of patient support groups or patient advocates so it is easier for clinical trials to recruit new participants and to keep the participants engaged throughout the life of the clinical trial[7].

Use of More Decentralized Clinical Research

A decentralized clinical trial (DCT) is defined as a clinical study executed through telemedicine and mobile /local healthcare provider processes and technologies that brings the trials activities to the patient at home rather than using the traditional model of bringing patients to a trial site[8]. Because much of the world was in lockdown mode to deal with the implications of COVID-19, clinical researchers increased the use of DCTs during 2020. This included the use of more virtual encounters and technology to connect clinical trial participants with the investigators. It is anticipated that this will occur more in the future as researchers can gather better data when it is easier for patients to report the data. With DCTs, patients can report data via their smart phone or tablets from home instead of having to be physically present at a clinical research site[9]. Use of DCTs is also seen as a successful tool in recruiting the appropriate patient populations by increasing both access to clinical trials and the overall diversity of trial participants[10]. Having a diverse group of clinical trial participants can help ensure that the drug or device being tested is safe and effective[11].

Increased use of Digital Technology

The use of digital technology by patients and participants in clinical trials has steadily increased over the last several years. During COVID-19 and with the increase in DCTs, the use of mobile devices such as smart phones or tablets, digital wearables or other types of biosensors have steadily increased[12]. The use of this digital technology provides clinical researchers with access to continuous data for longer periods of time and it is easier for clinical trial participants to use this technology on a daily basis without disruption to their daily lives. The use of digital technology has also increased the opportunity for clinical trial sponsors to obtain real-world data (RWD) and real-world evidence (RWE) from clinical study participants. This result stemmed in part from the FDAs launch of a program focused on the increased use of RWD and RWE[13]. This kind of information has been used to support clinical trial designs and studies to generate innovative approaches to clinical studies[14].

Is there a silver lining from COVID-19 when it comes to clinical trials?

The long term impacts of COVID-19 across the health care spectrum still remain to be determined, but one of the short term impacts of this global pandemic could prove to be potentially significant and positive changes in the way that the clinical research industry operates. These changes could lead to a faster clinical research process that embraces the use of new technology such as digital therapeutics and development of a broader and more diverse base of clinical participants.

For a look at the regulatory framework for clinical trials in the life science industry and the risks faced by companies within the industry including a discussion of potential future changes caused by the pandemic watch Nexsen Pruets on-demand webinar, Understanding Clinical Research Framework and Challenges in the Life Sciences Industry, presented by Matthew Roberts of Nexsen Pruet and Rakel Meir of Biogen.

[1] The Impact of COVID-19 on clinical trials, News Medical, July 22, 2021

[2] No place like home? Stepping up the decentralization of clinical trials, McKinsey & Company, June 10, 2021

[3] The lightning fast quest for COVID vaccines and what it means for other diseases, Philip Ball, Nature, December 18, 2020

[4] How COVID-19 vaccines were made so quickly without cutting corners Rachel Lane, Science News, June 29, 2021

[5] Id

[6] Id

[7] Clinical Trials In Crisis: Building On COVID-19s Lessons Toward A Better Future, HealthAffairs, August 25, 2021, Esther Krofah, Steven K. Galson, Robert M. Califf, Gregory Simon

[8] No place like home? Stepping up the decentralization of clinical trials, McKinsey & Company, June 10, 2021

[9] Why Decentralized Clinical Trials Are the Future in Post-COVID World, Anju Team, September 2021.

[10] Clinical Researcher, The Modernization of Clinical Trials: COVID-19s Lasting Impact, April 2021, (Volume 34, Issue 3) Mark Clements, MD, PhD, CPI, FAAP, Komathi Stem, MS.

[11] The Case for Diversity in Clinical Trials, Lionbridge, December 10, 2020, Nataliya Volohov

[12] The Modernization of Clinical Trials: COVID-19s Lasting Impact (Volume 34, Issue 3), Mark Clements, MD, PhD, CPI, FAAP, and Komathi Stem, MS, April 2021

[13] Id

[14] Id

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The Impact of COVID-19 on Clinical Research in the Life Sciences Industry: Is there a Silver Lining? - JD Supra

NGM Bio Announces Clinical Trial Collaboration with Merck Related to Ongoing Phase 1/2 Trial of NGM707, an ILT2/ILT4 Dual Antagonist Antibody, in…

Posted: at 1:51 am


NGM entered into a clinical trial collaboration and supply agreement with Merck to evaluate the potential of NGM707 in combination with KEYTRUDA for the treatment of patients with advanced or metastatic solid tumors

NGM707 is part of NGMs wholly-owned portfolio of immuno-oncology programs focused on releasing myeloid checkpoints to reprogram myeloid cells to reverse immune suppression

ILT2 and ILT4, upregulated in certain tumor types, are believed to serve as myeloid checkpoints, helping tumors evade immune detection

NGM707 is designed to reprogram ILT4-expressing myeloid cells and stimulate the activity of ILT2 expressing myeloid and lymphoid cells to enhance anti-tumor immunity

NGMs additional myeloid checkpoint inhibitor candidates include NGM831 and NGM438, ILT3 and LAIR1 antagonist antibodies

SOUTH SAN FRANCISCO, Calif., Dec. 06, 2021 (GLOBE NEWSWIRE) -- NGM Biopharmaceuticals, Inc. (NGM) (Nasdaq: NGM), a biotechnology company focused on discovering and developing transformative therapeutics for patients, today announced a clinical trial collaboration and supply agreement with Merck (known as MSD outside of the United States and Canada) to evaluate NGM707, NGMs wholly-owned novel ILT2/ILT4 dual antagonist antibody, in combination with Mercks anti-PD-1 therapy, KEYTRUDA. NGM is currently enrolling patients in the Phase 1/2 trial, initiated in June 2021, to evaluate the potential of NGM707 as a monotherapy and in combination with KEYTRUDA in adult patients with advanced or metastatic solid tumors with elevated expression of ILT2 and ILT4.

ILT2 and ILT4 are among a group of myeloid immune checkpoint receptors that are upregulated in patients who do not respond to T-cell checkpoint therapy, suggesting that they are potential resistance mechanisms that generate an immunosuppressive state in the tumor microenvironment. Were excited by the unique profile of NGM707 in the myeloid checkpoint inhibition space. Our preclinical studies suggest that NGM707s dual blockade of ILT2 and ILT4 may be more effective than blockade of either receptor alone in reversing myeloid based immune suppression, which is known to limit anti-tumor immunity, said Hsiao D. Lieu, M.D., Chief Medical Officer at NGM Bio.

Story continues

Dr. Lieu continued, Were pleased to enter into this agreement with Merck for our ongoing Phase 1/2 trial of NGM707. In preclinical models, we have demonstrated that NGM707 in combination with KEYTRUDA acts additively to increase T cell activation and cytokine secretion. We look forward to evaluating how these mechanisms of action translate in the clinic to potentially enable broader and deeper anti-tumor immune responses, bringing the promise of immunotherapy to more cancer patients.

ILT2 and ILT4, inhibitory receptors with enriched expression on myeloid cells in the tumor microenvironment, are myeloid checkpoints that may enable certain tumors to evade immune detection, thereby suppressing patients anti-tumor response. NGM707 is being developed with the goal of improving patient immune response to tumors by inhibiting both ILT2 and ILT4. By inhibiting both ILT2 and ILT4, NGM707 may be able to overcome the potential redundant role the two receptors play when co-expressed in myeloid cells and reprogram those cells to enhance T cell activity and proliferation. In addition, ILT2 blockade may drive further benefit through reducing suppression in certain lymphoid cells capable of directly attacking tumor cells.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

About the NGM707 Phase 1/2 Trial Design

The Phase 1 portion (n60) of the trial includes a monotherapy dose escalation arm (Part 1a) and a dose-finding arm in combination with KEYTRUDA (pembrolizumab) (Part 1b). The Phase 2 portion (n120) of the trial will employ a basket design that will include expansion cohorts of patients treated with NGM707 monotherapy (Part 2a) or NGM707 in combination with KEYTRUDA (Part 2b) in a variety of selected solid tumor types.

For additional information about the trial, including types of cancers being evaluated and other eligibility criteria, please click here to visit the listing on clinicaltrials.gov.

About NGMs Oncology Portfolio

NGMs currently disclosed oncology product candidates are all derived from the companys in-house discovery engine and are wholly owned by NGM. These oncology programs include: NGM120, a GFRAL antagonist antibody in a Phase 2 trial for the treatment of metastatic pancreatic cancer; NGM707, an ILT2/ILT4 (LILRB1/LILRB2) dual antagonist antibody in a Phase 1/2 trial for the treatment of advanced solid tumors; NGM831, an ILT3 (LILRB4) antagonist antibody, planned to enter into a Phase 1 trial in advanced solid tumors in the first half of 2022; and NGM438, a LAIR1 antagonist antibody, also planned to enter into a Phase 1 trial in advanced solid tumors in the first half of 2022.

Abbreviations (in Alphabetical Order) GFRAL=Glial Cell-Derived Neurotrophic Factor Receptor Alpha-Like; ILT2=Immunoglobin-Like Transcript 2; ILT3=Immunoglobin-Like Transcript 3; ILT4=Immunoglobin-Like Transcript 4; LAIR1=Leukocyte-Associated Immunoglobulin-Like Receptor 1; LILR= Leukocyte Immunoglobin-Like Receptor [ILT2 = LILRB1, ILT3=LILRB4, ILT4=LILRB2]

About NGMNGM is a biopharmaceutical company focused on discovering and developing novel therapeutics based on scientific understanding of key biological pathways underlying retinal diseases, cancer and liver and metabolic diseases. We leverage our biology-centric drug discovery approach to uncover novel mechanisms of action and generate proprietary insights that enable us to move rapidly into proof-of-concept studies and deliver potential first-in-class medicines to patients. At NGM, we aspire to operate one of the most productive research and development engines in the biopharmaceutical industry. All of our therapeutic candidates have been generated by our in-house discovery engine; today, we have seven disclosed programs, including four in Phase 2 or 2b studies, across three therapeutic areas. Visit us at http://www.ngmbio.com for more information.

Forward Looking StatementsStatements contained in this press release regarding matters that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as will, may, believed, designed, suggesting, suggest, look forward, potentially, potential, promise, goal, planned, aspire and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These statements include those related to: the therapeutic potential of NGM707, including the potential of NGM707 in combination with KEYTRUDA to potentially enable broader and deeper anti-tumor immune responses; Merck supplying KEYTRUDA to NGM under the clinical trial collaboration; the design of the Phase 1/2 trial of NGM707; the ability of NGM707 to inhibit ILT2 and ILT4 and the potential benefits of ILT2 and ILT4 inhibition; the planned commencement of Phase 1 clinical trials of NGM831 and NGM438, and the anticipated timing thereof; and other statements that are not historical fact. Because such statements deal with future events and are based on NGMs current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of NGM could differ materially from those described in or implied by the statements in this press release. These forward-looking statements are subject to risks and uncertainties, including, without limitation, risks and uncertainties associated with the costly and time-consuming pharmaceutical product development process and the uncertainty of clinical success, including risks related to failure or delays in successfully initiating, enrolling, reporting data from or completing clinical studies, as well as the risks that results obtained in clinical trials to date may not be indicative of results obtained in ongoing or future trials and that NGMs product candidates, including NGM707, may otherwise not be tolerable and effective treatments in their planned indications; NGMs ability to maintain its clinical trial collaboration with Merck, including the risk that if Merck were to breach or terminate the clinical trial collaboration, the evaluation of NGM707 in combination with KEYTRUDA could be delayed, perhaps substantially, and NGMs costs to conduct the Phase 1/2 trial of NGM707 could substantially increase; the ongoing COVID-19 pandemic, which has adversely affected, and could materially and adversely affect in the future, NGMs business and operations, including NGMs ability to timely supply, initiate, enroll and complete its ongoing and future clinical trials; the time-consuming and uncertain regulatory approval process; NGMs reliance on third-party manufacturers for NGM707, NGM831 and NGM438 and the risks inherent in manufacturing and testing pharmaceutical products; the sufficiency of NGMs cash resources, including to fund its wholly-owned programs such as NGM707, and NGMs need for additional capital; and other risks and uncertainties affecting NGM and its development programs, including those discussed in the section titled Risk Factors in NGMs quarterly report on Form 10-Q for the quarter ended September 30, 2021 filed with the United States Securities and Exchange Commission (SEC) on November 4, 2021 and future filings and reports that NGM makes from time to time with the SEC. Except as required by law, NGM assumes no obligation to update these forward-looking statements, or to update the reasons if actual results differ materially from those anticipated in the forward-looking statements.

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NGM Bio Announces Clinical Trial Collaboration with Merck Related to Ongoing Phase 1/2 Trial of NGM707, an ILT2/ILT4 Dual Antagonist Antibody, in...

Innovent Releases Results of a Phase 1 Clinical Study of IBI362, a Dual Glucagon-like Peptide-1 and Glucagon Receptor Agonist in Chinese Patients with…

Posted: at 1:51 am


SAN FRANCISCO and SUZHOU, China, Dec. 6, 2021 /PRNewswire/ -- Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, metabolic, autoimmune and other major diseases, announces that results of a phase 1 clinical trial of IBI362 (LY3305677), a dual glucagon-like petide-1 (GLP-1) and glucagon receptor agonist in patients with type 2 diabetes are presented as an e-poster at the International Diabetes Federation Congress 2021.

This randomized, double-blind, placebo-controlled multiple-ascending-dose phase 1b study evaluated the safety, tolerability and pharmacokinetics/ pharmacodynamics of IBI362 in Chinese patients with type 2 diabetes, with dulaglutide as an active control. Fourteen patients were enrolled in each of the three cohorts and randomized 8:4:2 to receive once weekly IBI362, placebo or 1.5 mg dulaglutide subcutaneously for 12 weeks. Dose escalation regimens for IBI362 and placebo were 1.0-2.0-3.0 mg (cohort 1), 1.5-3.0-4.5 mg (cohort 2) or 2.0-4.0-6.0 mg (cohort 3), with each dose level administered for 4 weeks. IBI362 was well tolerated and showed a safety profile comparable to dulaglutide. Gastrointestinal adverse events and decreased appetite were the most commonly-reported adverse events, mostly transient and mild in severity. At week 12, mean changes from baseline in HbA1c levels were 1.46%, 2.23% and 1.66% for patients receiving IBI362 in cohort 1,2 and 3, respectively (1.98% for dulaglutide). Given the variations brought by limited sample size, after removing patients with maximum and minimum changes from baseline to week 12 in HbA1c in each dose group, the adjusted mean changes from baseline in HbA1c levels were 1.46%, 2.28% and 1.87% for patients receiving IBI362 in cohort 1,2 and 3, respectively (1.46% for dulaglutide). Meanwhile, mean percent changes from baseline to week 12 in body weight were 0.9%5.0% and 5.4% for patients receiving IBI362 in cohort 1,2 and 3, respectively (0.9% for dulaglutide). Improvements in waist circumference, body mass index, blood pressure and lipid levels were observed in patients receiving IBI362, with overall trends similar with those observed in phase 1b study in participants with overweight or obesity[1].

Professor Wenying Yang of China-Japan Friendship Hospital, primary investigator of the study, stated: "In recent years, GLP-1 receptor agonists have demonstrated weight loss and cardio-renal benefits to patients with diabetes while achieving glycemic control, delivering broad application prospect. We are delighted to see that IBI362, as a novel dual GLP-1 receptor and glucagon receptor agonist, has shown a favorable safety profile in Chinese patients with type 2 diabetes, together with multiple benefits of glycemic control, weight loss and metabolic profiles. These results showed the great advantage of IBI362as a next generation GLP-1 dual agonist over mono-agonists. I am confident in the future clinical development of IBI362, and believe that IBI362will continue to demonstrate impressive results and bring further clinical benefits in the ongoing phase II clinical trial with larger sample size and longer study duration."

Dr. Lei Qian, Executive Director of Innovent, stated: "In addition to the glycemic control efficacy of GLP-1 receptor agonism, IBI362, as a dual GLP-1 receptor and glucagon receptor agonist, may be able to promote energy expenditure by activating glucagon receptor, achieve prolonged and more pronounced weight loss compared to selective GLP-1 receptor agonists, and bring multiple metabolic benefits to patients with type 2 diabetes. Substantial weight loss has also been observed in the phase 1b clinical study of IBI362 in participants with overweight or obesity[1]. In this 12-week phase 1b study in Chinese patients with type 2 diabetes, IBI362 showed favorable safety, significant glycemic control and weight loss, with comprehensive benefits on blood pressure, lipid levels and liver enzymes generally similar to the trends observed in the previous clinical study[1]. We look forward to witness more robust results in subsequent clinical studies."

[1] Ji L, Jiang H, An P, et al. (2021) IBI362 (LY3305677), a weekly-dose GLP-1 and glucagon receptor dual agonist, in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple ascending dose phase 1b study. EClinicalMedicine 39: 101088. 10.1016/j.eclinm.2021.101088

About Diabetes

The prevalence of diabetes among adults in China is 11.6%, of which type 2 diabetes accounts for about 90% of the total number of diabetic patients, and the number of patients is still increasing. Poor glycemic control will lead to irreversible microvascular and macrovascular complications such as decreased visual acuity, blindness, renal insufficiency, peripheral neuropathy, myocardial infarction, stroke, amputation, etc. As a latent disease with serious complications and high incidence, diabetes mellitus has seriously threatened human health. Currently, there are many treatment options for diabetes, and the development of new hypoglycemic drugs will also explore the additional benefits for diabetic patients in terms of weight loss, cardiovascular risk reduction, and renal protection in addition to effective glycemic control.

About IBI362

Innovent entered into a licensing agreement with Eli Lilly and Company (Lilly) for the development and potential commercialization of OXM3 (also known as IBI362 or LY3305677), a dual GLP-1 and glucagon receptor agonist, in China. In parallel, Lilly is developing OXM3 outside China. IBI362 is a long-acting synthetic peptide related to mammalian oxyntomodulin (OXM), which uses a fatty acid side chain to prolong the duration of action and allow once-weekly administration. IBI362 is thought to exert its biological effects by activating GLP-1 receptor and glucagon receptor in human beings, which is estimated to improve glucose tolerance and induce weight loss, mimicking the effects of endogenous oxyntomodulin.

In addition to the effects of GLP-1 receptor agonists on promoting insulin secretion, lowering blood glucose and reducing body weight, IBI362 may also increase energy expenditure and improve hepatic fat metabolism through the activation of glucagon receptor. The treatment of metabolic diseases by activating multiple metabolism-related targets simultaneously is currently the worldwide trend in drug development.

About Innovent

Inspired by the spirit of "Start with Integrity, Succeed through Action," Innovent's mission is to develop, manufacture and commercialize high-quality biopharmaceutical products that are affordable to ordinary people. Established in 2011, Innovent is committed to developing, manufacturing and commercializing high-quality innovative medicines for the treatment of cancer, autoimmune, metabolic and other major diseases. On October 31, 2018, Innovent was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 01801.HK.

Since its inception, Innovent has developed a fully integrated multi-functional platform which includes R&D, CMC (Chemistry, Manufacturing, and Controls), clinical development and commercialization capabilities. Leveraging the platform, the company has built a robust pipeline of 26 valuable assets in the fields of cancer, metabolic, autoimmune disease and other major therapeutic areas, with 6 products approved for marketing in China TYVYT (sintilimab injection), BYVASDA (bevacizumab biosimilar injection), SULINNO (adalimumab biosimilar injection), HALPRYZA (rituximab biosimilar injection) , Pemazyre (pemigatinib oral inhibitor) and olverembatinib (BCR-ABL TKI), a Biologics License Application (BLA) for sintilimab accepted for review in the U.S., 5 assets in Phase 3 or pivotal clinical trials, and an additional 15 molecules in clinical studies.

Innovent has built an international team with advanced talent in high-end biological drug development and commercialization, including many global experts. The company has also entered into strategic collaborations with Eli Lilly and Company, Adimab, Incyte, MD Anderson Cancer Center, Hanmi and other international partners. Innovent strives to work with many collaborators to help advance China's biopharmaceutical industry, improve drug availability and enhance the quality of the patients' lives. For more information, please visit: http://www.innoventbio.com. and http://www.linkedin.com/company/innovent-biologics/.

Note:

TYVYT (sintilimab injection) is not an approved product in the United States.

BYVASDA (bevacizumab biosimilar injection), SULINNO, and HALPRYZA (rituximab biosimilar injection) are not approved products in the United States.

TYVYT (sintilimab injection, Innovent)

BYVASDA (bevacizumab biosimilar injection, Innovent)

HALPRYZA (rituximab biosimilar injection, Innovent)

SULINNO (adalimumab biosimilar injection, Innovent)

Pemazyre (pemigatinib oral inhibitor, Incyte Corporation). Pemazyre was discovered by Incyte Corporation and licensed to Innovent for development and commercialization in Mainland China, Hong Kong, Macau and Taiwan.

Disclaimer:

1. This indication is still under clinical study, which hasn't been approved in China.

2. Innovent does not recommend any off-label usage.

3. For medical and healthcare professionals only.

Forward-Looking Statements

This news release may contain certain forward-looking statements that are, by their nature, subject to significant risks and uncertainties. The words "anticipate", "believe", "estimate", "expect", "intend" and similar expressions, as they relate to Innovent, are intended to identify certain of such forward-looking statements. Innovent does not intend to update these forward-looking statements regularly.

These forward-looking statements are based on the existing beliefs, assumptions, expectations, estimates, projections and understandings of the management of Innovent with respect to future events at the time these statements are made. These statements are not a guarantee of future developments and are subject to risks, uncertainties and other factors, some of which are beyond Innovent's control and are difficult to predict. Consequently, actual results may differ materially from information contained in the forward-looking statements as a result of future changes or developments in our business, Innovent's competitive environment and political, economic, legal and social conditions.

Innovent, the Directors and the employees of Innovent assume (a) no obligation to correct or update the forward-looking statements contained in this site; and (b) no liability in the event that any of the forward-looking statements does not materialise or turn out to be incorrect.

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Innovent Releases Results of a Phase 1 Clinical Study of IBI362, a Dual Glucagon-like Peptide-1 and Glucagon Receptor Agonist in Chinese Patients with...

Karyopharm Announces the Appointment of Peter K Honig, MD, MPH to its Board of Directors – PRNewswire

Posted: at 1:51 am


NEWTON, Mass., Dec. 6, 2021 /PRNewswire/ -- Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced the appointment of Peter K Honig, MD, MPH, to the Board of Directors, effective December 3, 2021. Dr. Honig brings to Karyopharm over 30 years of drug development and regulatory sciences experience from past leadership roles with Pfizer, Merck and the U.S. Food and Drug Administration (FDA). Dr. Honig replaces Mikael Dolsten, MD, PhD, who has transitioned off the Board due to competing professional demands, effective December 2, 2021.

"We are honored to welcome Dr. Honig to our Board of Directors. His deep knowledge of drug development and life cycle management, coupled with his strong background in regulatory sciences and oversight, further expands the breadth of experience of our Board. We look forward to benefiting from his advice and perspectives as we continue to grow the business and pursue our goal of improving the lives of patients with cancer," said Barry E. Greene, Lead Director of Karyopharm. "Since joining our Board six years ago, Dr. Dolsten has been a trusted advisor who has made invaluable contributions and helped advance our clinical development programs. On behalf of the entire Board, I would like to thank Mikael for his dedicated service to Karyopharm and for his help in identifying his successor."

"I'm thrilled to join the Board of Karyopharm at such an exciting time in the Company's growth and evolution," said Dr. Honig. "I look forward to collaborating with my fellow Board members and the entire Karyopharm management team to advance the pipeline and deliver meaningful therapies to patients with cancer."

Dr. Honig is an experienced leader in drug development with expertise in clinical pharmacology, clinical program and trial design, compliance, and product safety and regulation. From 2014 to July 2021, Dr. Honig held various positions at Pfizer, most recently as Senior Vice President and Head of Global Regulatory Affairs and Group Head of Development for China and Japan, overseeing regulatory effectiveness, quality control and compliance. Prior to joining Pfizer, he held senior leadership positions at AstraZeneca, Merck Research Laboratories and the FDA, including as the first Director of the Office of Drug Safety in the FDA's Center for Drug Evaluation and Research (CDER). In addition to his industry and FDA experience, Dr. Honig was the PhRMA representative to the International Conference on Harmonisation (ICH) Steering Committee from 2002 to 2021, is a past President of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) and is currently an associate editor of their flagship journal.

Dr. Honig serves on the Boards of several life science companies and other healthcare organizations, including Sesen Bio, Alopexx Enterprises, LLC, the Drug Information Association, the Centre of Regulatory Excellence and the Accelerating Therapeutics for Opportunities in Medicine Consortium. He also serves on the Scientific Advisory Board of Travecta Therapeutics. Dr. Honig received his BA, MD and MPH from Columbia University.

About Karyopharm Therapeutics

Karyopharm Therapeutics Inc. (Nasdaq: KPTI) is a commercial-stage pharmaceutical company pioneering novel cancer therapies and dedicated to the discovery, development, and commercialization of first-in-class drugs directed against nuclear export for the treatment of cancer and other diseases. Karyopharm's Selective Inhibitor of Nuclear Export (SINE) compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). Karyopharm's lead compound, XPOVIO (selinexor), is approved in the U.S. in multiple hematologic malignancy indications, including in combination with Velcade (bortezomib) and dexamethasone for the treatment of adult patients with multiple myeloma after at least one prior therapy, in combination with dexamethasone for the treatment of adult patients with heavily pretreated multiple myeloma and as a monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma. NEXPOVIO (selinexor) has also been granted conditional marketing authorization in combination with dexamethasone for adult patients with heavily pretreated multiple myeloma by the European Commission. In addition to single-agent and combination activity against a variety of human cancers, SINE compounds have also shown biological activity in models of neurodegeneration, inflammation, autoimmune disease, certain viruses and wound-healing. Karyopharm has several investigational programs in clinical or preclinical development. For more information, please visit http://www.karyopharm.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the expected benefits of Mr. Honig's service on the board of directors of Karyopharm and Karyopharm's plans for growth and advancement of its programs. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm's control, that may cause actual events or results to differ materially from Karyopharm's current expectations. For example, there can be no guarantee that Karyopharm will successfully commercialize XPOVIO; that regulators will grant confirmatory approval in the European Union based on theBOSTONstudy in adult patients with multiple myeloma; or that any of Karyopharm's drug candidates, including selinexor and eltanexor, will successfully complete necessary clinical development phases or that development of any of Karyopharm's drug candidates will continue. Further, there can be no guarantee that any positive developments in the development or commercialization of Karyopharm's drug candidate portfolio will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: the risk that the COVID-19 pandemic could disrupt Karyopharm's business more severely than it currently anticipates, including by negatively impacting sales of XPOVIO, interrupting or delaying research and development efforts, impacting the ability to procure sufficient supply for the development and commercialization of selinexor or other product candidates, delaying ongoing or planned clinical trials, impeding the execution of business plans, planned regulatory milestones and timelines, or inconveniencing patients; the adoption of XPOVIO in the commercial marketplace, the timing and costs involved in commercializing XPOVIO or any of Karyopharm's drug candidates that receive regulatory approval; the ability to obtain and retain regulatory approval of XPOVIO or any of Karyopharm's drug candidates that receive regulatory approval; Karyopharm's results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, including with respect to the need for additional clinical studies; the ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respective obligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm's ability to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development or regulatory approval of drug candidates by Karyopharm's competitors for products or product candidates in which Karyopharm is currently commercializing or developing; and Karyopharm's ability to obtain, maintain and enforce patent and other intellectual property protection for any of its products or product candidates. These and other risks are described under the caption "Risk Factors" in Karyopharm's Quarterly Report on Form 10-Q for the quarter endedSeptember 30, 2021, which was filed with the Securities and Exchange Commission (SEC) onNovember 3, 2021, and in other filings that Karyopharm may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and, except as required by law, Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

XPOVIO and NEXPOVIO are registered trademarks of Karyopharm Therapeutics Inc. Any other trademarks referred to in this release are the property of their respective owners.

SOURCE Karyopharm Therapeutics Inc.

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IO Biotech Announces Third Clinical Collaboration with Merck to Evaluate IO102-IO103 in Combination With KEYTRUDA (pembrolizumab) as First-Line…

Posted: at 1:50 am


NEW YORK, Dec. 06, 2021 (GLOBE NEWSWIRE) -- IO Biotech (Nasdaq: IOBT), a clinical-stage biopharmaceutical company developing novel, immune-modulating cancer therapies based on its T-win technology platform, announced today that it has entered into a third clinical trial collaboration and supply agreement with Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the US and Canada), through a subsidiary. The purpose of the collaboration is to evaluate IO Biotechs lead candidate, IO102-IO103, in combination with KEYTRUDA (pembrolizumab), Mercks anti-PD-1 (programmed death receptor-1) therapy, in previously untreated patients with three different tumor types metastatic non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and metastatic urothelial bladder cancer (UBC). IO102-IO103 is an investigational novel immunotherapeutic agent designed to target the mechanisms mediated by key immunosuppressive proteins such as Indoleamine 2,3-dehydrogenase (IDO) and PD-L1.

We are pleased to be collaborating once again with Merck to study the potential of our IDO and PD-L1 derived immune-modulating therapy in combination with pembrolizumab as part of our broad, late-stage development program, said Mai-Britt Zocca, PhD, CEO and founder of IO Biotech. We believe IO102-IO103 has the potential to show utility for multiple cancer indications, and we look forward to expanding our dataset in these additional settings.

The planned Phase 2 trial will evaluate the safety and efficacy of the combination of IO102-IO103 with pembrolizumab in patients with previously untreated metastatic NSCLC, SCCHN, or UBC. Additional correlative endpoints will also be explored to elucidate the mechanism of action. Under the terms of the agreement, IO Biotech will sponsor the Phase 2 trial and Merck will supply pembrolizumab. IO Biotech maintains global commercial rights to IO102-IO103.

About IO102-IO103/IOB-022

Based on the results from a Phase 1/2 clinical trial, IO102-IO103, in combination with pembrolizumab, was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) for treatment of unresectable/metastatic melanoma. IO Biotech plans to initiate a Phase 3 combination trial of IO102-IO103 and KEYTRUDA (pembrolizumab), as first-line treatment in metastatic melanoma patients which is designed to be potentially registrational for IO102-IO103.

About IO Biotech

IO Biotech is a clinical-stage biopharmaceutical company developing novel, immune-modulating cancer therapies based on its T-win technology platform. The T-win platform is a novel approach to cancer immunotherapy designed to activate naturally occurring T cells to target immunosuppressive mechanisms. IO Biotech is advancing in clinical studies its lead immuno-oncology candidate, IO102-IO103, targeting IDO and PD-L1, and through clinical and preclinical development its other pipeline candidates. IO Biotech is headquartered in Copenhagen, Denmark. For further information, please visit http://www.iobiotech.com

Forward-Looking Statement

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements, including regarding future clinical trials, are based on IO Biotechs current assumptions and expectations of future events and trends, which affect or may affect its business, strategy, operations or financial performance, and actual results and other events may differ materially from those expressed or implied in such statements due to numerous risks and uncertainties. Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. Because forward-looking statements are inherently subject to risks and uncertainties, you should not rely on these forward-looking statements as predictions of future events. These forward-looking statements speak only as of the date hereof and should not be unduly relied upon. Except to the extent required by law, IO Biotech undertakes no obligation to update these statements, whether as a result of any new information, future developments or otherwise.

Company Contact:Mai-Britt Zocca, Ph.D.CEO and founder of IO Biotechmz@iobiotech.com

Investor Inquiries:Corey Davis, Ph.D.LifeSci Advisors+1 212-915-2577cdavis@lifesciadvisors.com

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,Kenilworth, NJ, USA

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IO Biotech Announces Third Clinical Collaboration with Merck to Evaluate IO102-IO103 in Combination With KEYTRUDA (pembrolizumab) as First-Line...

Y-mAbs Hosting Virtual Research and Development Day – GlobeNewswire

Posted: at 1:50 am


NEW YORK, Dec. 06, 2021 (GLOBE NEWSWIRE) -- Y-mAbs Therapeutics, Inc. (the Company or Y-mAbs) (Nasdaq: YMAB) a commercial-stage biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, today announced that it will host a virtual research and development day on Wednesday, December 15, 2021 at 12pm Eastern Time.

The Y-mAbs research and development day will feature presentations from oncology key opinion leaders (KOLs) Javier E. Oesterheld, M.D. (Atrium Health) and Jaume Mora, M.D., Ph.D. (SJD Barcelona Children's Hospital).

Dr. Oesterheld will present on the current treatment landscape in the U.S. with DANYELZA (naxitamab-gqgk); and Dr. Mora will present dosing experience with naxitamab for patients with pediatric high-risk neuroblastoma and other solid tumors from compassionate use.

An update on Y-mAbs Therapeutics broad and advanced product pipeline, including the SADA technology, will follow from Vignesh Rajah, MBBS, DCH, MRCP(UK) MBA, (SVP, Chief Medical Officer at Y-mAbs) and Steen Lisby, M.D., DMSc, (SVP, Chief Scientific Officer at Y-mAbs).

A question and answer session will follow the formal presentations. To register for the event, please click here.

Featured KOLs:

Jaume Mora, M.D., Ph.D. is the scientific director of Oncology and Hematology at SJD Barcelona Children's Hospital, as well as the director of its Developmental Tumours Laboratory. He is a member of several national and international scientific societies, including the International Pediatric Oncology Society, which awarded him the Schweisguth Prize, and the American Society of Clinical Oncology (ASCO), which in 2000 honored him with the young investigator award (YIA), as well as the Career Development Award (CDA). In 2011, Dr. Mora was the recipient of the annual BBVA Foundation Award and in 2006 he was awarded first prize of the Spanish Association Against Cancer (AECC) award for the study of child cancer.

Javier E. Oesterheld, M.D., is board certified in pediatric hematology-oncology and is helping to lead the ongoing pursuit of better treatments for childhood cancer. In 2017, he was named the first Jeff Gordon Childrens Foundation Endowment Chair - Levine Childrens Cancer and Blood Disorders Program, a role that supports his mission to improve lives and outcomes of pediatric cancer patients. Hes also the principal investigator for Carolinas Kids Cancer Research Coalition, in conjunction with the developmental therapeutics program at Levine Childrens Hospital. Additionally, Dr. Oesterheld is the study chair and/or site principal investigator for multiple clinical research studies into acute leukemia, refractory pediatric acute lymphoblastic leukemia, relapsed and refractory Neuroblastoma, and relapsed sarcomas. His research has been published in top journals and has led to numerous lecture invitations.

About DANYELZA (naxitamab-gqgk)

DANYELZA (naxitamab-gqgk) is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. This indication was approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefits in a confirmatory trial. DANYELZA includes a Boxed Warning for serious infusion-related reactions, such as cardiac arrest and anaphylaxis, and neurotoxicity, such as severe neuropathic pain and transverse myelitis. See full Prescribing Information for complete Boxed Warning and other important safety information.

About Y-mAbs

Y-mAbs is a commercial-stage biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer. The Company has a broad and advanced product pipeline, including one FDA approved product, DANYELZA (naxitamab-gqgk), which targets tumors that express GD2, and one pivotal-stage product candidate, omburtamab, which targets tumors that express B7-H3.

Forward-Looking Statements

Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to, statements about our business model and development, commercialization and product distribution plans; current and future clinical and pre-clinical studies and our research and development programs; expectations related to the timing of the initiation and completion of regulatory submissions; regulatory, marketing and reimbursement approvals; rate and degree of market acceptance and clinical utility as well as pricing and reimbursement levels; retaining and hiring key employees; our commercialization, marketing and manufacturing capabilities and strategy; our intellectual property position and strategy; additional product candidates and technologies; collaborations or strategic partnerships and the potential benefits thereof; expectations related to the use of our cash and cash equivalents, and the need for, timing and amount of any future financing transaction; our financial performance, including our estimates regarding revenues, expenses, capital expenditure requirements; developments relating to our competitors and our industry; and other statements that are not historical facts. Words such as anticipate, believe, contemplate, continue, could, estimate, expect, hope, intend, may, might, plan, potential, predict, project, should, target, will, would and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Our product candidates and related technologies are novel approaches to cancer treatment that present significant challenges. Actual results may differ materially from those indicated by such forward-looking statements as a result of various factors, including but not limited to: the risk that we may not close the transaction for the sale of our PRV voucher and would not have the additional funds provided by such sale to reinvest into our research and development programs; risks associated with our financial condition and need for additional capital; risks associated with our development work; cost and success of our product development activities and clinical trials; the risks of delay in the timing of our regulatory submissions or failure to receive approval of our drug candidates; the risks related to commercializing any approved pharmaceutical product including the rate and degree of market acceptance of our product candidates; development of our sales and marketing capabilities and risks associated with failure to obtain sufficient reimbursement for our products; the risks related to our dependence on third parties including for conduct of clinical testing and product manufacture; our inability to enter into partnerships; the risks related to government regulation; risks related to market approval, risks associated with protection of our intellectual property rights; risks related to employee matters and managing growth; risks related to our common stock, risks associated with the pandemic caused by the novel coronavirus known as COVID-19 and other risks and uncertainties affecting the Company including those described in the "Risk Factors" section included in our Annual Report on Form 10-K and in our other SEC filings. Any forward-looking statements contained in this press release speak only as of the date hereof, and the Company undertakes no obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise.

DANYELZA and Y-mAbs are registered trademarks of Y-mAbs Therapeutics, Inc.

Contact:

Y-mAbs Therapeutics, Inc.230 Park Avenue, Suite 3350New York, NY 10169USA

+1 646 885 8505

E-mail: info@ymabs.com

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