StemCell Therapy

An empath or highly sensitive person (HSP) is someone who experiences the emotions of others. Empaths have the unique ability to sense and absorb others emotions, which typically makes them extremely caring, compassionate, and understanding people.

Empaths have the ability to easily see another persons perspective. On one hand, this is a wonderful trait, but it can create some real challenges. Empaths can feel misunderstood or become easily overwhelmed.

It can be especially challenging when an empath is exposed to emotionally intense information on the daily.

According to the American Psychological Associations Stress in America Survey, theres plenty of conflict between the need to stay informed about current events and the stress that it causes. The survey indicates that 95 percent of adults follow the news regularly, but 56 percent of those who do so say it causes them stress.

For empaths, this stress is even more acute.

A 2017 study found that many people avoid empathy due to its cognitive costs. Thats not possible for empaths. For us, it becomes increasingly difficult to navigate shocking events.

As the media is designed to get the attention of the rest of the population who do not feel deeply and have sensitive nervous systems, a sensitive person will feel emotionally bombarded, overwhelmed, and overstimulated if they consume as much media as a less sensitive person, says Katie T. Larson, PhD.

Larson is a researcher, author, and growth coach who works exclusively with highly sensitive people, empaths, and intuitives.

It wasnt until my late 20s that I began to realize I process emotions differently than others. I felt vulnerable to every hurt and injustice but came across as cold and distant in an effort to shield myself.

Ive experienced both ends of the spectrum. In some cases, I attracted narcissists and emotional manipulators. Other times, I was written off as indifferent because I didnt know how to care without getting completely crushed.

Fortunately, Ive learned ways to cope. While Im not always able to follow these guidelines perfectly, I feel a huge difference in my mental health when I do.

One of the most practical ways to cope with shocking events is to limit your time scrolling social media and watching the news.

I cant even begin to count how many times Ive looked up to realize I just spent hours scrolling. Scheduling your news and even using an actual timer makes a world of difference.

Dr. Tiffany Caplan, DC, is a celebrity doctor, board certified in integrative medicine, and a self-described empath. She has resorted to getting creative about keeping up with world events.

My husband is very good about being objective about events and keeps up with everything going on. I, therefore, rely on him for just the facts of whats going on so I dont personally have to see images or read things that will upset me, Caplan says.

I dont say no well. When I do, I often feel incredibly guilty even when I shouldnt.

This is sometimes referred to as jellyfish boundaries because you easily get stung. You become drained, irritable, and overwhelmed, leading to more guilty feelings.

While it may seem like setting boundaries doesnt apply to watching current events, its important to know that some outlets present news in sensational ways to evoke emotional responses.

Take the time to find and consume news founded on logic, reason, and balance. Or try comedic sources of news for a lighthearted approach.

Setting boundaries with others when discussing current events is important too.

Not only are we often consuming negativity through the news, many of us then find ourselves stuck in conversations about it. You can make it clear to others if you dont feel comfortable or need a break from discussing current events.

Catastrophizing is a pattern of thinking that jumps to the worst-case scenario. Focusing on what-ifs often increases feelings of stress and anxiety. In truth, we dont need much help exaggerating current events.

Start by getting clear on the current situation. Ask yourself, Whats actually true right now?

Be honest with yourself when youre focused on what-ifs. You can tell yourself, This isnt actually happening. Its just a fantasy.

If you find yourself starting to spiral with panic and anxiety, its important to ground yourself back in the present moment. You can do this by using the 5-4-3-2-1 method, meditation, and guided imagery.

Larson suggests creating a visualization or audio mantra that keeps you safe within your own energetic field. Some people choose phrases like white bubbles or I am safe and repeat them throughout the day to keep their nervous system calm and intact.

Annie McDonnell is a licensed acupuncturist and sound therapy practitioner who focuses on giving patients self-care tools for emotional health and resilience. According to McDonnell, it helps to focus on the nervous system.

By stimulating the vagus nerve to go into parasympathetic mode (rest and digest vs. fight or flight), we can help regulate our breathing, heart rate, and digestion. There are a few different ways to activate this mode, she says.

One way to do this is with deep belly breathing.

While there are many wonderful breathing techniques, this is the simplest one for when your anxiety is triggered, McDonnell says.

Another option is a soothing ear massage.

Note: While research suggests there are health benefits, the Food and Drug Administration (FDA) doesnt monitor or regulate the purity or quality of essential oils. Its important to talk with your healthcare provider before you begin using essential oils. Be sure to research the quality of a brands products. Always do a patch test before trying a new essential oil.

You can also take 10 minutes to tune into a sound bath or make your own sound vibration therapy by closing your eyes and humming.

Part of the problem for empaths and anyone who suffers from headline anxiety is that you want to help everyone but you cant.

Its impossible to make things better for everyone, but you can still do it for a few. Take action by volunteering for a cause thats important to you, or engage in a simple act of kindness.

Simple acts of empathy can restore your sense that theres good in the world too.

When you take up a hobby, exercise, or explore your feelings through journaling, youre focusing on the now.

Exercise can be especially potent in changing your energy state.

Allow your body to move and literally shake off the emotions that are not yours. Movement is key, as there is much research to suggest actual immobility keeps emotions stuck as well, says Larson.

Even if you dont like exercise, anything that brings you joy can help.

We have been conditioned to react to headlines with outrage at all times, so our nervous systems become addicted to that pathway. When we engage in joyful, delightful, and pleasurable activities more often, we are retraining the pathways of our brain, adds Larson.

Everyone wants alone time at some point, but empaths need it. Its the main way we recharge our batteries and cleanse our emotional palate.

For me, thats usually getting lost in a good book or hiking. It can be whatevers best for you. Its ideal to do it as part of your regular routine instead of waiting until youve hit complete overload.

Shocking news events are challenging for everybody these days, especially empaths. Know there are things you can do.

You can take control of your media consumption by limiting the duration and timing. You dont have to let your mind run rampant with negative news.

If youve been exposed, find ways to release the negative energy you have inside of you. You can replace it with positivity through meditation, mindfulness, and acts of kindness.

You dont have to let shocking news control your life.

Ashley Hubbard is a freelance writer based in Nashville, Tennessee, focusing on sustainability, travel, veganism, mental health, social justice, and more. Passionate about animal rights, sustainable travel, and social impact, she seeks out ethical experiences whether at home or on the road. Visit her website.

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How an Empath Copes with Shocking Events - Healthline

The pandemic has upended some industries entirely, leaving workers scrambling to figure out their Plan B. As they weigh their options, theyre considering the staying power of other occupations. Amainstay of traditional Chinese medicine dating back to 3,000 years ago, it's safe to say that acupuncture is here for the long run. This multi-track field combines caring for others with flexible work schedules and lifelong learning, says Jessica Frier, DAOM, LAc, and dean of the College of Acupuncture and Chinese Medicine at Northwestern Health Sciences University in Bloomington.

People are drawn to acupuncture as a second career, because they want to help others in a way that focuses on a persons own innate ability to heal, she says. So, youre helping patients take control of their health, their pain, or their diet.

For many, acupuncture is their first career choice, but other practitioners are finding that acupuncture is a natural extension of work they are already doing.

You see people coming from the nursing field, or they have been yoga practitioners and they want to do more with a holistic viewpoint of health care, Frier says. Thats generally what attracts people to a second career in acupuncture.

She points to an array of acupuncture specialties and an increasing number of places to put that training to work, including chiropractic offices, primary care clinics, hospitals, pain clinics, physical therapy departments, athletic facilities, hospices and massage therapy practices. You could also open your own business and practice in that manner, Frier says.

Kate Moknes Bowman, DACM, LAc, says everyones journey into Chinese medicine is different. Her journey began in a pre-med program that led her to degrees in social work and business and, eventually, a doctorate in acupuncture and Chinese medicine.

I really like medicine, but how I got onto this track is that I really wanted to know more about nutrition and the root cause behind why we get sick, she says. And that is really what Chinese medicine is all abouta functional medicine approach.

Now she puts her social work training, business education, and doctorate to work in her acupuncture clinic and NWHSUs Human Performance Center, where she helps elite athletes stay healthy and recover from injuries.

I love doing both, seeing the patients, having all of the issues come into the clinic and whats going on in the community, and then Im able to translate going back and teaching the students, Bowman says.

She also teaches a new generation of acupuncture practitioners at NWHSU and makes time to study advances in science about the biomedical effects of acupuncture and Chinese medicine.

She once found it puzzling when engineers studied acupuncture as a second career, she says, but she realized they were drawn to the field for the same reason she wasproblem solving.

For me, its really about finding what actually is the root of the health issue, she says. So, I think thats how engineering comes in, although it is a different path than mine.

How do you make the leap to acupuncture and determine if its the right fit for you? Bowman says its easy to find out. Go shadow someone and make sure its something you want to do something youre passionate about.

The gateway to becoming an acupuncturist is through NWHSUs masters program, says Frier. It gives you a solid foundation in all of the modalities that encompass being an acupuncturist.

Depending on the program, it takes two-and-a-half to four years worth of study to earn a masters. But students are ready to begin practicing as an acupuncturist as soon as they complete their degree, because they have completed clinical work during their studies.

We have one of the most robust clinical experiences of any college in the country, Frier says. That includes specialty clinics out in the community with special populations like HIV patients, geriatric patients. We have a number of hospital rotations, too.

NWHSU offers flexible schedules to allow students to earn degrees while they are working or raising a family, which explains why it can take as little as two-and-a-half years or as long as four years to earn a degree.

Were accustomed to working with people like that, Frier says. It might take you a little longer to get done, but eventually we get you through. Classes begin in September and January, but those embarking on a fall program can take summer classes to hit the ground running in September.

For those who want to lean into more theory, clinical applications of Chinese medicine and research, a doctorate in acupuncture is often a goal. At NWHSU, it takes a little over three years to complete the degree. And, yes, acupuncturists with a masters can return and earn a doctorate.

Frier describes it as looking more into the integrative perspective around health care and the acupuncturists role in health care. So, it really is a dive into medicine.

One of the beautiful parts of East Asian or Chinese medicine in general is the flexibility, she says, the ability to practice in a way that makes sense to you.

Located in Bloomington,Northwestern Health Sciences Universityis a pioneer in integrative natural health care education, offering degree programs in chiropractic, acupuncture, Chinese medicine, massage therapy, medical assisting, medical laboratory programs, post-bac/pre-health, radiation therapy, and B.S. completion. ItsBloomington clinicis open to the public andprovides chiropractic treatment,acupuncture, Chinese medicine, massage therapy, naturopathic medicine, and cupping.

See more content fromNorthwestern Health Sciences University.

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Working in Wellness: The Allure of Acupuncture - Mpls.St.Paul Magazine

The report by Orbis Pharma Reports also includes a dedicated section on pandemic management guide. According to expert financial analysts, global economy is anticipated to take a derogatory turn, while plummeting to tremendous lows in the coming months, also likely to continue at the same pace even in 2021. Therefore, this report is mindfully developed to aid all financial investments on the part of new aspirants and leading players, aiming to seek easy market penetration. The report is also likely to come in handy for all established players in the competitive landscape as well who are amidst unprecedented crisis and seeking appropriate guidance for making adequate investment decisions to maintain sustainability.

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The report is an ideal source of vivid information that allow report readers to realign their growth strategies and tactical business discretion. With ample cues available in this high end research report, interested players across the value chain may initiate profitable business strategies and expansion plans across emerging markets as well as popular growth hubs as observed by Health Coaching research professionals.

Major Company Profiles operating in the Health Coaching Market:

Wellcoaches School of CoachingAetnaNational Consortium for Credentialing of Health & Wellness CoachesDuke Integrative MedicineHumanaNational Society of Health Coaches

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Health EducatorsHealth CoachesWellness Coaches

By the application, this report covers the following segments

RadiologyObstetrics and GynecologyCardiovascularGastroenterologyOther Applications

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At Orbispharma we curate the most relevant news stories, features, analysis and research reports on the important challenges undertaken by the pharmaceutical and related sectors. Our editorial philosophy is to bring you sharp, focused and informed perspective of industries, the end users and application of all upcoming trends into the pharma sector. Orbispharma believes in conversations that can bring a change in one of the most crucial economic sectors in the world. With these conversations we wish our customers to make sound business decisions with right business intelligence.

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Health Coaching Industry Market 2021 Growth Analysis, Competitive Insights, by Key Players:Wellcoaches School of Coaching, Aetna, National Consortium...

One of the most dramatic examples was the abrupt substitution of telemedicine for in-person visits to the doctors office. Although telemedicine technology is decades old, the pandemic demonstrated how convenient and effective it can be for many routine medical problems, Dr. Navathe said.

Feb. 14, 2021, 6:09 p.m. ET

Telemedicine is more efficient and often just as effective as an office visit. It saves time and effort for patients, especially those with limited mobility or who live in remote places. It lowers administrative costs for doctors and leaves more room in office schedules for patients whose care requires in-person visits.

Even more important, the pandemic could force a reckoning with the environmental and behavioral issues that result increasingly in prominent health risks in this country. We need to stop blaming genetics for every ailment and focus more on preventable causes of poor health like a bad diet and inactivity.

Consider, for example, the health status of those who have been most vulnerable to sickness and death from Covid-19. Aside from advanced age, about which we can do nothing, its been people with conditions that are often largely preventable: obesity, Type 2 diabetes, high blood pressure, coronary artery disease and smoking. Yet most physicians are unable to influence the behaviors that foster these health-robbing conditions.

Many people need help to make better choices for themselves, Dr. Navathe said. But the professionals who could be most helpful, like dietitians, physical trainers and behavioral counselors, are rarely covered by health insurance. The time is long overdue for Medicare and Medicaid, along with private insurers, to broaden their coverage, which can save both health and money in the long run.

Policy wonks should also pay more attention to widespread environmental risks to health. Too many Americans live in areas where healthful food is limited and prohibitively expensive and where the built environment offers little or no opportunity to exercise safely.

Individuals, too, have a role to play. The pandemic has fostered an opportunity for patients to take on a more active role in their care, Dr. Shrank said in an interview.

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Pandemic Lessons in Improving the Medical System - The New York Times

The growing importance of hormonal health is becoming an integral component of modern medicine especially as the focus shifts toward maintaining and boosting immunocompetence in the population. Many plausible benefits of hormonal factors on autoimmunity have received growing attention in recent years from the scientific community. Research has been conducted investigating the relationship between immune system function and sex hormones testosterone and estrogen.

Importantly, the immune systems of men and women are known to function differently with 80% of autoimmune diseases occurring in women who tend to show stronger immune responses than their male counterparts. Stronger immune responses in women produce faster pathogen clearance and improved vaccine responsiveness while also contributing to their increased susceptibility to inflammatory and autoimmune diseases.

Results from previous experimental studies have revealed that testosterone can have a medium-sized immunosuppressive effect on immune function, however, the impact of estrogen can vary depending on the immune marker measured. Such differences in immune function and responses have contributed to health- and life-span disparities between sexes yet the role of hormones in immune system aging remains to be understood.

Immune Differences and Dimorphism

The differences in immunocompetency between male and female patients are associated with varying testosterone and estrogen levels major regulators of the immune system. Differences in gene expression between the sexes contribute to the concept of immune dimorphism though they are limited to one or a few types of immune cells. Furthermore, genomic differences between sexes have been found to become more prominent after the age of 65 with men having a higher innate and pro-inflammatory activity along with lower adaptive activity.

Female and males have different energy and nutrient requirements largely based on interactions between external factors and sex hormones; interactions between hormones and a patients environment, including cigarette smoke and viral infections, can lead to variable responses in both genders. While enhanced immunity has been reported in female patients, making them less susceptible to viral infections, their hyper immune response can predispose them to immune-pathogenic effects. In addition, sex hormones can control the immune response via circadian rhythms and their ability to regulate T-cell mediated inflammation.

Microbial Composition

Emerging evidence also indicates that sex hormones can impact the guts microbial composition and thus, impact immunocompetency. Studies have shown that diet-based effects on the microbiome are more prominent in men than in women implicating that dietary interventions may have an influence on sex-based immune responses.

The gut microbiota landscape can impact the systemic levels of testosterone, changing metabolic profiles which may heighten the risk for chronic disease including diabetes. However, current knowledge of the mechanism by which microbiome-derived sex steroids impact immunity remains limited.

Previous research has shown that hormonal contraceptives can increase bacterial species, highlighting sex-hormone-dependent differences and their effects on systemic immune responses. However, the gut microbial composition can be influenced by a variety of factors outside of hormonal levels, such as genetics and dietary habits.

The mechanism underlying sex hormone expression and immunocompetency continues to be investigated; this may result in the improvement of future designs for targeted therapeutics that mitigate sex hormone-inflammatory activity or autoimmune diseases. Clinicians interested in expanding their knowledge on the role of hormones in immune function and longevity are invited to attend the cutting-edge, interactive online Role of Hormones in Immunocompetency and Longevity workshop taking place on February 20, 2021.

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The Role of Hormones in Immunocompetence - Anti Aging News

BETHESDA, Md., Feb. 11, 2021 /PRNewswire/ --The third annual Medical Genetics Awareness Week will be celebrated April 1316, 2021. Through Medical Genetics Awareness Week, the American College of Medical Genetics and Genomics (ACMG) aims to promote awareness of the importance of medical genetics professionals on the healthcare team, including medical geneticists, laboratory geneticists, genetic counselors, nurses and physician assistants. The theme of Medical Genetics Awareness Week is "Celebrating the Contributions of the Entire Medical Genetics Team to Patient Care and Public Health."

New for 2021 are high-quality face masks and a Zoom virtual background to help individuals "Share Your Medical Genetics Pride." Participants can share their pictures to social media wearing a Medical Genetics Awareness Week face mask (free for ACMG members) or a Medical Genetics Awareness Week hashtag button; using a new Medical Genetics Awareness Week Zoom virtual background; or displaying a Medical Genetics Awareness Week sticker.

Since 2019, Medical Genetics Awareness Week has brought together people from across the globe to celebrate the important work of medical genetics professionals. Medical Genetics Awareness Week is celebrated to recognize the critical contributions that medical genetics healthcare professionals make in the diagnosis, management and prevention of genetic diseases, and the difference these professionals make in the lives of patients and families. Medical Genetics Awareness Week is also intended to educate other healthcare professionals and students and trainees on who medical geneticists are, how they are trained and what they do in the clinic and laboratory.

Also new for 2021 are themed days that will include a Diversity Day and a Student and Trainee Day. Follow Medical Genetics Awareness Week on social media by searching the #MedicalGeneticsAwareness hashtagand sign up to receive news and updates about Medical Genetics Awareness Week by clicking here. Log in (or create a free ACMG account) and, on the privacy preferences page, opt in to receive news and updates about Medical Genetics Awareness Week.

"Medical genetics and genomics is now deeply wedged into nearly all disciplines of medicine," said ACMG President Anthony R. Gregg, MD, MBA, FACOG, FACMG. "It is a natural extension that we remind the public and all healthcare professionals that those of us who practice medical genetics in clinics, clinical laboratories and research environments work tirelessly and with great enthusiasm. Our singular common goal is to bring accurate genetic information to the bedside that will improve people's lives."

Events related to Medical Genetics Awareness Week will be held during the ACMG Annual Clinical Genetics Meeting A Virtual Experience, April 1316, 2021, but participants don't need to be a meeting registrant to participate in the week's activities. The ACMG Annual Meeting is the largest conference specifically for clinical and laboratory geneticists in the United States. Those interested in collaborating with ACMG to celebrate Medical Genetics Awareness Week, holding their own events or becoming an "ambassador" for medical genetics are invited to email ACMG Communications Coordinator Reymar Santos at [emailprotected]for more information.

"Medical genetics is for all of us," said Max Muenke, MD, FACMG, ACMG'schief executive officer. "I am delighted to celebrate my colleagues in this important field: genetic counselors, laboratory geneticists, medical geneticists, and other allied healthcare professionals who are committed to optimal patient care."

Visit the Medical Genetics Awareness Week web pageson ACMG's website for resources and tips designed to support the week's celebrationsand to join the Medical Genetics Awareness Week email list. When posting on social media, participants are encouraged to tag @TheACMG and include the following hashtags in posts related to Medical Genetics Awareness Week:

#MedicalGeneticsAwareness#IamaMedicalGeneticist#FutureGeneticsProfessional#IamaLabGeneticist#IamaGeneticCounselor#IamaGeneticsPA#IamaNurseinGenetics#IamaGeneticsNP

About the American College of Medical Genetics and Genomics (ACMG) and ACMG Foundation

Founded in 1991, the American College of Medical Genetics and Genomics (ACMG) is the only nationally recognized medical society dedicated to improving health through the clinical practice of medical genetics and genomics and the only medical specialty society in the US that represents the full spectrum of medical genetics disciplines in a single organization. The ACMG is the largest membership organization specifically for medical geneticists, providing education, resources and a voice for more than 2,400 clinical and laboratory geneticists, genetic counselors and other healthcare professionals, nearly 80% of whom are board certified in the medical genetics specialties. ACMG's mission is to improve health through the clinical and laboratory practice of medical genetics as well as through advocacy, education and clinical research, and to guide the safe and effective integration of genetics and genomics into all of medicine and healthcare, resulting in improved personal and public health. Four overarching strategies guide ACMG's work: 1) to reinforce and expand ACMG's position as the leader and prominent authority in the field of medical genetics and genomics, including clinical research, while educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease; 2) to secure and expand the professional workforce for medical genetics and genomics; 3) to advocate for the specialty; and 4) to provide best-in-class education to members and nonmembers. Genetics in Medicine, published monthly, is the official ACMG journal. ACMG's website (www.acmg.net) offers resources including policy statements, practice guidelines, educational programs and a 'Find a Genetic Service' tool. The educational and public health programs of the ACMG are dependent upon charitable gifts from corporations, foundations and individuals through the ACMG Foundation for Genetic and Genomic Medicine.

Kathy Moran, MBA[emailprotected]

SOURCE American College of Medical Genetics and Genomics

http://www.acmg.net

Continued here:
Celebrate the Third Annual Medical Genetics Awareness Week April 13-16, 2021 - PRNewswire

SALT LAKE CITY, Feb. 11, 2021 (GLOBE NEWSWIRE) -- Myriad Genetics, Inc. (NASDAQ: MYGN), a leader in genetic testing and precision medicine, announced today that it will participate at multiple upcoming health and technology conferences, sharing insights on how the company is intensifying its focus on serving patients and healthcare providers in Womens Health, Oncology and Mental Health.

Paul J. Diaz, president and CEO at Myriad Genetics, and R. Bryan Riggsbee, CFO, will participate in a fireside chat at the BTIG Virtual MedTech, Digital Health, Life Science & Diagnostic Tools Conference on February 19 at 10:30 a.m. EST.

On February 24, 2021, Mr. Riggsbee will participate in a fireside chat at the Leerink Global Healthcare Conference at 5:00 p.m. EST.

On March 2, 2021, Mr. Diaz will participate in a fireside chat at the Cowen Annual Healthcare Conference at 9:50 a.m. EST.

The presentations will be available through a live audio webcast link in the investor information section of Myriads website at http://www.myriad.com.

About Myriad GeneticsMyriad Genetics, Inc. is a leading genetic testing and precision medicine company dedicated to improving health and transforming patient lives worldwide. Myriad discovers and commercializes genetic tests that: determine the risk of developing disease, accurately diagnose disease, assess the risk of disease progression, and guide treatment decisions across medical specialties where critical genetic insights can significantly improve patient care and lower healthcare costs. For more information, visit the Company's website: http://www.myriad.com.

Myriad, the Myriad logo, BART, BRACAnalysis, Colaris, Colaris AP, myPath, myRisk, Myriad myRisk, myRisk Hereditary Cancer, myChoice, myPlan, BRACAnalysis CDx, Tumor BRACAnalysis CDx, myChoice CDx, Vectra, Prequel, Foresight, GeneSight, riskScore and Prolaris are trademarks or registered trademarks of Myriad Genetics, Inc. or its wholly owned subsidiaries in the United States and foreign countries. MYGN-F, MYGN-G.

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Myriad Genetics to Participate in Multiple Upcoming Health and Technology Conferences - GlobeNewswire

Doctors and researchers understand much more now than they did a year ago about virus spread and the damage it can inflict. Treatments have improved greatly. It is apparent who is most at risk, although people of all ages, races and socio-economic backgrounds have been hospitalized and died.

Public health leaders and infectious disease specialists includingDr. John Sellick Jr., aprofessor of medicine at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, encourage Western New Yorkers to practice Covid-prevention measures and refrain from travel until vaccination rates lower fears about the spread of new coronavirus variants.

The vaccination race will be critical to whether we need to resume the kinds of lockdowns that have taken place in recent months in Great Britain, Sellick said, but again, its back to the basics: masks, use of physical distancing, avoiding crowds, good hand hygiene. The more we do that, the more we're going to neutralize the effect of one of these more easily transmissible strains.

Q: What if a relative or a friend is planning a trip south or west to enjoy warmer weather?

I don't want those people around me for even five minutes, Sellick said, because travel in such uncertain times especially to places with beaches, outdoor restaurants and other magnets for large gatherings raises the risk of contracting the virus, or a variant, and endangering others.

Q: What states pose the greatest risk for contracting and spreading the virus?

The positive virus test rate in the region at the end of last week was about 3.5%. The rate in Florida was twice that, and it was more than three times higher in Texas and Georgia. The rate was at least five times higher in Iowa, Idaho, Kansas, Kentucky and South Dakota, according toBeckers Hospital Review.

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How will WNY fare in the race between vaccines and coronavirus variants? - Buffalo News

(UroToday.com)Genomics, both of the tumor (somatic) and germline, are increasingly being incorporated into clinical oncologic care, both with regard to specific targeted therapy selections (e.g.PARP inhibitors) and therapy intensity (e.g.aggressive variants,e.g.genomic alterations inRB1, TP53).Often re-biopsy can impose an additional barrier for a patient, or is limited by site of metastasis, such as bone.These realities are justifications for the herald of the non-invasive evaluation of tumor genomics from the circulating (blood) compartment via circulating tumor DNA (ctDNA).Herein, Dr. Tukachinsky and colleagues endeavored to evaluate via hybrid-capture-based targeted gene panel next generation sequencing (NGS) the landscape of genomic alterations (GA) found in the plasma of patients with metastatic castration-resistant prostate cancer (mCRPC), and, in a subset, evaluate concordance with tissue-based NGS assessments.

Plasma samples were culled from 3334 men with advanced prostate cancer, including 1674 subjects from the TRITON2/3 studies of rucaparib and 1660 non-trial clinical samples.The observed GA landscape was compared to 2006 metastatic biopsies, with concordance assessed in 837 patients.In keeping with previous reports of ctDNA burden, 94% (3127) of subjects had detectable ctDNA with 8.8% (295) with mutations inBRCA1/2.Concordance with tissue evidence ofBRCA1/2mutations was observed in 93% of evaluable subjects (67/72) and 20 subjects had evidence of such mutationsonlyin ctDNA.Notably, subclonal reversion mutations inBRCA1/2were observed in 10 of 1660 routine clinical specimens, suggesting a mechanism for PARPi resistance, at least in a subpopulation evaluated.

Alterations inAR, the gene encoding the androgen receptor, were detected in 42% (940/2213) samples, including amplifications and hotspot mutations.Among the mutations detected are specific alterations which confer resistance to commonly used highly-potent ARSIs, such as abiraterone acetate and enzalutamide.The authors also describe a subset of samples with rare compound double mutations and novel potentially activating mutations in AR. Additional GAs were detected in relevant signaling pathways including PI3K/AKT/mTOR (14%), WNT/beta-catenin (17%), and RAS/RAF (5%).Microsatellite instability was rare (1.4% of 2213 patients).

These data lend further support to the relative reliability (as compared to tissue assays) of using plasma for evaluating relevant tumor genomic alterations in the advanced metastatic setting, reflecting genomics data demonstrating that dominant metastatic clones found at autopsy can be found in the circulating compartment1.This is particularly powerful as detection of resistant subclones that may not be in a tissue-based sample, either because these cells reflect occult or unsampled metastatic samples, could impact therapeutic decisions. It should be considered that use of subjects from the TRITON studies, which comprised approximately half of the cohort may result in higher rates of observed GAs inBRCA1/2than in daily practice, given the enrichment in such genomic alterations as ground truth in this group.As noted by the authors, the limitations of the assay in these studies includes an inability to detect deletions inBRCA1/BRCA2, as well as other clinically-relevant commonly-deleted prostate cancer genes (e.g. PTEN). Further evaluation using orthogonal assays, such as RNAseq, would add additional detail, particularly along the AR signaling axis, to these promising results. Finally, the authors astutely recommend that a degree of caution must be taken when interpreting liquid biopsy results, given the influence of alterations representing clonal hematopoiesis.

Publication of full length publication can be found in the February 8thissue ofClinical Cancer Research.

Presented by: Hanna Tukachinsky, PhD, Foundation Medicine Inc., Cambridge, MA

Written by: Jones Nauseef MD, PhD. Fellow, Division of Hematology and Oncology, Weill Cornell Medicine/New York Presbyterian Hospital. Twitter: @DrJonesNauseefduring the2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021

References:1. Woodcock DJ, Riabchenko E, Taavitsainen S, et al., Prostate cancer evolution from multilineage primary to single lineage metastases with implications for liquid biopsy. Nature Comm. 11:5070 (2020). DOI:10.1038/s41467-020-18843-5.

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ASCO GU 2021: The Landscape of Genetic Alterations Using ctDNA-based Comprehensive Genomic Profiling in Pat... - UroToday

Graduate and medical school interviews are not democratic spaces. Whatever the interviewer says during that 30 minutes, is the rule of law.

Surely there were policies about the legality of certain questions, but those often arent operational during the interview. Those of us in the chair only hope that the questions arent too difficult, that the interviewer doesnt focus on (or conjure) a flaw in our application, spend the 30 minutes of our engagement berating us for it, breaking our self-esteem for all of eternity.

One interview day during the fall of 2001, however, was special. Interviewer Z, as we will call them, had a different agenda than most.

Across a wooden desk they sat, their attention focused on a computer slightly off to my left. They tilted the monitor so that we could both see it, and walked me through a few of the things that they had worked on.

Interviewer Z was a physician turned basic scientist who made a name for themself as a virologist. In the last several years, they had moved into studying adenovirus-associated vectors (AAV) that were being used as delivery vehicles for gene therapy.

They told me that I was a promising researcher and were curious why I wanted to bother with clinical medicine at all (they were onto something). In light of that, they preferred to spend our interview time teaching me how to build a successful scientific career.

Their tips to building a career? Identify somethinga gene, a protein, a pathway, perhaps an organismand study a feature of it that no one has, in great depth. Study it well enough to publish results in a reasonably well-regarded journal. Present broadly on this topic. Talk to multiple audiences, make a case for why the thing you work on reveals everything about everything.

The advice they were giving me was about how they were able to be nimble, relevant and well-funded. I sat and listened closely.

With your microbiology background, you need to find a way to cash in on the human genome craze. Us virologists are going to win a Nobel Prize for it, you know.

They learned over and said, almost under their breath:

This is how we win.

THE NATURE AND NURTURE OF A SKEPTIC

Before this interview, I had never thought about scientific ambition in such organized terms. My scientific mentors until that pointa young physical chemist named Vernon Morris, and bacterial geneticist Susan Gottesmandidnt appear to work that way. That is, while each had their strategies (like all successful scientists do), they didnt describe their scientific ambitions like a military operation: no fields to take over, no one to defeat, nothing to win.

From my vantage point (nave at the time), they seemed to love the ideas, loved working with people, and only wanted to do good in the world (their behaviors reflected that).

My experience with Interviewer Z took place less than a year after the announcement of the completion of the first draft of the human genome. The announcement shook the world but was especially exciting for me because it was something of a local affair. I was working at the National Cancer Institute (NCI) at the time, on the campus of the National Institutes of Health (NIH) in Bethesda, Md. (where the Human Genome Project lived and where I commuted to work, while pursuing my degree at Howard University in nearby Washington, D.C.).

The months that followed the February 2001 announcement would be defined by as much scientific evangelism as you will ever see. The claims? That the completion of a draft of the human genome was our moon landing, our generations moment when we transcended possibility, forever saw the universe in a different light.

But while this hyper-optimism certainly lived in the vapors of the NIH campus, it didnt follow me into the laboratory where I worked.

My advisor, Susan Gottesman, barely spoke of the announcement. Not because she denied its importance, but rather, because she had other things to do and think about.

Her research program almost functioned as the anti-announcement: she studied gene regulation in Escherichia coli, the most unpretentious of model systems. Biology didnt operate further from the spectacle of human biology than the vagaries of E. coli and phage genetics. But these were her instruments, where shed built an international reputation for genetic approaches to understanding how proteins are managed inside of cells, how microbes respond to stressful environments.

Rather than grand statements about what understanding a genome could do in a fight against superbugs across the universe, Gottesman would speak directly about how studying single sets of genes, in a single species of bacteria (E. coli) could tell us about the quirks of microbial metabolism and physiology, how they operated like a board of modules and switches.

So detailed and pure in thought was she that she barely made reference to disease in her work, even though her discoveries absolutely applied to pathogenic organisms (for example, the small regulatory RNAs that she helped to discover in E. coli have now been found to regulate virulence genes in pathogens like Vibrio cholerae).

But her greater gospel, that I learned by osmosis (we didnt talk much about matters not directly about the work), is that the details matter at least as much as the hifalutin concepts do.

This was an important spirit to be around at that time. I was a college activist, who was consuming and reciting big ideas in the genus of social justice (ideas I stand behind, even today). My favorite writers were James Baldwin and Stephen Jay Gould, both authors of bold and beautiful manifestos (even in short essay form).

And it was all of these forces, a nonlinear mix of nature and nurturemy politics, my background (a young, financially disadvantaged African American, raised in a single parent home), and the environments in which my scientific ethics were madethat made me a natural skeptic of big announcements, big pronouncements and scientific grandstanding.

And yes, this included the notion that the draft of the human genome was our moon landing.

LESSONS FROM GELSINGER

After Interviewer Zs advice on how to win, I tried my hand at offering a real response in the form of a question.

Given recent events, did they plan on pivoting away from the study of adenovirus-associated viral vectors for delivering gene therapy? I asked it with a rebellious buzz in my chest, but it was a perfectly reasonable question.

In September 1999, roughly two years before that interview, a young person named Jesse Gelsinger had died while enrolled in a clinical trial for gene therapy run by the University of Pennsylvania. Gelsingers death had a large effect on me: we were close in age, and his death happened less than two years after the release of Gatttaca, a film about a perilous future defined by genetic discrimination.

Since the Gelsinger death, I had noticed a subtle signature of virology programslike the one run by Interviewer Zmigrating away from a gene-therapy focus vectors and into other areas of virus biology.

The brand of gene therapy that had been in voguenear the turn of the millenniumwas one where the corrected form of genes were delivered to the site of interest using viral vectors. Thousands of viruses have evolved machinery to integrate their DNA into their hosts. The logic followed that this aspect of viruses, where they can deliver genes to certain parts of the host genome, could be manipulated for our own goodwe can fix gene variants associated with disease. And after some early promising results, clinical trials were set up to test this in patients.

Gelsinger died during a clinical trial to cure ornithine transcarbamylase deficiency, a genetic condition that he suffered from. After injection with an adenovirus vector, Gelsingers body mounted a large immune response against the virus, which led to a cascade of events culminating in his death.

The Gelsinger death, combined with my personality, experiences and developing ethics, was the reason that the announcement of the completion of the first draft didnt land on me the way it did many others. I had already seen big ideas in science rise and fall.

Twenty years later, I can say that some of my skepticism was poorly founded and misguided. I can proudly admit that almost every field of biology has been irreversibly changed, if not revolutionized, by technology that sprung from that announcement.

We now understand more about the origins of species, the ones that Darwin speculated on, than we ever have.

We have almost real-time outbreak pictures of bacterial and viral genomes creeping through sequence space, sometimes landing on jackpot solutions that facilitate adaptations (but more often landing nowhere, and quite often, off a cliff towards genetic doom).

Genomic technologies driven by the announcement allow us to assess our risk for many important diseases and afflictions.

We can even quantify, to some degree, the magical biodiversity that populates our planet.

The completion of the draft of the human genome helped to democratize the technology, through making genomic sequencing more affordable. You no longer need to study a well-funded human genetic disease in order to afford the tools to sequence and analyze DNA. People who study rainbow trout use genomics. People who study archaea use genomics.

But while some of my young takes might have been sophomoric, others were mature and responsible (even wise).

Among the central messages during the last two decades of genomic science is that the relationship between genotype and phenotype does not function like the pieces of a puzzle. Genes and mutations speak to each other and the environments in which they operate, in surprising ways that defy any existing analogies.

Weve learned that resolving phylogenetic relationships between species and organisms can be a nightmare because biology doesnt operate according to the categories that make it easy to understand. (To put this in perspective, we cant even agree on the very basics, like whether there are two or three domains of life)

Weve learned that genes for disease A often dont cause disease at all. And paradoxically, many people with disease A dont have any identifiable genetic predisposition.

And Homo sapiens? Were an even messier story than we ever predicted: not only are social ideas like race unhelpful for understanding anything essential about the species, they are plainly in the way of a full grasp of the increasingly complex picture of our true origins. Genes from several nonhuman species are peppered throughout our genomes in nontrivial amounts, telling a story of wanderlust and widespread copulation.

As it turns out, my education about the rules of biology over the past two decades has functioned a lot like my education about the rules of real life.

With regard to the latter, there are truths that I can and will hold onto: nice people are great. Greed is bad, and so is racism.

But life isnt that simple.

Because Ive also learned that some people are mean for a reason, greed might happen by accident, and maybe weve all been raised to be bigoted in one way or another. Ive learned the challenge and joy in being empathetic, recognizing our privileges, and dealing with our own biases.

Similarly, DNA is the most fascinating and important string of information in the universe. It tells powerful stories about this bizarre collection of matter that we call life on earth. And it is a privilege to be a part of the species that can study and discuss what it is and how it works.

But it isnt everything. Because life isnt that simple.

And this is what Interviewer Z has since learned. Opportunism around big announcements didnt land them where they hoped. And ironically, the discovery that created the modern face of genetic modification and was awarded a Nobel Prize in 2020CRISPRwas the product of tinkering in microbes in a manner that resembled Susan Gottesmans methods, more than it did Interviewer Zs Art of War tactics.

Months after the interview, I would begin a two-decade-long scientific adventure, where Ive since engaged insect ecology, medicine, biophysics, evolutionary biology and othersalmost entirely (I believe) based on inspiration.

I have landed as an academic who runs my own research program in infectious disease, and am not much younger today than Interviewer Z was at the time of our 2001 interview.

But the advice I give young people today is much different than theirs:

Who the hell knows where the next big discovery will come from? Just hustle and flow, enjoy learning, and ignore the fads and big announcements.

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The Human Genome and the Making of a Skeptical Biologist - Scientific American

Scientists in the Perelman School of Medicine have uncovered the molecular causes of a congenital form of dilated cardiomyopathy (DCM), an often-fatal heart disorder.

This inherited form of DCMwhich affects at least several thousand people in the United States at any one time and often causes sudden death or progressive heart failureis one of multiple congenital disorders known to be caused by inherited mutations in a gene called LMNA. The LMNA gene is active in most cell types, and researchers have not understood why LMNA mutations affect particular organs such as the heart while sparing most other organs and tissues.

In a study published in Cell Stem Cell, the Penn Medicine scientists used stem cell techniques to grow human heart muscle cells containing DCM-causing mutations in LMNA. They found that these mutations severely disrupt the structural organization of DNA in the nucleus of heart muscle cellsbut not two other cell types studiedleading to the abnormal activation of non-heart muscle genes.

Were now beginning to understand why patients with LMNA mutations have tissue-restricted disorders such as DCM even though the gene is expressed in most cell types, says study co-senior author Rajan Jain, an assistant professor of cardiovascular medicine and cell and developmental biology at the Perelman School of Medicine.

This story is by Sophie Kluthe. Read more at Penn Medicine News.

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Stem cell study illuminates the cause of an inherited heart disorder | Penn Today - Penn Today

Misfolded proteins (orange) in the endoplasmic reticulum may play a role in Wolfram syndromes many symptoms.

By Mitch LeslieFeb. 11, 2021 , 2:00 PM

Maureen Marshall-Doss says the first sign that her vision was deteriorating came when she misidentified the color of a dress. At a backyard get-together about 20 years ago, the Indianapolis resident pointed out an attractive yellow dress another woman was wearing. You see that as yellow? Shes wearing a pink dress, Marshall-Doss recalls her husband responding.

Today, Marshall-Doss is virtually blind. With help from custom made eyeglasses that magnify objects 500 times, I can see shapes, she says. But she can no longer drive and had to quit the job she loved as a school librarian. Along with her dimming vision, she has type 1 diabetes and has lost her sense of taste and smell.

Marshall-Doss is one of 15,000 to 30,000 people around the world with Wolfram syndrome, a genetic disease. For decades, the condition remained enigmatic, untreatable, and fatal. But in the past few years, insights into its mechanism have begun to pay off, leading to the first clinical trials of drugs that might slow the illness and sparking hopes that gene therapy and the CRISPR DNA-editing tool might rectify the underlying genetic flaws. Here is a rare disease that the basic science is telling us how to treat, says physiologist Barbara Ehrlich of the Yale School of Medicine.

The research could also aid more than the relatively few patients with Wolfram syndrome. Driving the diseases many symptoms is a malfunction of the endoplasmic reticulum (ER), the multichambered organelle that serves as a finishing school for many cellular proteins. Known as ER stress, the same problem helps propel far more common illnesses, including type 2 diabetes, amyotrophic lateral sclerosis (ALS), Parkinsons disease, and Alzheimers disease. Wolfram syndrome is the prototype of an endoplasmic reticulum disorder, says medical geneticist Fumihiko Fumi Urano of Washington University School of Medicine in St. Louis. Because Wolfram syndrome is simpler, says Scott Oakes, a cell biologist and pathologist at the University of Chicago, researchers think it could illuminate the mechanisms of other ER-disrupting diseases, which affect hundreds of millions of people worldwide.

In the late 1930s,four children with diabetes were going blind, and doctors were stumped. Like many other people in the United States struggling through the Great Depression, the siblings ate a paltry diet, subsisting on potatoes, bread, oatmeal, and a little milk. But after examining three of the children, Donald Wolfram, a physician at the Mayo Clinic in Rochester, Minnesota, and an ophthalmologist colleague ruled out malnutrition as the cause of their puzzling condition. Lead poisoning and syphilisthough common enoughwerent to blame, either. When Wolfram and his partner wrote up the cases in 1938, they concluded that the symptoms could be manifestations of an hereditary or acquired cerebral lesion.

The physicians were right that the syndrome eventually named for Wolfram is hereditary. Recessive mutations in the gene for a protein called wolframin are responsible for most cases, with glitches in a second gene causing most of the rest. However, the pair was wrong to think the defect lies only in the brain. Instead, the symptoms stem from widespread cell death. Its definitely a disease that affects the whole body, Marshall-Doss says.

The first sign of the illness, appearing when patients are children, is usually diabetes mellitus, or faulty sugar metabolism, sparked by the demise of insulin-secreting beta cells in the pancreas. Most patients also develop the unrelated condition diabetes insipidus, in which the pituitary gland doesnt dole out enough of a hormone that helps control the bodys fluid balance, causing the kidneys to produce huge amounts of urine.

Mutations in the gene for wolframin disrupt the endoplasmic reticulum and lead to cell death throughout the body, causing a range of symptoms.

V. Altounian/Science

Ellie White, 19, of Centennial, Colorado, who was diagnosed with Wolfram syndrome 12 years ago, says she hasnt had a full night of sleep since she was 3 years old. She gets up again and again to use the bathroom and monitor her blood sugar.

Yet she and other patients say that as disruptive as those problems are, they are not the diseases most dismaying consequence. The biggest symptom of Wolfram syndrome that affects me the most is my vision, White says. Because neurons in the optic nerve perish, patients usually go blind within 10 years of their first visual symptoms.

Other neurons die as well. As the disease progresses, brain cells expire, and walking, breathing, and swallowing become difficult. Most people with Wolfram syndrome die before age 40, often because they can no longer breathe. At 57, Marshall-Doss is one of the oldest patients; one of her mutated genes may yield a partly functional version of wolframin, triggering a milder form of the disease, Urano says.

Two advanceshave made it possible to begin to tackle those symptoms. The first was Uranos discovery nearly 20 years ago that linked Wolfram syndrome to ER stress. The ER is where about one-third of a cells newly made proteins fold into the correct shapes and undergo fine-tuning. Cells can develop ER stress whenever they are under duress, such as when they dont have enough oxygen or when misfolded proteins begin to pile up inside the organelle.

In test tube experiments, Urano and his colleagues were measuring the activity of genes to pinpoint which ones help alleviate ER stress. One gene that popped up encodes wolframin, which scientists had shown in 1998 was mutated in patients with Wolfram syndrome. Following up on that finding, Urano and his team determined that wolframin takes part in whats known as the unfolded protein response, which is a mechanism for coping with ER stress in which cells take steps including dialing back protein production.

Scientists think wolframin plays a key role in the unfolded protein response, though they havent nailed down exactly how. When wolframin is impaired, cells become vulnerable to ER stress. And if they cant relieve that stress, they often self-destruct, which could explain why so many neurons and beta cells die in the disease.

Defective wolframin may harm cells in other ways. The ER tends the cells supply of calcium, continually releasing and absorbing the ion to control the amount in the cytoplasm. Changes in calcium levels promote certain cellular activities, including the contraction of heart muscle cells and the release of neurotransmitters by neurons. And wolframin affects calcium regulation.

Beta cells genetically engineered to lack functional wolframin brim with calcium, Ehrlich and colleagues reported in July 2020 in theProceedings of the National Academy of Sciences. When exposed to lots of sugar, the altered cells release less insulin and are more likely to die than healthy beta cells, the team found. The cells share that vulnerability with beta cells from patients with Wolfram syndrome. We think that excess calcium is leading to excess cell death, Ehrlich says.

ER malfunctions could hamstring other organelles as well. The ER donates calcium to the mitochondria, the cells power plants, helping them generate energy. In 2018, a team led by molecular biologist Ccile Delettre and molecular and cellular biologist Benjamin Delprat, both of the French biomedical research agency INSERM, discovered that in cells from patients with Wolfram syndrome, mitochondria receive less calcium from the ER and produce less energy. Those underpowered mitochondria could spur the death of optic nerve cells, the researchers speculate.

Fumihiko Urano holds dantrolene, a muscle relaxant drug he helped test as a treatment for Wolfram syndrome.

The link between ER stress and Wolfram syndrome has been crucial for identifying potential treatments because otherwise we would have nothing to target, Urano says. But a second development was also key, he says: the advocacy and support of patient organizations, such as the Snow Foundation and the Ellie White Foundation, headed by its namesakes mother. The foundations have stepped up with money for lab research and clinical trials when other sources, including government agencies, didnt come through.

Scientists, patients, and their advocates say Urano also deserves much of the credit. Besides treating patients, he heads the international registry of cases and has taken the lead in organizing clinical trials, screening compounds for possible use as treatments, and devising potential therapies. Fumi is clearly the driving force, says Stephanie Snow Gebel, co-founder of the Snow Foundation, who about 10 years ago helped persuade him to forgo a plum job as department chair at a Japanese university and take over the Wolfram program at Washington University.

Patients could soonstart to reap the benefits. In 2016, Urano and colleagues started the worlds first clinical trial for the disease: a phase 1/2 study of dantrolene, an approved muscle relaxant. The molecule was a top performer when they screened 73 potential treatments for their ability to save cells with terminal ER stress. Dantrolene didnt improve vision in the 22 participants, including White, the scientists reported in an October 2020 preprint. But in some patients, beta cells appeared to be working better and releasing more insulin. The drug is safe, but Urano says it will need to be chemically tweaked to target its effects before future trials are warranted.

Researchers are pursuing other possible treatments targeting ER stress or calcium levels. In 2018, U.K. scientists launched a trial that will include 70 patients to evaluate sodium valproate, a therapy for bipolar disorder and epilepsy that, in the lab, prevents cells with faulty wolframin from dying. Last year, another compound that emerged from Uranos screens, the diabetes drug liraglutide, entered a clinical trial. Also last year, an experimental drug developed by Amylyx Pharmaceuticals for Alzheimers disease and ALS received orphan drug designation from the U.S. Food and Drug Administration for Wolfram syndrome because it curbs ER stress. That designation offers tax breaks and other incentives, and it will get trials started sooner, Urano says.

Ehrlich and her team have a candidate of their own that they have begun to test in rodents: the drug ibudilast, which is approved in Japan to treat asthma. The researchers found it reduces calcium levels in beta cells lacking wolframin and boosts their survival and insulin output. New screening projects may reveal still more candidates.

But Urano knows that even if a treatment receives approval, it would be only a Band-Aid for Wolfram syndrome. Hoping to develop a genetic cure, he and colleagues are introducing replacement genes into cells from patients and from mice engineered to replicate the disease. The researchers are endowing the cells with healthy copies of the gene for wolframin or the gene for a protein that reduces ER stress to determine whether they restore cellular function and reduce cell death. At INSERM, Delettre and colleagues are also evaluating whether directing a working gene into optic nerve cells can curtail vision loss in mice with faulty wolframin. The scientists are still gathering data, but early results suggest the treatment can halt the deterioration.

Urano and his collaborators have also turned to the genome editor CRISPR, deploying it to correct the gene defect in patients stem cells and then growing them into beta cells. When the researchers transplanted the revamped cells into mice with diabetes, the animals blood sugar returned to healthy levels, the team reported in April 2020 inScience Translational Medicine.

Stem cell biologist Catherine Verfaillie of KU Leuven is collaborating on the CRISPR research. But she notes that because the faulty wolframin gene affects so many tissues, researchers will have to figure out how to deliver the CRISPR components to most cells in large organs such as the brain and livera prospect she calls pretty daunting. Urano agrees, predicting that CRISPR-based Wolfram therapies might take 10 to 20 years to develop. The alternative approach, gene therapy, could reach clinical trials more quickly, in 3 to 10 years, he says, because researchers have more experience with gene therapy and have created several treatments that have already been approved for other illnesses.

Because it stems from a single genetic glitch, Wolfram syndrome could also help scientists tease out the role of the ER in more complex diseases, including neurological conditions, type 2 diabetes, and cancer. The ER also falters in those diseases, causing cells to die, but the mechanism is harder to discern because they stem from myriad genetic and environmental factors. In Alzheimers disease, for instance, neurons develop ER stress as misfolded proteins accumulate inside and outside the cells.

Besides deepening researchers understanding of other conditions, the research on Wolfram syndrome might even deliver candidate treatments. Everyone would be very excited if we can make advances in targeting ER stress in Wolfram syndrome, Oakes says. It would open up the whole field to doing this in other degenerative diseases.

See the rest here:
The race to treat a rare, fatal syndrome may help others with common disorders like diabetes - Science Magazine

REDWOOD CITY, Calif.--(BUSINESS WIRE)--Jasper Therapeutics, Inc., a biotechnology company focused on hematopoietic cell transplant therapies, today announced positive preliminary findings from its ongoing multicenter Phase 1 clinical trial of JSP191, a first-in-class anti-CD117 (stem cell factor receptor) monoclonal antibody, as a conditioning agent in older patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) undergoing hematopoietic (blood) cell transplantation.

Data from the first six patients who received a single dose of JSP191 prior to transplantation showed successful engraftment in all six patients. Complete donor myeloid chimerism (equal or greater than 95%) was observed in five of six evaluable patients at 28 days, and all three evaluable patients had total donor chimerism equal or greater than 95% observed at day 90. In addition, at 28 days, three of five evaluable patients showed complete eradication of measurable residual disease (MRD) as measured by next-generation sequencing. Two of the five evaluable patients showed substantial reductions in MRD. No treatment-related serious adverse events were reported.

The findings were presented by lead investigator Lori Muffly, M.D., M.S., Assistant Professor of Medicine (Blood and Bone Marrow Transplantation) at Stanford Medicine, as a late-breaking abstract at the 2021 Transplantation & Cellular Therapy (TCT) Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR).

These early clinical results are the first to demonstrate that JSP191 administered in combination with a standard non-myeloablative regimen of low-dose radiation and fludarabine is well tolerated and can clear measurable residual disease in older adults with MDS or AML undergoing hematopoietic cell transplantation a patient population with historically few options, said Kevin N. Heller, M.D., Executive Vice President, Research and Development, of Jasper Therapeutics. These patients could be cured by hematopoietic cell transplantation, but the standard-of-care myeloablative conditioning regimens used today are highly toxic and associated with high rates of morbidity and mortality particularly in older adults. Traditional lower intensity transplant conditioning regimens are better tolerated in older adults, but are associated with higher rates of relapse in MDS/AML patients with measurable residual disease. JSP191, a well-tolerated biologic conditioning agent that targets and depletes both normal hematopoietic stem cells and those that initiate MDS and AML, has the potential to be a curative option for these patients.

The open-label, multicenter Phase 1 study (JSP-CP-003) is evaluating the safety, tolerability and efficacy of adding JSP191 to the standard conditioning regimen of low-dose radiation and fludarabine among patients age 65 to 74 years with MDS or AML undergoing hematopoietic cell transplantation. Patients were ineligible for full myeloablative conditioning. The primary outcome measure of the study is the safety and tolerability of JSP191 as a conditioning regimen up to one year following a donor cell transplant.

We designed JSP191 to be given as outpatient conditioning and to have both the efficacy and safety profile required for use in newborn patients and older patients for successful outcomes, said Wendy Pang, M.D., Ph.D. Executive Director, Research and Translational Medicine, of Jasper Therapeutics. We are enthusiastic about the reduction of measurable residual disease seen in these patients, especially given that it is associated with improved relapse-free survival. We are excited to continue our research in MDS/AML, with plans for an expanded study. We are evaluating JSP191, the only antibody of its kind, in two ongoing clinical studies and are encouraged by the positive clinical data seen to date.

About MDS and AML

Myelodysplastic syndromes (MDS) are a group of disorders in which immature blood-forming cells in the bone marrow become abnormal and do not make new blood cells or make defective blood cells, leading to low numbers of normal blood cells, especially red blood cells.1 In about one in three patients, MDS can progress to acute myeloid leukemia (AML), a rapidly progressing cancer of the bone marrow cells.1 Both are diseases of the elderly with high mortality. Each year, about 5,000 patients with MDS and 8,000 people with AML in the G7 countries receive hematopoietic cell transplants. These transplants are curative but are underused due to the toxicity of the current high-intensity conditioning regimen, which includes the chemotherapy agents busulfan and fludarabine.

About JSP191

JSP191 (formerly AMG 191) is a first-in-class humanized monoclonal antibody in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow. JSP191 binds to human CD117, a receptor for stem cell factor (SCF) that is expressed on the surface of hematopoietic stem and progenitor cells. The interaction of SCF and CD117 is required for stem cells to survive. JSP191 blocks SCF from binding to CD117 and disrupts critical survival signals, causing the stem cells to undergo cell death and creating an empty space in the bone marrow for donor or gene-corrected transplanted stem cells to engraft.

Preclinical studies have shown that JSP191 as a single agent safely depletes normal and diseased hematopoietic stem cells, including in animal models of SCID, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Treatment with JSP191 creates the space needed for transplanted normal donor or gene-corrected hematopoietic stem cells to successfully engraft in the host bone marrow. To date, JSP191 has been evaluated in more than 90 healthy volunteers and patients.

JSP191 is currently being evaluated in two separate clinical studies in hematopoietic cell transplantation. A Phase 1/2 dose-escalation and expansion trial is evaluating JSP191 as a sole conditioning agent to achieve donor stem cell engraftment in patients undergoing hematopoietic cell transplantation for severe combined immunodeficiency (SCID), which is potentially curable only by this type of treatment. Data presented at the 62nd American Society of Hematology (ASH) Annual Meeting showed that a single dose of JSP191 administered prior to stem cell transplantation in a 6-month-old infant was effective in establishing sustained donor chimerism followed by development of B, T and NK immune cells. No treatment-related adverse events were reported. A Phase 1 clinical study is evaluating JSP191 in combination with another low-intensity conditioning regimen in patients with MDS or AML undergoing hematopoietic cell transplantation. For more information about the design of these two ongoing clinical trials, visit http://www.clinicaltrials.gov (NCT02963064 and NCT04429191).

Additional studies are planned to advance JSP191 as a conditioning agent for patients with other rare and ultra-rare monogenic disorders and autoimmune diseases.

About Jasper Therapeutics

Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The companys lead compound, JSP191, is in clinical development as a conditioning antibody that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplant. This first-in-class conditioning antibody is designed to enable safer and more effective curative hematopoietic cell transplants and gene therapies. For more information, please visit us at jaspertherapeutics.com.

1 https://www.cancer.org/cancer/myelodysplastic-syndrome/about/what-is-mds.html

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Jasper Therapeutics Announces Positive Data from Phase 1 Clinical Trial of JSP191 as Targeted Stem Cell Conditioning Agent in Patients with...

Even as a hollow ball of embryonic cells, developing fish and mammals are not entirely defenceless.

The very first tissue, formed on the surface of a vertebrate blastula, has been shown to possess an innate immune response.

Incredible new research has shown that long before the development of organs or specialized immune cells, this simple protective layer, known as the epithelium, can reach out with its arm-like protrusions and detect, ingest, and destroy defective cells - helping to increase the embryo's chance of survival.

This 'surprisingly' efficient process, which was filmed in zebrafish and later confirmed in mice, is the earliest sign of an immune response in vertebrates.

Better understanding how it works could help researchers figure out why some embryos fail to form in those earliest states, potentially leading to new approaches for treating infertility or early miscarriages.

"Here we propose a new evolutionarily conserved function for epithelia as efficient scavengers of dying cells in the earliest stages of vertebrate embryogenesis," says cell biologist Verena Ruprecht from the Centre for Genomic Regulation.

"Our work may have important clinical applications by one day leading to improved screening methods and embryo quality assessment standards used in fertility clinics."

In developing animals, it's not uncommon for embryos to produce cellular errors during rapid cell division, and these can cause the whole embryo to fail if not taken care of. In fact, such mistakes are thought to be a leading reason for why embryos do not survive to reach implantation.

Scientists have long suspected there is an innate immune response at play, keeping fragile young embryos from threats such as sporadic cell death, inflammation, and infectious agents.

Recent research has revealed such innate immune responses in both mouse and human embryonic stem cells. But up until now, no one had ever seen it in action at the earliest stages.

This newest study is the first to explain how 'garbage collectors' like apoptotic cells are cleared out of the blastula without a specialised immune system. As you can see in the footage below, it looks a little like PAC-MAN.

So how does it work?

The blastula is a hollow ball, one cell thick, and the first stage of embryogenesis. The next stage includes further division into three germ layers, known as the gastrula.

In both these preliminary stages, researchers found evidence for the clearance of apoptotic cells, which initiate cell death.

Using four dimensional in vivo imaging of mice and zebrafish embryos, the authors show two types of epithelial 'arms' that seem to gobble up and destroy these apoptotic cells.

The first protrusion is called a phagocytic cup, and it helps scoop up and swallow the apoptotic target, a process known as phagocytosis. This structure is not unlike what we see in adult organisms, where epithelial phagocytosis keep organs and tissues healthy from infection and inflammation.

The second protrusion is a previously undescribed structure that is fast and can mechanically push apoptotic targets around, herding them into manageable positions.

"The cells cooperate mechanically," explains developmental biologist Esteban Hoijman, "like people distributing food around the dining table before tucking into their meal, we found that epithelial cells push defective cells towards other epithelial cells, speeding up the removal of dying cells."

Three dimensional tracking of these defective cells show they actually accumulate inside the epithelium, which suggests this protective layer is singling out certain cells specifically and gulping them up.

Even in conditions with abundant apoptosis, or cell death, occurring, zebrafish embryos were able to survive, which suggests this immune response is a highly efficient one.

Within two hours, in fact, the authors found the embryonic epithelium could remove 68 apoptotic particles.

Even when programmed cell death was triggered in the blastula using only two photons of illumination, the embryo showed epithelial clearance, indicating an impressive level of sensitivity.

"Together, these observations establish epithelial clearance as an error-correction mechanism that is present at the blastula stages of embryonic development," the authors conclude.

Zebrafish are model organisms for studying embryonic development, but to see whether this 'epithelial scavenging' also stood in mammals, the authors investigated what cell death looks like in mouse blastocysts.

Through time lapse imaging, the results reveal several apoptotic events, whereby cells are forced out of the blastocyst cavity and later ingested by the trophoblast. This is a tissue on the outside of the mammalian embryo that later forms a large part of the placenta. It also shows some level of innate immune response.

When mouse blastocysts were transplanted with apoptotic embryonic stem cells, the authors observed trophoblast cells eating up the targets.

Similar functions have also been documented in the human trophectoderm, which suggests the phagocytic epithelium has also been conserved in mammals and doesn't just appear in fish.

Knowing how mammal embryos survive from blastocyst to implantation could not only allow scientists to develop better fertility treatments, it could also teach us something about the early immune system - a power we could possibly try to replicate in adult tissues.

"Here we show that during early vertebrate development, epithelial cells specialize to perform phagocytic immune functions in the complete absence of immune cells," the authors write.

"At later developmental stages, professional phagocytes differentiate and can share their phagocytic tasks with mesenchymal or epithelial cells."

Future research will determine if the same innate immune process is also observed in invertebrates.

The study was published in Nature.

Continue reading here:
The Very First Signs of an Immune Response Have Been Filmed in a Developing Embryo - ScienceAlert

Gorgeous little Arlo McArthur looks the picture of health and happiness.

Loved and adored by his family this little lively three-year-old from Milngavie is spoiled rotten by his three big sisters and his ultimate day out is playing golf with his daddy.

But behind the cheeky grin lies a devastating truth - he's a "ticking-timebomb" and needs a stem cell transplant to save his life.

So today, we've joined with Arlo's mum Nicole, dad Ian and his three doting sisters Carys, Brooke and Holly in asking Glasgow Live readers to step up and help this brave little boy.

They need young men, between 16 and 30 to volunteer to be tested to see if they are a match for the toddler. There's not much to it, a simple swab test carried out at home is enough for the experts to determine if you're a match.

The more people who register to be tested the better chance there is of finding the ideal candidate willing to donate the bone marrow little Arlo desperately needs.

For this family your help could mean the difference between life and death.

They've lived with the knowledge since he was 10 weeks old that a rare genetic condition could rob their precious little boy of his future.

Diagnosed with Wiskott-Aldrich Syndrome, it means Arlo's immune system doesn't function properly and it's difficult for his bone marrow to produce platelets, making him prone to bleeding.

Its estimated there are between 1 and 10 cases per million males worldwide. Arlo was only the third case at Queen Elizabeth University Hospital.

Doctors say they cant take the risk with an older donor as he was lucky to survive a previous transplant which failed when he was a baby.

His back-up is his dad Ian, 31, but he's only a half-match.

Sadly little Arlo's story isn't unique, across the country 2,300 people a year need a stem cell transplant and charity Anthony Nolan coordinates the search and raises money to support their vital work.

Nicole, 37, dreams of seeing her little boy attend his first day at school next August and believes someone out there can help that dream come true.

She pleaded: "Were asking as many people as possible to register and help give Arlo the life he deserves.

"We want to love and enjoy having our little boy around for a long time. He should be able to live out his life of dreams.

"Put yourself in the shoes of a parent whose child is ill, or someone else who is about to lose a loved one. Youve just been told in a room that they wont make it without stem cells. How does it feel?

"Its not just our Arlo, there are plenty of Arlos out there who need your help."

"People don't realise how easy it is to do. It's not this big operation, just a few injections and a day at an out-patient clinic to save someone's life. I wish it was opt-out, like organ donation.

"We dont have much time but I know in my heart the right match is out there."

To find out how you can can join the register and help the fight to save little Arlo and others just like visit Anthony Nolan's website here.

Read more from the original source:
Arlo's Army needs stem cell donor as mum begs for help to save three-year-old's life - Glasgow Live

TOKYO and BOTHELL, Wash., Feb. 12, 2021 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN) today announced primary results from the phase 3 EV-301 trial comparing PADCEV (enfortumab vedotin-ejfv) to chemotherapy in adult patients with locally advanced or metastatic urothelial cancer who were previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. At the time of pre-specified interim analysis, patients who received PADCEV in the trial lived a median of 3.9 months longer than those who received chemotherapy. Median overall survival was 12.9 vs. 9.0 months, respectively (HR=0.70 [95 percent Confidence Interval (CI): 0.56-0.89], p=0.001). For patients in the PADCEV arm of the trial, maculopapular rash, fatigue and decreased neutrophil count were the most frequent Grade 3 or greater treatment-related adverse events (TRAEs) occurring in more than 5 percent of patients.

Urothelial cancer is the most common type of bladder cancer and can also be found in the renal pelvis, ureter and urethra.1

Thefindings were published in the New England Journal of Medicine and presented during the virtual scientific program of the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) (Abstract 393).

"Improving survival is especially meaningful in patients who have had their cancer progress following chemotherapy or other treatment," said Daniel P. Petrylak, M.D., Professor of Medicine and of Urology, Yale Cancer Center, and corresponding author of the published study.

"Enfortumab vedotin is the first medicine to reduce the risk of death compared to chemotherapy in patients with locally advanced or metastatic urothelial cancer who have received a platinum-containing chemotherapy and an immunotherapy," said Professor Thomas Powles, M.D., Director, Barts Cancer Centre, Queen Mary University of London, who presented results at ASCO GU.

Patients who received PADCEV in the trial also showed improvement in the following secondary endpoints:

Other safety findings included:

"Patients who received PADCEV lived longer than those who received chemotherapy an important finding, especially in light of the high unmet need faced by people with advanced urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas.

"Since its accelerated approval by the FDA in late 2019, physicians have adopted PADCEV into their practice, and these confirmatory results provide additional evidence of its benefit for people living with advanced bladder cancer," said Roger Dansey, M.D., Chief Medical Officer, Seagen.

Results of EV-301 are expected to be submitted to the U.S. Food and Drug Administration by the end of March as the confirmatory trial following the drug's accelerated approval in 2019. The results of EV-301 will also be included in submissions to global health authorities.

About Urothelial Cancer Urothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.1 Globally, approximately 549,000 new cases of bladder cancer and 200,000 deaths are reported annually.2

About the EV-301 Trial The EV-301 trial (NCT03474107) is a global, multicenter, open-label, randomized phase 3 trial designed to evaluate enfortumab vedotin versus physician's choice of chemotherapy (docetaxel, paclitaxel or vinflunine) in approximately 600 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/L1 inhibitor and platinum-based therapies. The primary endpoint is overall survival and secondary endpoints include progression-free survival, overall response rate, duration of response and disease control rate, as well as assessment of safety/tolerability and quality-of-life parameters.

About PADCEV (enfortumab vedotin-ejfv) PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA's Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.3

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.3,4 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).4 PADCEV is co-developed by Astellas and Seagen.

PADCEV Important Safety Information

Warnings and Precautions

Adverse Reactions Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab Abnormalities In one clinical trial, Grade 3-4 laboratory abnormalities reported in 5% were: lymphocytes decreased (10%), hemoglobin decreased (10%), phosphate decreased (10%), lipase increased (9%), sodium decreased (8%), glucose increased (8%), urate increased (7%), neutrophils decreased (5%).

Drug Interactions

Specific Populations

For more information, please see the full Prescribing Information for PADCEV here.

About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+ healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at https://www.astellas.com/en.

About Seagen Seagen Inc. is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people's lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on our marketed products and robust pipeline, visit http://www.seagen.com and follow @SeagenGlobal on Twitter.

About the Astellas and Seagen Collaboration Astellas and Seagen are co-developing enfortumab vedotin under a collaboration that was entered into in 2007 and expanded in 2009.

Astellas Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release is not intended to constitute an advertisement or medical advice.

Seagen Forward Looking Statements Certain statements made in this press release are forward looking, such as those, among others, relating to the submission of data from the EV-301 trial for presentation at an upcoming scientific congress; intended regulatory actions, including plans to submit the results of the EV-301 trial to the FDA as the confirmatory trial following the drug's accelerated approval in the U.S. and plans to seek global registrations; and the therapeutic potential of PADCEV, including its efficacy, safety and therapeutic uses. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the possibilities that we may experience delays in the submission of results to the FDA; that the results from the EV-301 trial may not be sufficient to convert PADCEV's accelerated approval in the U.S. to regular approval or to support any other global registrations; that, even if PADCEV receives regular approval in the U.S. or any other global registrations, the product labeling may not be as broad or desirable as anticipated; that ongoing and subsequent clinical trials may fail to establish sufficient efficacy; that adverse events or safety signals may occur; and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seagen is contained under the caption "Risk Factors" included in the company's Annual Report on Form 10-K for the year ended December 31, 2020filed with the Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

References

1American Society of Clinical Oncology. Bladder cancer: introduction (5-2019). https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed January 27, 2021. 2Cancer today: data visualization tools for exploring the global cancer burden in 2020. https://gco.iarc.fr/today/home. Accessed January 27, 2021. 3PADCEV [package insert] Northbrook, IL: Astellas Pharma Inc. 4Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76(10):3003-13.

SOURCE Astellas Pharma Inc.

http://www.us.astellas.com

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Astellas and Seagen Announce Phase 3 Trial Results Demonstrating Survival Advantage of PADCEV (enfortumab vedotin-ejfv) in Patients with Previously...

Introduction

Head and neck squamous cell carcinoma (HNSCC) is one of the major causes of cancer-associated illness and death, with more than 600,000 newly diagnosed cases worldwide each year1 and a continuously increasing incidence rate.2 HNSCC includes cancers of the oral cavity, pharynx, and larynx. The anatomical structures of the head and neck can be damaged by the tumor itself or treatments such as surgical resection and chemoradiotherapy, which sometimes cause speech, swallowing, and breathing impairments.3,4 Patients with HNSCC have been shown to bear greater psychological distress than those with other types of cancer.5

Despite the currently available therapies, patients with advanced HNSCC still experience poor outcomes.68 For example >50% of patients with locoregionally advanced HNSCC experience recurrence or metastases development within 3 years of treatment.911 Treatment options for patients with the recurrent and metastatic disease following progression after a platinum-based regimen are limited, and the median overall survival of such patients is less than 7 months.1215

The recurrence and metastasis of HNSCC are facilitated by immune evasion;16 therefore, as one of the methods to inhibit immune evasion, the use of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway inhibitors is considered effective in the treatment of recurrent HNSCC.1719 Nivolumab, a fully human IgG4 antiPD-1 monoclonal antibody, has shown remarkable antitumor efficacy and safety when administered to patients with recurrent HNSCC whose disease had progressed within 6 months of platinum-based chemotherapy;19 Furthermore, nivolumab treatment has been shown to improve the quality of life of these patients.20 However, PD-1 inhibitors can upregulate T cells in vivo, which may lead to the development of graft-versus-host disease (GVHD) in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).2123 To the best of the authors knowledge, no studies have investigated the safety and efficacy of nivolumab in patients with HNSCC after allo-HSCT. Here, we report the case of a patient who experienced excellent control of left buccal squamous cell carcinoma with nivolumab after the failure of platinum-based chemotherapy despite receiving allogeneic bone marrow transplantation.

Without any family history of tumor, a 33-year-old man was diagnosed with Philadelphia chromosome-positive T cell acute lymphoblastic leukemia on March 19, 2014. He received one course of vincristine and prednisone therapy and four courses of vincristine, daunorubicin, cyclophosphamide, and prednisone therapy. He was in complete remission at the end of therapy. Subsequently, allogeneic bone marrow transplantation was performed; the donor was his human leukocyte antigen (HLA)-haploidentical sibling (sister). He experienced chronic GVHD (c GVHD) of the oral cavity and skin 3 months after transplantation, for which he was treated with steroid hormone- and cyclosporine-based therapies. Skin rejection lasted for more than 3 years. Imatinib mesylate was administered for 2 years after transplantation, and his leukemia was well controlled.

In August 2018, the patient developed an ulcer of approximately 0.5 0.5 cm size in the left buccal mucosa; the ulcer was slightly painful and covered with white moss. In September 2018, the patient was admitted to Peking University Stomatological Hospital, where a biopsy of the buccal mucosa was performed. The pathology results showed the presence of squamous cell carcinoma in the left cheek. Unfortunately, this patient was not a right candidate for HNSCC in terms of exposure to risk factors, such as long terms of smoking and drinking. On October 10, 2018, 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (CT) showed that the mass in the left cheek was metabolically active, which is consistent with the activity of a malignant tumor. One course of an adjuvant therapy regimen (nimotuzumab [200 mg d0] + docetaxel [60 mg d1, 8]+ nedaplatin [60 mg d2, 3]) was administered on October 26, 2018. Following this, the patient developed degree II thrombocytopenia and redness, swelling, and ulceration of the cheek, which had discharge with a peculiar smell. On November 29, 2018, a head and neck CT scan showed a left buccal malignant tumor with the destruction of the neighboring mandibular bone and lymph node enlargement in the left submaxillary region and right carotid sheath. The CT examination revealed disease progression. Following a multidisciplinary consultation in our hospital, surgery was not recommended; instead, a chemotherapy-based comprehensive treatment was recommended as a better option for the patient. The patient received chemotherapy with albumin paclitaxel (200 mg d1, 8)+ bleomycin (15,000 units d2, 9) from November 30, 2018 to January 9, 2019. On another CT scan, the curative effect was evaluated as partial remission (showed in Video 1, Figure 1A); subsequently, two courses of a chemotherapy regimen comprising nivolumab (140 mg d1) + albumin paclitaxel (200 mg d1, d8) were administered. A CT examination showed stable disease (SD) on March 12, 2019, following which the patient was administered 120 mg of nivolumab once every 2 weeks from March 15 to May 23, 2019. Another CT examination was performed on May 28, 2019 (showed in Video 2, Figure 1B). During the therapy course, the related tumor markers showed an overall downward trend, the new metastases did not appear, the patients status became better than before. Subsequently, another CT examination performed in August 02, 2019 showed the extent of the tumor was obvious reduction than before (showed in video 3, Figure 1C). And the corresponding CT report in August 02, 2019 was described as follows Compared with the CT on 28 May, 2019, the extent of the tumor in the left cheek became obviously smaller, the tubercle in the left submandibular and the lymph nodes in the left neck also became smaller. There were no other significant changes in this image. Most importantly, the patient did not develop any form of GVHD following nivolumab administration.

Figure 1 Head and neck CT images showing tumor before (A) and after treatment with nivolumab (B, C, respectively).

Abbreviation: CT, computed tomography.

Note: The arrows indicate the maximum length diameter of tumor or tumor site.

Reliable data on the clinical safety and efficacy of nivolumab in the treatment of recurrent or metastatic HNSCC have been obtained in a Phase III randomized clinical trial (CheckMate 141).19 In this trial, 361 patients with recurrent HNSCC for whom disease had progressed within 6 months after platinum-based chemotherapy were enrolled between May 29, 2014, and July 31, 2015. The median follow-up duration for overall survival (OS) was 5.1 months (range, 016.8 months). OS was significantly greater in patients randomized to receive nivolumab than in those who received standard second-line, single-agent systemic therapy with either methotrexate, docetaxel, or cetuximab (hazard ratio, 0.70; 97.73% confidence interval (CI), 0.510.96; P = 0.01). The median OS was 7.5 months (95% CI, 5.59.1) in the nivolumab group versus 5.1 months (95% CI, 4.06.0) in the standard therapy group. The one-year survival was also greater in patients who received nivolumab than in those who received standard therapy (36.0%vs. 16.6%). Furthermore, the response rate was higher in those who received nivolumab than in those who received standard therapy (13.3% vs 5.8%); however, the median progression-free survival was not significantly different between the groups (2.0 vs 2.3 months; P=0.32). In this study, patients who were treated with nivolumab had a longer OS than those treated with standard therapy, regardless of tumor PD-L1 expression or p16 status. Grade 3 or 4 treatment-related adverse events occurred in 13.1% of patients who received nivolumab and 35.1% of those who received standard therapy. Physical function, role functioning, and social functioning were stable in the nivolumab group, whereas they were substantially worse in the standard therapy group.20 Moreover, among Asian patients, the survival benefits were consistent with the global group.24

It was unclear whether nivolumab could be used in patients with recurrent HNSCC after allo-HSCT, though Khaddour et al proved the efficacy and safety of Pembrolizumab in patients who underwent allo-HSCT after relapsed and refractory Szary Syndrome and cutaneous squamous cell carcinoma.25 However, some case reports (Table 1) and clinical trials (Table 2) have reported the efficacy and safety of nivolumab when administrated to patients with recurrent hematological malignancies (mostly Hodgkins lymphoma) after allo-HSCT.

Table 1 Case Reports of Nivolumab Use After Allo-HSCT

Table 2 Studies on Nivolumab Use After Allo-HSCT

In Herbaux et al, nivolumab (3 mg/kg, once every 2 weeks) was administered to 20 patients with Hodgkins lymphoma who experienced relapse after allo-HSCT. The overall response rate was 95%, the 1-year progression-free survival rate was 58.2%, and the 1-year OS rate was 78.8%.26 Compared with other treatment options, nivolumab was more effective in these patients.2730 Haverkos et al reported results after a median follow-up duration was 428 days (range, 133833 days). After treatment with PD-1 inhibitors [nivolumab 3 mg/kg, once every 2 weeks (n = 28) and pembrolizumab (n =3)], the overall response rate of 31 patients with relapsed lymphoma after allo-HSCT was 77%, the median progression-free survival was 591 days (range,400644 days), and 68% of the patients survived to the end of the study.23 These two studies showed that nivolumab is effective when administered to patients with recurrent blood cancers after allo-HSCT, which is consistent with the results of several other case reports3134 and case series.35,36 The PD-1/PD-L1 pathway plays a key role in the regulation of the balance among T cell activation, T-cell tolerance, and immune-mediated tissue damage. This pathway protects healthy cells from excessive inflammatory or autoimmune responses.37,38 Some studies have shown that the activation of the PD-1/PD-L1 pathway can reduce acute and chronic GVHD, whereas its blockade can accelerate the graft-versus-host response and increase the associated mortality.21,22,39 It is unclear whether the PD-1 inhibitor nivolumab increases the risk of GVHD and the associated mortality in patients after allo-HSCT.23,26 Some clinical studies and case reports have shown that nivolumab treatment-related GVHD and consequent death in patients after allo-HSCT might be affected by the following factors. First, GVHD after antiPD-1 treatment has been observed most frequently in matched sibling donor transplants; for which Haverkos et al reported an incidence of 75%.23 In a Phase I pilot study, without GVHD or G3/G4 immune toxicity after receiving multiple doses of nivolumab was only among one patient whose donor source was Haploidentical+cord blood Fludarabine.40 Second, a history of GVHD, especially for the acute GVHD, may lead to an increased risk of nivolumab treatment-related GVHD after allo-HSCT. In a French cohort, all patients who presented with acute GVHD after nivolumab treatment had a prior history of acute GVHD, among which three patients presented with steroid-refractory nivolumab-induced GVHD, and GVHD was not observed among patients without a history of GVHD.26 This phenomenon was also observed in Steinerovs medical report.41 In the study by Haverkos et al, 63% of patients with a history of GVHD prior to antiPD-1 treatment developed treatment-emergent GVHD after receiving antiPD-1.23 Third, the shorter the interval between transplantation and nivolumab use, the greater the risk of GVHD. In the study by Herbaux et al, the median intervals between transplantation and nivolumab use in cases with the presence and absence of GVHD were 8.5 months and 28.5 months, respectively.26 In another study by Wang et al, the reported four patients all experienced immune-related adverse events following nivolumab treatment and the median time from transplantation to nivolumab use was 7.8 months.40 Fourth, dose is a risk factor for nivolumab treatment-related GVHD. In a case report, chronic skin GVHD was observed when the dose of nivolumab was adjusted from 0.5 mg/kg to 2 mg/kg.33 Other factors, such as immunosuppressive therapy at the time of nivolumab administration, may also influence nivolumab treatment-related GVHD. Recently, a comprehensive literature review was launched by Awais et al to assess the safety and efficacy of the use of checkpoint inhibitors (ipilimumab, nivolumab and pembrolizumab) in blood cancers before and after allo-HSCT. Collective data showed that checkpoint inhibitors use after allo-HSCT for post-transplant relapse had higher efficacy but the risk of GVHD was significant. Moreover, the investigation indicated that higher drug doses, shorter intervals between checkpoint inhibitors exposure and allo-HSCT and prior history of GVHD had a positive correlation with the risk of GVHD.42

In the present case, HNSCC was effectively controlled without any nivolumab treatment-related acute or chronic GVHD after nivolumab administration, while the weight loss being the only adverse event. After comprehensive analysis, we found that many factors may impede the development of nivolumab treatment-related GVHD in our patient. On one hand, the appropriate donor, no use of checkpoint inhibitors prior to allo-HSCT, the long interval between nivolumab administration and allo-HSCT (36 months) and the standard dose use of nivolumab were the negative factors for GVHD development. On the other hand, the chronic GVHD of the oral cavity and skin before nivolumab use might lead to the development of GVHD. However, it remained unknown what role the immunosuppressant therapy played in the occurrence of GVHD, though we definitely known that immunosuppressant was administered more than 2 years after allo-HSCT and discontinued for 2 years before treatment with nivolumab in our patient. Finally, whether the two primary cancers in our case affected the efficacy and safety of nivolumab by some unknown pathways were unclear, which needed further exploration.

Nivolumab has been shown to be effective in patients with HNSCC for whom platinum-based therapy has failed. However, little is known about the efficacy and safety of nivolumab in patients with HNSCC who have undergone allo-HSCT. Our case report shows that nivolumab could be used effectively and safely in such patients, however, more clinical trials are required to confirm these results.

This study was approved by the Medical Ethics Committee of Tianjin Medical University Cancer Institute and Hospital. The authors state that they have obtained verbal and written informed consent from the patient for the inclusion of their medical and treatment history within this case report.

This work was supported by the Tianjin Science and Technology Commission (18ZXXYSY00070), Key Task Project of Tianjin Health and Family Planning Commission (16KG128), Anticancer Key Technologies R&D Program of Tianjin (12ZCDZSY16200), and Natural Science Foundation of Tianjin (18JCYBJC91600).

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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2. Jakobsen KK, Gronhoj C, Jensen DH, et al. Increasing incidence and survival of head and neck cancers in Denmark: a nation-wide study from 1980 to 2014. Acta Oncol. 2018;57:11431151. doi:10.1080/0284186X.2018.1438657

3. Sobecki-Ryniak D, Krouse HJ. Head and neck cancer: historical evolution of treatment and patient self-care requirements. Clin J Oncol Nurs. 2013;17(6):659663. doi:10.1188/13.CJON.659-663

4. Licitra L, Mesia R, Keilholz U. Individualised quality of life as a measure to guide treatment choices in squamous cell carcinoma of the head and neck. Oral Oncol. 2016;52:1823. doi:10.1016/j.oraloncology.2015.10.020

5. Singer S, Krauss O, Keszte J, et al. Predictors of emotional distress in patients with head and neck cancer. Head Neck. 2012;34(2):180187. doi:10.1002/hed.21702

6. Licitra L, Felip E. Squamous cell carcinoma of the head and neck: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(Suppl 4):121122. doi:10.1093/annonc/mdp149

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27. Peggs KS, Kayani I, Edwards N, et al. Donor lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for hodgkins lymphoma. J Clin Oncol. 2011;29:971978. doi:10.1200/JCO.2010.32.1711

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[Full text] Successful Use of Nivolumab in a Patient with Head and Neck Cancer Aft | OTT - Dove Medical Press

There is also hope that influenza antivirals such as favipiravir and molnupiravir could be repurposed in the fight against coronavirus, with small trials showing they improve lung function. Large trials are under way, with results expected in the spring.

One clever antiviral treatment in the pipeline is called Recombinant ACE-2. To infect the body, coronavirus uses grippy rods called spike proteins to latch on to the human ACE-2 protein on the outside of cells. In laboratory studies, scientists have shown they can deploy artificial ACE-2 proteins as decoys, thereby luring the virus away from real cells. However, it has yet to be proven in animals or humans.

Drugs that boost the immune system also look promising. Scientists are currently testing whether the blood plasma of recovered patients could improve survival rates. Using the blood of patientsurvivors of an illness dates back to the 1918 Spanish Flu pandemic, before vaccines or antivirals were available. It relies on the fact that the blood of recovered patients contains powerful antibodies already trained to fight the virus.

Last week, a large trial by Oxford showedthat blood plasma does not prevent death in seriously ill patients, but the team is still awaiting a full breakdown of results to see if it benefited certain sub-groups. International trials are also currently testing whether plasma works if used earlier.

Similar to blood plasma, synthetic antibodies are also giving hope. Scientists look for people who have mounted a strong response to coronavirus then artificially replicate their immune proteins.

Eli Lilly's monoclonal antibody bamlanivimab has been shown to reduce people's risk of being hospitalised by 72 per cent compared to a placebo. It is currently under review by the Medicines and Healthcare Products Regulatory Agency (MHRA). Likewise, Regeneron's antibody cocktail reduced visits to hospital by 57 per cent.

Giving monoclonal antibodies as a prophylactic also appears to be beneficial, with bamlanivimab found to reduce the risk of developing coronavirus by 80 per cent for care home residents and staff.

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine (LSHTM), said: "They are the first anti-viral drugs that demonstrably work in the first phase of the disease just after the virus has infected someone but before it has had time to cause a lot of damage."

Another way of boosting immunity is to give patients synthetic interferons. When the body is under attack, it produces molecules called interferons which boost the immune system while also keeping it in check.

Last summer, the British pharma company Synarigen published results showing its inhaled form of interferon "SNG001" lowered the risk of severe Covid-19 in infected patients. Larger studies are ongoing.

For many seriously ill coronavirus patients, the immune system does not need any help, but requires dampening down.The steroid dexamethasone has been shown to cut deaths of severely ill patients by one-third and is now given to severely ill NHS patients as standard.

The rest is here:
The drug treatments offering the best hope of a way out of the Covid crisis - Telegraph.co.uk

Fortunately, many viruses produce an enzyme called an RNA-dependent RNA polymerase. Nearly a decade ago, the pharmaceutical company Gilead began work on a drug called Remdesivir to target the enzyme. It was the first drug rolled out to NHS patients last May, and clinical trials have shown it helps patients get out of hospital four days earlier.

There is also hope that influenza antivirals such as favipiravir and molnupiravir could be repurposed in the fight against coronavirus, with small trials showing they improve lung function. Large trials are under way.

One clever antiviral treatment in the pipeline is called Recombinant ACE-2. Scientists have shown they can deploy artificial ACE-2 proteins as decoys, thereby luring the virus away from real cells. However, it has yet to be proven in animals or humans.

Drugs which boost the immune system also look promising. Scientists are testing whether the blood plasma of recovered patients could improve survival rates. Last week, a large trial by Oxford shows that blood plasma does not prevent death in seriously ill patients, but the team is waiting to see if it benefited certain sub-groups.

Synthetic antibodies are also giving hope. Scientists look for people who have mounted a strong response to coronavirus then artificially replicate their immune proteins.

Eli Lilly's monoclonal antibody bamlanivimab has been shown to reduce people's risk of being hospitalised by 72 per cent and is under review by the Medicines and Healthcare Products Regulatory Agency. Regeneron's antibody cocktail reduced trips to the hospital by 57 per cent. Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, said: "They are the first anti-viral drugs that demonstrably work in the first phase of the disease, just after the virus has infected someone but before it has had time to cause a lot of damage."

Another way of boosting immunity is to give synthetic interferons, which boost the immune system while also keeping it in check. Last year, British pharma company Synairgen published results showing interferon "SNG001" lowered the risk of severe Covid-19.

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In the war against Covid, an arsenal of drugs is on the way - Telegraph.co.uk

PRINCETON, N.J., & ALAMEDA, Calif.--(BUSINESS WIRE)--Bristol Myers Squibb (NYSE: BMY) and Exelixis, Inc. (NASDAQ: EXEL) today announced results from new analyses from the pivotal Phase 3 CheckMate -9ER trial, demonstrating clinically meaningful, sustained efficacy benefits as well as quality of life improvements with the combination of OPDIVO (nivolumab) and CABOMETYX (cabozantinib) compared to sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC). These data will be presented in two posters at the virtual American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium from February 11 to 13, 2021 and featured in the Poster Highlights Session on February 13, 2021 from 9:00 a.m. 9:45 a.m. EST.

Abstract #308: Nivolumab + cabozantinib (NIVO+CABO) vs. sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate -9ER (Motzer, et. al.)

With a median follow-up of two years (23.5 months), OPDIVO in combination with CABOMETYX continued to show superior progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) versus sunitinib, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation. No new safety signals were identified with extended follow-up. Across the full study population:

In an exploratory subgroup analysis of 75 patients with sarcomatoid features, the combination of OPDIVO and CABOMETYX showed benefit in this population typically associated with a poor prognosis, reducing the risk of death by 64% vs. sunitinib (HR 0.36; 95% CI: 0.17 to 0.79) and demonstrating both superior PFS (10.3 months vs. 4.2 months) and ORR (55.9% vs. 22.0%).

Abstract #285: Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: the CheckMate -9ER trial (Cella, et. al.)

In a separate analysis from the CheckMate -9ER trial conducted with 18.1 months of median follow-up, patients treated with the combination of OPDIVO and CABOMETYX reported statistically significant health-related quality of life benefits. Treatment with OPDIVO in combination with CABOMETYX was associated with a lower treatment burden, decreased risk of deterioration and a reduction of disease-related symptoms compared to sunitinib. These exploratory outcomes were measured using Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), a quality of life tool specific to kidney cancer, and EQ-5D-3L instruments.

There is a continued need for new therapies that show benefit across subgroups of patients with advanced renal cell carcinoma, said Robert Motzer, M.D., Kidney Cancer Section Head, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center. In CheckMate -9ER, nivolumab in combination with cabozantinib doubled progression-free survival, increased overall survival and response rate and, in an exploratory analysis, showed impressive disease control, and these promising efficacy results were sustained with extended follow-up. Also of note, patients in this study reported significant quality of life improvements, which are important for patients undergoing treatment for this challenging disease.

These additional data from CheckMate -9ER provide strong evidence that OPDIVO in combination with CABOMETYX may help patients achieve and maintain control of their disease, said Dana Walker, M.D., M.S.C.E., vice president, development program lead, genitourinary cancers, Bristol Myers Squibb. This regimen brings together two proven agents in advanced renal cell carcinoma, and we believe it will play an important role alongside other first-line treatment options. We look forward to the potential to build on our heritage of transforming patient outcomes with OPDIVO-based combinations across a wide range of tumor types.

The overall survival benefit and quality-of-life measures reported in these findings continue to show improvement with the combination of CABOMETYX and OPDIVO after an extended follow-up of two years, said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. These new findings from CheckMate -9ER and the recent FDA approval of the combination regimen are extremely encouraging as we further explore the potential of CABOMETYX in combination with immunotherapies to help more patients with difficult-to-treat tumor types.

OPDIVO in combination with CABOMETYX was approved for the first-line treatment of advanced RCC by the U.S. Food and Drug Administration (FDA) in January 2021, and further applications are under review with health authorities globally.

Bristol Myers Squibb and Exelixis thank the patients and investigators involved in the CheckMate -9ER clinical trial.

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized, multi-national Phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L11%) were randomized to receive OPDIVO plus CABOMETYX (n=323) vs. sunitinib (n=328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS) and objective response rate (ORR). The primary efficacy analysis is comparing the doublet combination vs. sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 179,000 deaths worldwide each year. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. The five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 13%.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision transforming patients lives through science. The goal of the companys cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patients life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About OPDIVO

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the bodys own immune system to help restore anti-tumor immune response. By harnessing the bodys own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivos leading global development program is based on Bristol Myers Squibbs scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Companys Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

OPDIVO INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is 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 benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is 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 benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is 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 benefit in the confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is 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 benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 10% (5/49) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%) and Grade 2 (5%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO monotherapy in Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients. In patients receiving OPDIVO 1 mg/ kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%) and Grade 2 (2.5%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushings syndrome.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated rash occurred in 15% (76/511) of patients, including Grade 3-5 (2.5%) and Grade 2 (12%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.

In separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg monotherapy, infusion-related reactions occurred in 2.9% (28/982) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in 2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=154). The most frequent serious adverse reactions reported in 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, pneumonia, and anemia. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in 4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in 2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 227, the most common (20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigators choice. In Checkmate 275, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Checkmate 238, the most common adverse reactions (20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Attraction-3, the most common adverse reactions (20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%).

In a separate Phase 3 trial of YERVOY 3 mg/kg, the most common adverse reactions (5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

Clinical Trials and Patient Populations

Checkmate 037previously treated metastatic melanoma; Checkmate 066previously untreated metastatic melanoma; Checkmate 067previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 227previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LApreviously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 017second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 743previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 214previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ERpreviously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025previously treated renal cell carcinoma; Checkmate 205/039classical Hodgkin lymphoma; Checkmate 141recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275urothelial carcinoma; Checkmate 142MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040hepatocellular carcinoma, as a single agent or in combination with YERVOY; Checkmate 238adjuvant treatment of melanoma; Attraction-3esophageal squamous cell carcinoma

CABOMETYX INDICATIONS

CABOMETYX(cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

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OPDIVO (nivolumab) in Combination with CABOMETYX (cabozantinib) Shows Sustained Survival and Response Rate Benefits as First-Line Treatment for...