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FDA Issues Final Guidance on Animal Drug Compounding from Bulk Drug Substances

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FDA Issues Final Guidance on Animal Drug Compounding from Bulk Drug Substances

April 13, 2022: “The U.S. FDA issued a final guidance, entitled “Compounding Animal Drugs from Bulk Drug Substances,” that will help protect animal health by recognizing the need for access to certain compounded animal drugs.

The guidance describes the agency’s approach to situations where veterinarians use unapproved compounded drugs to provide appropriate care for the medical needs of the diverse species they treat.

The FDA recognizes that this final guidance covers a wide range of stakeholders and plans to focus on education and stakeholder engagement before shifting resources toward inspectional activities in Fiscal Year 2023.

We will take appropriate actions, as we currently do, when compounding practices threaten human or animal health.

Animal drug compounding is the process of combining, mixing or altering ingredients to create a medication tailored to the needs of an individual animal or a small group of animals.

Animal drug compounding using an FDA-approved drug as the starting point is already allowed under existing law and regulations.

Animal drugs compounded from bulk drug substances are not FDA-approved and the agency has not evaluated them to ensure that they are safe, effective, properly manufactured to ensure consistent quality, and the labeling is complete and accurate.

“We are taking this step because we recognize the need for veterinarians to have access to compounded animal drugs that aren’t available as approved products and that would make a clinical difference in patient care,” said Steven M. Solomon, D.V.M., M.P.H., director of the FDA’s Center for Veterinary Medicine.

“We believe this policy strikes the right balance between maintaining access to drugs veterinarians need to treat diverse animal populations, while ensuring human and animal health is protected from poorly-compounded products, or ones that attempt to copy existing FDA-approved drugs.” 

There are more than 1,600 drugs that are FDA-approved, conditionally approved or indexed for use in animals, as well as approximately another 20,000 FDA-approved human drugs that could be prescribed for animal use.

At the same time, there are many different species of animals, each with various diseases and conditions for which no suitable FDA-approved or indexed drugs are available for which access to compounded animal drugs may be necessary. 

The FDA released this guidance in 2019 and received comments from veterinarians, pharmacy compounders and other stakeholders.

In response, the agency has made significant changes to the final guidance to recognize flexibilities for veterinarians to access animal drugs compounded from bulk drug substances for those animals that need them. 

The final guidance:

  • Addresses compounding of unapproved animal drugs from bulk drug substances, which is the practice of preparing a medication without using an FDA-approved or indexed drug as the starting point. 
  • Outlines flexibilities for pharmacists and veterinarians who compound animal drugs from bulk drug substances for individual patients, as well as for those essential drugs needed for immediate or emergency use that they need to keep in their inventory (also known as “office stock”). 
  • Balances the need for accessing animal drugs compounded from bulk drug substances for the patients that need them, while also providing ways to better identify safety issues associated with compounded products.
  • Describes the types of animal drugs compounded from bulk drug substances that the FDA believes pose the greatest risk to human and animal health. The agency will prioritize these products for enforcement action, as well as those made under poor compounding practices. 
  • Explains FDA’s policy on animal drugs compounded from bulk drug substances that are copies (same active ingredient and route of administration) of marketed FDA-approved or indexed drugs.
    The agency generally intends to prioritize these products for enforcement action when the compounding pharmacy has not recorded a medical rationale for prescribing a copy instead of an FDA-approved or indexed drug.

The FDA understands there may be many questions about the final guidance and has committed to a proactive outreach and education period for veterinarians and animal drug compounding pharmacies as part of implementation.

During this period, the FDA will continue meeting with interested stakeholders to discuss the new guidance and address questions about content and implementation.

The agency has also created a library of tools to help inform stakeholders on details of the policy.”

https://www.fda.gov/news-events/press-announcements/fda-issues-final-guidance-animal-drug-compounding-bulk-drug-substances

FDA Takes Important Steps to Increase Racial and Ethnic Diversity in Clinical Trials

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FDA Takes Important Steps to Increase Racial and Ethnic Diversity in Clinical Trials

April 13, 2022: “The U.S. FDA issued a new draft guidance to industry for developing plans to enroll more participants from underrepresented racial and ethnic populations in the U.S. into clinical trials –  expanding on the agency’s previous guidances for industry to improve clinical trial diversity.

“The U.S. population has become increasingly diverse, and ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health,” said FDA Commissioner Robert M. Califf, M.D.

“Going forward, achieving greater diversity will be a key focus throughout the FDA to facilitate the development of better treatments and better ways to fight diseases that often disproportionately impact diverse communities.

This guidance also further demonstrates how we support the Administration’s Cancer Moonshot goal of addressing inequities in cancer care, helping to ensure that every community in America has access to cutting-edge cancer diagnostics, therapeutics and clinical trials.” 

Despite having a disproportionate burden for certain diseases, racial and ethnic minorities are frequently underrepresented in biomedical research.

Clinical trials provide a crucial base of evidence for evaluating whether a medical product is safe and effective; therefore, enrollment in clinical trials should reflect the diversity of the population that is ultimately going to use the treatment.

It is known that biological differences exist in how people respond to certain therapies. For example, variations in genetic coding can make a treatment more or less toxic for one racial or ethnic group than another.

These variations can also make drugs like antidepressants and blood-pressure medications less effective for certain groups. 

This draft guidance, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Subgroups in Clinical Trials,” recommends that sponsors of medical products develop and submit a Race and Ethnicity Diversity Plan to the agency early in clinical development, based on a framework outlined in the guidance. 

Barriers to participation among racial and ethnic groups may include mistrust of the clinical research system due to historical abuses, aspects of the trial design such as inadequate recruitment and retention efforts, frequency of study visits, time and resource constraints for participants, transportation and participation conflicting with caregiver or family responsibilities.

In addition, language and cultural differences, health literacy, religion, limited access within the health care system and a lack of awareness and knowledge about what a clinical trial is and what it means to participate may impact clinical trial participation among racial and ethnic minority populations.  

The FDA remains committed to increasing enrollment of diverse populations in medical product and drug development and will continue to engage with federal partners, medical product manufacturers, healthcare professionals and health advocates to reach this important goal. 

To support the FDA’s efforts to advance diverse participation, the Office of Minority Health and Health Equity created the “Diversity in Clinical Trials Initiative,” which includes an ongoing public education and outreach campaign to help address some of the barriers preventing diverse groups from participating in clinical trials.

Barriers to participation are addressed through a variety of culturally and linguistically tailored strategies, tools and resources such as: educational materials in multiple languages, a dedicated webpage with public service announcements and videos, social media outreach and ongoing stakeholder engagement, collaborations and partnerships. 

In February, the Biden Administration revived the Cancer Moonshot initiative to further expand cancer prevention, detection, research and patient care efforts across the federal government.

The FDA Commissioner serves as a member of the White House Cancer Cabinet, comprised of departmental agencies and components organized to develop a unified strategy in the fight against the disease.

One of the goals of the Cancer Moonshot is to address inequities in access to cancer screening, diagnostics and treatment across race, gender, region and resources.

The FDA’s guidances on increasing diversity in clinical trials are aligned with the Cancer Moonshot goals. 

The draft guidance was developed by the Oncology Center of Excellence’s Project Equity, which aims to ensure that the data submitted to the FDA for approval of oncology medical products adequately reflects the demographic representation of participants for whom the medical products are intended.

As this guidance applies to all medical products, the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health also contributed to this collaborative effort.”

https://www.fda.gov/news-events/press-announcements/fda-takes-important-steps-increase-racial-and-ethnic-diversity-clinical-trials

ISA Pharmaceuticals announces novel technology for cancers

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ISA Pharmaceuticals announces novel technology for cancers

April 14, 2022: “ISA Pharmaceuticals announces that a clinical trial using ISA’s novel AMPLIVANT® adjuvant technology has started.

The trial, run by partner Scancell Holdings plc (AIM: SCLP, “Scancell”) is a multicentre clinical trial, testing the Moditope® vaccine Modi1.

This first-in-human clinical trial brings Modi-1 to patients with triple negative breast cancer, ovarian cancer, head and neck cancer, and renal cancer using the AMPLIVANT® adjuvant technology to boost immune response to the therapy.  

The main study is an open label clinical trial. The initial part of the trial will assess the safety and immunogenicity of Modi-1.

In addition, the effect of Modi-1 in promoting T-cell infiltration into the tumour will be assessed in a neoadjuvant cohort of patients with head and neck cancer treated with Modi-1, randomised to treatment with or without a checkpoint inhibitor, prior to the first surgical resection.

The Modi-1 peptides are linked to AMPLIVANT®, a potent adjuvant and toll-like receptor (TLR) 1/2 agonist, which enhances the immune response 10-100 fold, resulting in highly efficient tumour clearance, including protection against tumour recurrence, in preclinical models.

AMPLIVANT® is the subject of a worldwide non-exclusive licensing and collaboration agreement with Scancell for the manufacturing, development, and commercialisation of Modi-1.

Professor Kees Melief, Chief Scientific Officer, ISA Pharmaceuticals, commented: “Adjuvants are crucial components of vaccines which boost efficacy, however there is lack of new, innovative, and effective adjuvants in development to add to a limited armamentarium.

As such this is an important achievement and highlights the productive collaboration, we have with Scancell.

The trial provides a further opportunity to demonstrate the potent adjuvant properties that AMPLIVANT® confers on therapeutic vaccines to potentially benefit patients with a broad range of solid tumours.”

Professor Lindy Durrant, Chief Executive Officer, Scancell, commented: “This is the first time we have taken a product from our Moditope® platform into cancer patients and is a major step forward for Scancell and our collaboration with ISA Pharmaceuticals. We are very excited about the prospects for Modi-1 based on the dramatic regression of large tumours in our preclinical models.”

Amplivant ® is a registered trademark in Europe”

https://www.isa-pharma.com/isa-pharmaceuticals-announces-the-start-of-clinical-trial-using-its-novel-amplivant-technology/

GSK reaches agreement to acquire late-stage biopharmaceutical company Sierra Oncology for $1.9bn

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GSK reaches agreement to acquire late-stage biopharmaceutical company Sierra Oncology for $1.9bn

April 13, 2022: “GlaxoSmithKline and Sierra Oncology announced that the companies have entered into an agreement under which GSK will acquire Sierra Oncology, a California-based, late-stage biopharmaceutical company focused on targeted therapies for the treatment of rare forms of cancer, for $55 per share of common stock in cash representing an approximate total equity value of $1.9 billion (£1.5 billion).

Myelofibrosis is a fatal cancer of the bone marrow impacting the normal production of blood cells.

Anaemia represents a high unmet medical need in patients with myelofibrosis.

At diagnosis, approximately 40% of patients are already anaemic, and it is estimated that nearly all patients will eventually develop anaemia.

Patients treated with the most commonly used JAK inhibitor will often require transfusions, and more than 30% will discontinue treatment due to anaemia.

Anaemia and transfusion dependence are strongly correlated with poor prognosis and decreased overall survival.

Momelotinib has a differentiated mode of action with inhibitory activity along key signalling pathways.

This activity may lead to beneficial treatment effects on anaemia and reduce the need for transfusions while also treating symptoms. In January 2022, Sierra Oncology announced positive topline results from the MOMENTUM phase III trial.

The study met all its primary and key secondary endpoints, demonstrating that momelotinib achieved a statistically significant and clinically meaningful benefit on symptoms, splenic response, and anaemia.

Luke Miels, Chief Commercial Officer, GSK said: “Sierra Oncology complements our commercial and medical expertise in haematology.

Momelotinib offers a differentiated treatment option that could address the significant unmet medical needs of myelofibrosis patients with anaemia, the major reason patients discontinue treatment.

With this proposed acquisition, we have the opportunity to potentially bring meaningful new benefits to patients and further strengthen our portfolio of specialty medicines.”

Stephen Dilly, MBBS, PhD, President and Chief Executive Officer, Sierra Oncology said: “Uniting with GSK creates the best opportunity for Sierra Oncology to realise its mission of delivering targeted therapies that treat rare forms of cancer while also delivering compelling and certain value for our stockholders.

Now we have a partner with a global infrastructure and oncology expertise that enables us to deliver momelotinib to patients as quickly as possible and on a global scale.”

Momelotinib complements GSK’s Blenrep (belantamab mafodotin), building on GSK’s commercial and medical expertise in haematology.

The proposed acquisition aligns with GSK’s strategy of building a strong portfolio of new specialty medicines and vaccines.

If the transaction is completed and momelotinib is approved by regulatory authorities, GSK expects momelotinib will contribute to GSK’s growing specialty medicines business, with sales expected to begin in 2023, with significant growth potential and a positive benefit to the Group’s adjusted operating margin in the medium term.

Financial considerations

Under the terms of the agreement, the acquisition will be effected through a one-step merger in which the shares of Sierra Oncology outstanding will be cancelled and converted into the right to receive $55 per share in cash.

Subject to customary conditions, including the approval of the merger by at least a majority of the issued and outstanding shares of Sierra Oncology, and the expiration or earlier termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, the transaction is expected to close in the third quarter of 2022 or before.

The per share price represents a premium of approximately 39 per cent to Sierra Oncology’s closing stock price on 12 April 2022 and a premium of approximately 63 per cent to Sierra’s volume-weighted average price (VWAP) over the last 30 trading days.

Sierra Oncology’s Board of Directors has unanimously recommended that Sierra’s stockholders vote in favour of the approval of the merger.

Additionally, stockholders of Sierra Oncology holding approximately 28 per cent of Sierra’s outstanding shares, have agreed to vote their shares in favour of approval of the merger.

GSK will account for the transaction as a business combination and expects it to be accretive to adjusted EPS in 2024, the expected first full year of momelotinib’s sales.

New GSK reaffirms its full-year 2022 guidance, the medium-term outlook for 2021-2026 of more than 5% sales and 10% adjusted operating profit CAGR* at CER**, and long-term sales ambition.

The value of the gross assets of Sierra Oncology to be acquired (as of 31 December 2021) is $109 million (£83 million at the rate of £1 = $1.312, being the 31 March 2022 spot rate).

The net losses of the business were $95 million for the 12 months ended 31 December 2021 (£70 million, at the rate of £1 = $1.38, being the average rate for the period).”

https://www.gsk.com/en-gb/media/press-releases/gsk-reaches-agreement-to-acquire-late-stage-biopharmaceutical-company-sierra-oncology-for-19bn/

FDA and DEA Warn Online Pharmacies Illegally Selling Adderall to Consumers

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FDA and DEA Warn Online Pharmacies Illegally Selling Adderall to Consumers

April 12, 2022: “The U.S. FDA and the U.S. Drug Enforcement Administration recently issued joint warning letters to operators of two websites illegally selling Schedule II stimulants, including amphetamine drug products marketed as Adderall.

These websites sell Adderall online without a prescription, which places consumers at risk. 

Adderall is an FDA-approved prescription drug that has a high potential for abuse and addiction and should only be used under the supervision of a licensed health care professional.

This joint action demonstrates the federal government’s ongoing commitment to reduce the public health danger posed by drugs illegally sold online. 

“This action underscores the FDA’s commitment to use all available regulatory and compliance tools to stop online businesses illegally selling potentially harmful drug products to consumers,” said FDA Commissioner Robert M. Califf, M.D.

“The illegal sale of prescription drug stimulants online puts Americans at risk and contributes to potential abuse, misuse and overdose.

These particular types of online pharmacies also undermine our efforts to help consumers safely purchase legitimate prescription medicines over the internet.  

FDA will continue partnering with DEA in an effort to safeguard public health and protect consumers who need access to these important medicines.”

Illegally marketed prescription drugs pose significant risks to consumers who purchase those products.

Consumers who buy prescription drugs from unsafe online pharmacies may put their health at risk because the products, while being marketed as authentic, may be counterfeit, contaminated, expired or otherwise harmful. 

The warning letters were issued to: 

  • Kubapharm.com
  • Premiumlightssupplier.com 

Consumers should dispose of unused medicine from these websites and not purchase or use prescription drugs sold from these websites without a prescription.

The FDA urges consumers to obtain prescription drugs from state-licensed U.S. pharmacies or physicians located in the United States, where the FDA and state authorities can assure the quality of drug manufacturing, packaging, distribution, and labeling.

“These letters are not only a warning to the companies that illegally sell prescription medications, but they also serve as a warning to consumers who have bought or have considered buying medications online without a legitimate prescription,” said DEA Administrator Anne Milgram.

“Consumers cannot trust the safety or legitimacy of pills sold on unaccredited sites. DEA strongly urges anyone seeking controlled medications to obtain a prescription from a trusted medical professional and have it dispensed by a licensed pharmacy.

We will continue working closely with our FDA partners to protect the integrity of the prescription drug supply chain and ensure the safety and health of our communities.”

As noted in the warning letters, these websites sell amphetamine drug products, including Adderall, that are misbranded in violation of the Federal Food, Drug, and Cosmetic Act.

The website operators also violate the Ryan Haight Online Pharmacy Act (RHA) by failing to register their online pharmacies with the DEA despite knowingly or intentionally advertising the sale of controlled substances.

The RHA has, among other provisions, requirements that must be met for controlled substances to be legally distributed and dispensed via the internet.

For example, an entity must be registered with the DEA to specifically dispense controlled substances; none of these are currently registered with the DEA to dispense or distribute controlled substances online.

The online operators will have 15 business days to respond to the agencies with specific steps taken or steps they will take to address any violations and to prevent their recurrence. “

https://www.fda.gov/news-events/press-announcements/fda-and-dea-warn-online-pharmacies-illegally-selling-adderall-consumers

Myovant Sciences and Pfizer Provide Update on sNDA for MYFEMBREE for Endometriosis

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Myovant Sciences and Pfizer Provide Update on sNDA for MYFEMBREE for Endometriosis

April 12, 2022: “Myovant Sciences and Pfizer announced an update on the sNDA for MYFEMBREE® (relugolix 40 mg, estradiol 1 mg and norethindrone acetate 0.5 mg) for the management of moderate to severe pain associated with endometriosis.

In accordance with the ongoing review of the application, on April 6, 2022, the U.S. FDA provided notice to the companies that the agency identified deficiencies that preclude discussion of labeling and/or post-marketing requirements and commitments at this time.

The FDA did not provide additional detail. The FDA noted that the letter does not reflect a final decision on the pending sNDA and that the application is still under review.

Myovant and Pfizer will continue to work with the FDA to determine next steps with the application. 


About MYFEMBREE®
MYFEMBREE (relugolix, estradiol, and norethindrone acetate) is the first once-daily oral treatment for heavy menstrual bleeding associated with uterine fibroids in premenopausal women approved by the U.S. Food and Drug Administration, with a treatment duration of up to 24 months.

MYFEMBREE contains relugolix, which reduces the amount of estrogen (and other hormones) produced by ovaries, estradiol (an estrogen) which may reduce the risk of bone loss, and norethindrone acetate (a progestin) which is necessary when women with a uterus (womb) take estrogen.

For full prescribing information including Boxed Warning and patient information, please click here.

Indications and Usage
MYFEMBREE is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.

Limitations of Use: Use of MYFEMBREE should be limited to 24 months due to the risk of continued bone loss which may not be reversible.

Important Safety Information
BOXED WARNING: THROMBOEMBOLIC DISORDERS AND VASCULAR EVENTS
Estrogen and progestin combination products, including MYFEMBREE, increase the risk of thrombotic or thromboembolic disorders including pulmonary embolism, deep vein thrombosis, stroke and myocardial infarction, especially in women at increased risk for these events.

MYFEMBREE is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke or women with uncontrolled hypertension.

CONTRAINDICATIONS
MYFEMBREE is contraindicated in women with any of the following: high risk of arterial, venous thrombotic, or thromboembolic disorder; pregnancy; known osteoporosis; current or history of breast cancer or other hormone-sensitive malignancies; known hepatic impairment or disease; undiagnosed abnormal uterine bleeding; known hypersensitivity to components of MYFEMBREE.

WARNINGS AND PRECAUTIONS
Thromboembolic Disorders: Discontinue immediately if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected.

Discontinue at least 4 to 6 weeks before surgery associated with an increased risk of thromboembolism, or during periods of prolonged immobilization, if feasible.

Discontinue immediately if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis as these have been reported with estrogens and progestins.

Bone Loss: MYFEMBREE may cause a decrease in bone mineral density (BMD) in some patients, which may be greater with increasing duration of use and may not be completely reversible after stopping treatment.

Consider the benefits and risks in patients with a history of low trauma fracture or risk factors for osteoporosis or bone loss, including medications that may decrease BMD.

Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline and periodically thereafter. Consider discontinuing MYFEMBREE if the risk of bone loss exceeds the potential benefit.

Hormone-Sensitive Malignancies: Discontinue MYFEMBREE if a hormone-sensitive malignancy is diagnosed. Surveillance measures in accordance with standard of care, such as breast examinations and mammography are recommended. Use of estrogen alone or estrogen plus progestin has resulted in abnormal mammograms requiring further evaluation.

Depression, Mood Disorders, and Suicidal Ideation: Promptly evaluate patients with mood changes and depressive symptoms including shortly after initiating treatment, to determine whether the risks of continued therapy outweigh the benefits.

Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health professional, as appropriate.

Advise patients to seek immediate medical attention for suicidal ideation and behavior and reevaluate the benefits and risks of continuing MYFEMBREE.

Hepatic Impairment and Transaminase Elevations: Steroid hormones may be poorly metabolized in these patients.

Instruct women to promptly seek medical attention for symptoms or signs that may reflect liver injury, such as jaundice or right upper abdominal pain.

Acute liver test abnormalities may necessitate the discontinuation of MYFEMBREE use until the liver tests return to normal and MYFEMBREE causation has been excluded.

Gallbladder Disease or History of Cholestatic Jaundice: Discontinue MYFEMBREE if signs or symptoms of gallbladder disease or jaundice occur. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, assess the risk-benefit of continuing therapy.

Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease.

Elevated Blood Pressure: For women with well-controlled hypertension, monitor blood pressure and stop MYFEMBREE if blood pressure rises significantly.

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy: Advise women to use non-hormonal contraception during treatment and for one week after discontinuing MYFEMBREE.

Avoid concomitant use of hormonal contraceptives. MYFEMBREE may delay the ability to recognize pregnancy because it alters menstrual bleeding. Perform testing if pregnancy is suspected and discontinue MYFEMBREE if pregnancy is confirmed.

Risk of Early Pregnancy Loss: MYFEMBREE can cause early pregnancy loss. Exclude pregnancy before initiating and advise women to use effective non-hormonal contraception.

Uterine Fibroid Prolapse or Expulsion: Advise women with known or suspected submucosal uterine fibroids about the possibility of uterine fibroid prolapse or expulsion and instruct them to contact their physician if severe bleeding and/or cramping occurs.

Alopecia: Alopecia, hair loss, and hair thinning were reported in phase 3 trials with MYFEMBREE. Consider discontinuing MYFEMBREE if hair loss becomes a concern. Whether the hair loss is reversible is unknown.

Effects on Carbohydrate and Lipid Metabolism: More frequent monitoring in MYFEMBREE-treated women with prediabetes and diabetes may be necessary. MYFEMBREE may decrease glucose tolerance and result in increased blood glucose concentrations.

Monitor lipid levels and consider discontinuing if hypercholesterolemia or hypertriglyceridemia worsens.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations in triglycerides levels leading to pancreatitis. Use of MYFEMBREE is associated with increases in total cholesterol and LDL-C.

Effect on Other Laboratory Results: Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy.

Use of estrogen and progestin combinations may raise serum concentrations of binding proteins (e.g., thyroid-binding globulin, corticosteroid-binding globulin), which may reduce free thyroid or corticosteroid hormone levels.

Use of estrogen and progestin may also affect the levels of sex hormone-binding globulin, and coagulation factors.

Hypersensitivity Reactions: Immediately discontinue MYFEMBREE if a hypersensitivity reaction occurs.”

https://www.pfizer.com/news/press-release/press-release-detail/myovant-sciences-and-pfizer-provide-update-supplemental-new

Catalent Acquires Oxfordshire Facility to Expand Biologics Capabilities in UK and Europe

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Catalent Acquires Oxfordshire Facility to Expand Biologics Capabilities in UK and Europe

April 6, 2022: “Catalent, the global leader in enabling biopharma, cell, gene, and consumer health partners to optimize development, launch, and supply of better patient treatments across multiple modalities announced the acquisition from Vaccine Manufacturing and Innovation Centre UK Limited of a biologics development and manufacturing facility currently under construction near Oxford, U.K.

Catalent plans to invest up to $160 million (£120 million) to complete the building of the facility and equip it with state-of-the-art capabilities for the development and manufacture of biologic therapies and vaccines, including mRNA, proteins, and other advanced modalities.

It is expected that the new facility will employ more than 400 people and support public and private organizations seeking to develop and manufacture biotherapeutics.

“This acquisition allows Catalent to collaborate with the rich academic and biomedical science community centered around Oxford, with its world-class talent, and will result in a facility that provides opportunities to transform innovation into real treatments for patients across the United Kingdom, Europe, and beyond,” commented Mike Riley, President of Catalent Biotherapeutics.

“Our priority is to complete construction as soon as possible to be able to commence customer programs in 2022.

We will then integrate its capabilities within our existing network of biologics facilities across Europe to offer a flexible range of manufacturing, technology, and development solutions for the pipeline of thousands of development programs currently underway.”

“This deal ensures the VMIC site, when completed, will stay true to the original purpose of strengthening the U.K.’s vaccine manufacturing capability by bringing innovation to the sector and getting more vaccines to the clinic,” said Professor Robin Shattock, Head of Mucosal Infection and Immunity at Imperial College London, and Chair of the Board of Directors of VMIC Ltd.

“Catalent has the resources to ensure this facility can become operational and start contributing to the UK’s and Europe’s vaccines landscape at pace.

I would like to recognize employees at VMIC for their passion and commitment during the pandemic and the success that their work brought to the U.K.

In Catalent, we’ve found a new owner who shares the vision for what we wanted to achieve and has safeguarded the interests of the workforce.”

The new facility is located to the south of Oxford at the world-renowned Harwell Science and Innovation Campus, a leading site in the U.K. for science and technology research breakthroughs and home to more than 40 life science companies.

Catalent has a long-standing presence in the U.K., where its workforce already exceeds 1,300 people at its four facilities focused on development and manufacturing of oral dose forms, located in Nottingham, Swindon, Haverhill, and Dartford, in addition to a clinical trial supply site in Bathgate, Scotland.

The Catalent Biotherapeutics network also includes sites in Italy, Belgium, France, Switzerland, and the United States.

ABOUT CATALENT

Catalent is the global leader in enabling pharma, biotech, and consumer health partners to optimize product development, launch, and full life-cycle supply for patients around the world.

With broad and deep scale and expertise in development sciences, delivery technologies, and multi-modality manufacturing, Catalent is a preferred industry partner for personalized medicines, consumer health brand extensions, and blockbuster drugs.

Catalent helps accelerate over 1,000 partner programs and launch over 150 new products every year.

Its flexible manufacturing platforms at over 50 global sites supply over 70 billion doses of more than 7,000 products annually. Catalent’s expert workforce exceeds 18,000, including more than 2,500 scientists and technicians.”

https://www.catalent.com/catalent-news/catalent-acquires-facility-in-oxfordshire-to-expand-biologics-capabilities-in-the-uk-and-across-europe/

Sanofi’s Dupixent® approved for children aged 6 to 11 years with severe asthma

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Sanofi’s Dupixent® approved for children aged 6 to 11 years with severe asthma

April 7, 2022: “The EC has expanded the marketing authorization for Dupixent® (dupilumab) in the European Union.

Dupixent is now also approved in children aged 6 to 11 years as an add-on maintenance treatment for severe asthma with type 2 inflammation characterized by raised blood eosinophils and/or raised fractional exhaled nitric oxide (FeNO), who are inadequately controlled with medium to high dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.

Naimish Patel, M.D.
Head of Global Development, Immunology and Inflammation, Sanofi
 “We are excited to bring the well-established safety and efficacy of Dupixent to even younger patients living with uncontrolled severe asthma in Europe.

In addition to greatly reducing severe asthma attacks and improving lung function, patients in our clinical trial also reduced their oral corticosteroid use.

This is particularly meaningful as these are medicines that can carry significant safety risks if used long term.

This approval underscores our continued commitment to bringing Dupixent to as many patients as possible suffering from the negative effects of severe asthma with the hope of improving their quality of life.”

Asthma is one of the most common chronic diseases in children. Up to 85% of children with asthma may have type 2 inflammation and are more likely to have higher disease burden.

Despite treatment with current standard-of-care ICS and bronchodilators, these children may continue to experience serious symptoms such as coughing, wheezing and difficulty breathing.

Severe asthma may impact children’s developing airways and cause potentially life-threatening exacerbations.

Children with severe asthma also may require the use of multiple courses of systemic corticosteroids that carry significant risks. Uncontrolled severe asthma can interfere with day-to-day activities, like sleeping, attending school and playing sports.

Dupixent is a fully human monoclonal antibody that inhibits the signaling of the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways and is not an immunosuppressant.

The Dupixent Phase 3 clinical program, which has shown significant clinical benefit and a decrease in type 2 inflammation, has established that IL-4 and IL-13 are key and central drivers of the type 2 inflammation that plays a major role in in multiple related and often co-morbid diseases.

George D. Yancopoulos, M.D., Ph.D.
President and Chief Scientific Officer, Regeneron
 “Today’s approval in Europe recognizes the benefits of Dupixent in helping children living with the profound effects of severe asthma, including unpredictable asthma attacks, routine disruption to daily activities and the use of systemic steroids that can impede children’s growth. 

Dupixent is the only treatment available that specifically blocks two key drivers of type 2 inflammation, IL-4 and IL-13, which our trials show plays a major role in childhood asthma, as well as in related conditions such as chronic rhinosinusitis with nasal polyposis and the often co-morbid condition, atopic dermatitis.

In clinical trials, Dupixent significantly reduced asthma attacks, helped children breathe better and improved their health-related quality of life. We also remain committed to investigating Dupixent in other conditions where type 2 inflammation may significantly impact patients’ lives, including eosinophilic esophagitis, prurigo nodularis and chronic spontaneous urticaria.”

The EC decision is based on pivotal data from the Phase 3 VOYAGE trial evaluating the efficacy and safety of Dupixent combined with standard-of-care asthma therapy in 408 children with uncontrolled moderate-to-severe asthma.

Two pre-specified populations with evidence of type 2 inflammation were evaluated for the primary analysis: 1) patients with baseline blood eosinophils (EOS) ≥300 cells/μl (n=259) and 2) patients with either baseline FeNO ≥20 parts per billion (ppb) or baseline blood EOS ≥150 cells/μl (n=350).

Patients who added Dupixent to standard-of-care in these two groups, respectively, experienced:

  • Substantially reduced rates of severe asthma attacks, with a 65% and 59% average reduction over one year compared to placebo (0.24 and 0.31 events per year for Dupixent vs. 0.67 and 0.75 for placebo, respectively).
  • Improved lung function observed as early as two weeks and sustained for up to 52 weeks, measured by percent predicted FEV1 (FEV1pp).
    • At 12 weeks, patients taking Dupixent improved their lung function by 5.32 and 5.21 percentage points compared to placebo, respectively.
  • Improved asthma control, with 81% and 79% of patients reporting a clinically meaningful improvement at 24 weeks, based on disease symptoms and impact compared to 64% and 69% of placebo patients, respectively.
  • Improved health-related quality of life, with 73% and 73% of patients reporting a clinically meaningful improvement at 24 weeks, compared to 63% and 65% of placebo patients, respectively.
  • Reduced systemic corticosteroid use by an average of 66% and 59% over one year compared to placebo (0.27 and 0.35 courses per year for Dupixent vs. 0.81 and 0.86 for placebo, respectively).

The safety results from the trial were generally consistent with the known safety profile of Dupixent in patients aged 12 years and older with uncontrolled moderate-to-severe asthma.

The overall rates of adverse events were 83% for Dupixent and 80% for placebo.

Adverse events that were more commonly observed with Dupixent compared to placebo included injection site reactions (18% Dupixent, 13% placebo), viral upper respiratory tract infections (12% Dupixent, 10% placebo) and eosinophilia (7% Dupixent, 1% placebo).

Helminth infections were also more commonly observed with Dupixent in patients aged 6 to 11 years and were reported in 2% of Dupixent patients and 0% of placebo patients.

About the LIBERTY ASTHMA VOYAGE Trial

The Phase 3 randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of Dupixent (100 mg or 200 mg every two weeks, based on weight tier) combined with standard-of-care asthma therapy in 408 children aged 6 to 11 years with uncontrolled moderate-to-severe asthma.

More than 90% of children in the trial had at least one concurrent atopic medical condition such as allergic rhinitis and atopic dermatitis.

The primary endpoint was the annualized rate of severe asthma exacerbations over one year, and the key secondary endpoint was the change from baseline in percentage of predicted pre-bronchodilator FEV1 (FEV1pp) at week 12.

The FEV1pp seeks to evaluate a patient’s change in lung function compared to their predicted lung function based on age, height, sex and ethnicity to account for children’s growing lung capacity at different stages of development.

Additional secondary endpoints included responder rates for asthma control as measured by a ≥0.5 improvement on the Asthma Control Questionnaire-7 Interviewer Administered (ACQ-7-IA; 7-point scale) and health-related quality of life as measured by a ≥0.5 improvement on the Pediatric Asthma Quality of Life Questionnaire with Standardized Activities-Interviewer Administered (PAQLQ(S)-IA; 7-point scale).”

https://www.sanofi.com/en/media-room/press-releases/2022/2022-04-07-07-00-00-2418107

Pfizer to Acquire ReViral and Its Respiratory Syncytial Virus Therapeutic Candidates

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Pfizer to Acquire ReViral and Its Respiratory Syncytial Virus Therapeutic Candidates

April 07, 2022: “Pfizer Inc. and ReViral Ltd. announced that the companies have entered into a definitive agreement under which Pfizer will acquire ReViral, a privately held, clinical-stage biopharmaceutical company focused on discovering, developing, and commercializing novel antiviral therapeutics that target respiratory syncytial virus (RSV).

“At Pfizer, we have a strong heritage in, and commitment to, fighting infectious diseases, most recently evidenced by our delivery of the first authorized vaccine and oral therapy to combat COVID-19,” said Albert Bourla, Chairman and Chief Executive Officer, Pfizer.

“We’re continuing to grow our pipeline – through our own research-and-development efforts, such as our investigational RSV vaccine programs, as well as strategic investments in companies like ReViral – with a focus on end-to-end capabilities to help protect patients from severe illness, hospitalization, and death.”

RSV is a respiratory pathogen, which can lead to severe and life-threatening lower respiratory tract infections (LRTIs) in high-risk populations, including young infants, immunocompromised individuals, and older adults. It is estimated to cause infections in approximately 64 million people, resulting in about 160,000 deaths, globally each year.

ReViral has a portfolio of promising therapeutic candidates, including sisunatovir, an orally administered inhibitor designed to block fusion of the RSV virus to the host cell.

Sisunatovir significantly reduced viral load in a phase 2 RSV human challenge study in healthy adults and is currently in phase 2 clinical development in infants.

The development program for sisunatovir is expected to continue in both adult and pediatric populations.

A second program is focused on the inhibition of RSV replication targeting the viral N protein.

The lead candidate in this program is currently in phase 1 clinical development.

“Currently, treatment options for RSV are extremely limited and focus primarily on supportive care,” said Annaliesa Anderson, Ph.D., Senior Vice President and Chief Scientific Officer, Bacterial Vaccines and Hospital, at Pfizer.

“The proposed acquisition of ReViral’s pipeline of therapeutic candidates is complementary to our efforts to advance the first vaccine candidate to help protect against this harmful disease.

Combining the capabilities and expertise of our organizations will enable us to further the clinical development of a potential therapy for those with RSV disease.”

Sisunatovir has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA). In June 2021,

ReViral announced the successful completion of Part A of the phase 2 REVIRAL1 study of sisunatovir for the treatment of RSV infections in hospitalized infants.

REVIRAL1 is a global three-part adaptive study to evaluate the safety, tolerability, pharmacokinetic (PK) profile, antiviral effects, and clinical effect of single and multiple oral doses of sisunatovir in otherwise healthy infants between the ages of 1 and 36 months hospitalized with RSV LRTIs.

Following a thorough review by the REVIRAL1 Data Safety Monitoring Committee, sisunatovir showed a favorable safety and PK exposure profile to advance to Part B, the double-blind, placebo-controlled stage of the study where patients receive drug or placebo twice a day for five days.

“Since the foundation of the company a decade ago by Dr. Ken Powell and Dr. Stuart Cockerill, ReViral’s mission has always been to develop world-class therapies for RSV patients,” said Alex C. Sapir, CEO, ReViral.

“This acquisition represents a validation of the deep antiviral experience of the ReViral team and our unwavering commitment to deliver therapies for patients in need.

Pfizer is an optimal partner given their commitment to RSV through their ongoing RSV vaccine program, coupled with their world-class clinical, regulatory, manufacturing and commercial capabilities.

We look forward to working with our colleagues at Pfizer to bring these therapies to patients as quickly as possible.”

Under the terms of the agreement, Pfizer will acquire ReViral for a total consideration of up to $525 million, including upfront and development milestones.

If successful, Pfizer believes annual revenue for these programs has the potential to reach or exceed $1.5 billion.

The proposed transaction is subject to customary closing conditions, including receipt of regulatory approvals.

Clifford Chance LLP is acting as Pfizer’s legal advisor.

Centerview Partners LLC and BofA Securities served as ReViral’s financial advisors, with Goodwin Procter LLP acting as its legal advisor.

About ReViral

ReViral is a clinical-stage biopharmaceutical company focused on discovering, developing, and commercializing antiviral therapeutics, with an initial focus on treating respiratory syncytial virus (RSV).

The company’s lead product candidate, sisunatovir, is an orally administered fusion inhibitor currently being evaluated in a global phase 2 pediatric clinical study (REVIRAL1).

The company also has an RSV N-protein replication inhibitor program currently in phase 1 clinical development.”

Novartis announces tislelizumab for regulatory review in esophageal and lung cancers

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April 6, 2022: “Novartis announced that the EMA validated Marketing Authorization Applications (MAAs) for the immune checkpoint inhibitor tislelizumab for adults with:

  • Locally advanced or metastatic, squamous or non-squamous non-small cell lung cancer (NSCLC) as first-line treatment in combination with chemotherapy,
  • Locally advanced or metastatic NSCLC as monotherapy after prior chemotherapy, and
  • Unresectable, recurrent, locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) as monotherapy after prior chemotherapy.

Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody being developed both as a monotherapy and in combination with other therapies.

“This is an important step toward expanding treatment options for cancer patients in Europe, and builds on the US FDA filing acceptance for tislelizumab in esophageal cancer,” said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development.

“We look forward to working with the EMA to make tislelizumab available to people with these aggressive cancers, while continuing to expand our development program to investigate the potential of novel, synergistic combinations.”

The MAAs include data from the pivotal Phase III RATIONALE 302 trial, in which tislelizumab demonstrated a significant improvement in overall survival versus chemotherapy as treatment for people with ESCC who had received prior chemotherapy.

The submissions also include data from the pivotal Phase III RATIONALE 303 trial, which showed tislelizumab significantly improved overall survival versus chemotherapy in people with NSCLC after treatment with chemotherapy, and from RATIONALE 304 and 307, which showed tislelizumab plus chemotherapy significantly improved progression-free survival versus chemotherapy in people with untreated squamous and non-squamous NSCLC.

Lung cancer is one of the most common cancers worldwide, accounting for more than 2 million new cases diagnosed each year.

More people die of lung cancer every year than any other cancer.

ESCC is the most common type of esophageal cancer globally, with an estimated 604,000 new cases and 544,000 deaths from esophageal cancer internationally in 2020.

About RATIONALE Trials
RATIONALE 302 (NCT03430843) is a multi-regional, open-label, randomized Phase III study of tislelizumab versus chemotherapy in patients with advanced unresectable/metastatic esophageal squamous cell carcinoma who had received prior systemic therapy.

Approximately 513 patients were randomized 1:1 to receive tislelizumab or investigator chosen chemotherapy.

The primary endpoint is overall survival (OS); the key secondary endpoint was OS in the PD-L1 positive population. Other secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), health-related quality of life measures and safety.

RATIONALE 303 (NCT03358875) is a multi-regional, open-label, multicenter, randomized Phase III study of tislelizumab versus chemotherapy in patients with locally advanced or metastatic NSCLC who have progressed on a prior platinum-containing regimen.

Approximately 805 patients were randomized 1:1 to receive tislelizumab or chemotherapy.

The co-primary endpoints are OS in all patients and OS in PD-L1 positive patients. Secondary endpoints include PFS, ORR, DoR, health-related quality of life measures and safety.

RATIONALE 304 (NCT03663205) is an open-label, multicenter, randomized Phase III study of tislelizumab plus chemotherapy versus chemotherapy alone in patients with untreated advanced non-squamous NSCLC.

Approximately 334 patients were randomized 1:1 to receive either tislelizumab plus chemotherapy or chemotherapy. The primary endpoint is PFS. Secondary endpoints include OS, ORR, DoR, health-related quality of life measures and safety.

RATIONALE 307 (NCT03594747) is an open-label, multicenter, randomized Phase III study of tislelizumab plus chemotherapy versus chemotherapy in patients with untreated advanced squamous NSCLC.

Approximately 360 patients were randomized 1:1:1 to receive tislelizumab plus paclitaxel, tislelizumab plus nab-paclitaxel, or chemotherapy alone.

The primary endpoint is PFS. Secondary endpoints include OS, ORR, DoR, health-related quality of life measures and safety.

About Tislelizumab
Novartis is evaluating tislelizumab, a uniquely designed anti-PD-1 monoclonal antibody, in a global clinical development program consisting of 14 pivotal clinical trials across a broad array of solid tumors, with more than 8,800 patients enrolled to date in 35 countries.

Novartis four distinct therapeutic platforms (immunotherapy, radioligand therapy, cell and gene therapy, targeted therapy) offer a unique opportunity to study tislelizumab in differentiated, potentially synergistic combinations across our pipeline and portfolio of market compounds.

Novartis has the rights to develop, manufacture and commercialize tislelizumab in North America, Europe and Japan through a collaboration and license agreement with BeiGene.”

https://www.novartis.com/news/media-releases/novartis-announces-anti-pd-1-tislelizumab-accepted-ema-regulatory-review-esophageal-and-lung-cancers

Gilead’s Yescarta Approved for Treatment of Relapsed or Refractory LBCL

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Gilead’s Yescarta Approved for Treatment of Relapsed or Refractory LBCL

April 01, 2022: “Kite, a Gilead Company announced the U.S. FDA has approved Yescarta® (axicabtagene ciloleucel) CAR T-cell therapy for adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.

Yescarta demonstrated a clinically meaningful and statistically significant improvement in event-free survival (EFS; hazard ratio 0.398; P< 0.0001) over the current standard of care (SOC) that has been in place for decades.

EFS was determined by blinded central review and defined as the time from randomization to the earliest date of disease progression, commencement of new lymphoma therapy, or death from any cause.

Additionally, 2.5 times more patients receiving Yescarta (40.5%) were alive at two years without disease progression or need for additional cancer treatment, after their one-time infusion of Yescarta vs. SOC (16.3%), and the median EFS was four-fold greater (8.3 months vs. 2.0 months) with Yescarta vs. SOC.

Yescarta is also being reviewed by global regulatory authorities for additional indications inclusive of the ZUMA-7 patient population.

ZUMA-7 is considered a landmark trial for being the first and largest trial of its kind, with the longest follow-up.

Earlier this month, the National Comprehensive Cancer Network (NCCN) updated its Clinical Practice Guidelines in Oncology for B-cell Lymphomas to include Yescarta for “Relapsed disease <12 mo or Primary Refractory disease” under Diffuse Large B-cell Lymphoma (DLBCL) as a Category 1 recommendation.

Yescarta is the first CAR T-cell therapy to receive a NCCN Category 1 recommendation.

NCCN defines Category 1 as recommendations based upon high-level evidence with uniform NCCN consensus that the intervention is appropriate.

Christi Shaw, Chief Executive Officer of Kite: “Kite started with a very bold goal: creating the hope of survival through cell therapy. Today’s FDA approval brings that hope to more patients by enabling the power of CAR T-cell therapy to be used earlier in the treatment journey.

This milestone has been years in the making. On behalf of the entire Kite community, we would like to thank the patients and physicians who have been on this journey with us. You are what drives us every day to explore the full potential of cell therapy.”

CAR T-cell therapies are individually made starting from a patient’s own white blood cells, called T-cells.

The cells are removed through a process similar to donating blood and sent to Kite’s specialized manufacturing facilities where they are engineered to target the patient’s cancer, expanded, and then returned to the hospital for infusion back into the patient.

Referring physicians and patients can immediately begin accessing Yescarta CAR T-cell therapy for this new FDA-approved indication through Kite’s 112 authorized treatment centers across the U.S.

Frederick L. Locke, MD, ZUMA-7 Principal Investigator and Co-Leader of the Immuno-Oncology Program at Moffitt Cancer Center, Tampa, Florida: “Today’s approval marks an exciting new standard of care. The ZUMA-7 trial enabled us to look at the broader picture of what happens to patients after a decision is made to follow a particular treatment path.

What we found was that axi-cel resulted in three times as many patients receiving treatment with curative intent (CAR T-cell therapy), and an overall better outcome for patients than the previous standard of care.

Additionally, we have now amassed significant experience with CAR T-cell therapy to better manage or prevent side-effects, making this treatment more accessible for older patients and those with medical conditions for whom the standard of care might be difficult.”

SOC therapy for this patient population has historically been a multi-step process expected to end with a stem cell transplant.

The process starts with chemoimmunotherapy, and if a patient responds to and can tolerate further treatment, they move on to high-dose chemotherapy (HDT) followed by a stem cell transplant (ASCT).

Jason Westin, MD, MS, FACP, ZUMA-7 Principal Investigator, Director, Lymphoma Clinical Research, and Associate Professor, Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center: “Definitive clinical trial results such as these do not come along often and should drive a paradigm shift in how patients with relapsed or refractory LBCL are treated moving forward.

Patients who do not respond to or relapse after initial treatment should quickly be referred to a CAR T-cell therapy authorized treatment center for evaluation.”

Kite CAR T-cell therapy products are widely covered by commercial and government insurance programs in the U.S. Kite has also invested in expansion of manufacturing capacity ahead of today’s FDA decision to support patient access.

Lee Greenberger, PhD, Chief Scientific Officer of The Leukemia & Lymphoma Society (LLS): “LLS was an early supporter of CAR T-cell therapy research, and to be able to see this innovative advance become available as an earlier line of treatment is truly remarkable.

Current standard of care is a difficult process for patients, and no one knows at the start who will make it to stem cell transplant. With today’s FDA decision, patients will have earlier access to this potentially curative treatment.” ​

Yescarta was initially approved by the FDA in 2017 based on the ZUMA-1 trial for a smaller population of LBCL patients who failed two or more lines of therapy.

The ZUMA-1 trial has recently reported durable 5-year survival results, with Yescarta showing 42.6% of study patients alive at 5 years and that 92% of those patients alive at 5 years have needed no additional cancer treatment at this important milestone.

As the only company dedicated exclusively to the research, development, commercialization, and manufacturing of cell therapy on a global scale, Kite has all functions critical to cell therapy vertically integrated.

This structure enables the continual refinement and support of the highly specialized and complex end-to-end processes needed to support and improve upon patient outcomes with CAR T-cell therapy.

About ZUMA-7 Study

The FDA approval of Yescarta CAR T-cell therapy for adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy is based on results from the ZUMA-7 study.

Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous stem cell transplant (ASCT).

Results were presented in a Plenary session at the American Society of Hematology’s (ASH) Annual Meeting & Exposition in December 2021 and simultaneously published in the NewEngland Journal of Medicine (NEJM).

ZUMA-7 is a randomized, open-label, global, multicenter, Phase 3 study evaluating the safety and efficacy of Yescarta versus current standard of care (SOC) for second-line therapy (platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy [HDT] and ASCT in those who respond to salvage chemotherapy) in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy.

In the study, 359 patients in 77 centers around the world were randomized (1:1) to receive a single infusion of Yescarta or current SOC second-line therapy.

The primary endpoint is event-free survival (EFS) as determined by blinded central review and defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause.

Key secondary endpoints include objective response rate (ORR) and overall survival (OS). Additional secondary endpoints include patient reported outcomes (PROs) and safety.

Yescarta demonstrated a 2.5-fold increase in patients who were alive at two years and did not experience cancer progression or require the need for additional cancer treatment (40.5% vs. 16.3%) and a four-fold greater median EFS (8.3 mo. vs. 2.0 mo.) compared to SOC (hazard ratio 0.398; 95% CI: 0.308-0.514, P<0.0001).

In addition to being the largest and longest study of its kind, ZUMA-7 study participants on the Yescarta arm did not receive additional bridging chemotherapy that could have potentially confounded results.

Nearly three times as many patients randomized to Yescarta ultimately received the definitive CAR T-cell therapy treatment (94%) versus those randomized to SOC (35%) who received on-protocol HDT+ASCT. More patients responded to Yescarta (ORR: 83% vs. 50%, odds ratio: 5.31 [95% CI: 3.1-8.9; P<0.0001) and achieved a complete response (CR) with Yescarta (CR rate: 65% vs. 32%) than with SOC.

At a pre-specified interim analysis at the time of the primary EFS analysis, OS has not met the criteria for statistical significance, but favored Yescarta.

Fifty-five percent of patients in the SOC arm subsequently received CD19-directed CAR T-cell therapy off study.

In the study, Yescarta had a safety profile that was consistent with previous studies. Among the 168 Yescarta-treated patients evaluable for safety, Grade ≥3 cytokine release syndrome (CRS) and neurologic events were observed in 7% and 25% of patients, respectively.

In the SOC arm, 83% of patients had high grade events, mostly cytopenias (low blood counts).

The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a Risk Evaluation and Mitigation Strategy (REMS) due to these risks; see below for Important Safety Information.”

https://www.gilead.com/news-and-press/press-room/press-releases/2022/4/yescarta-receives-us-fda-approval-as-first-car-tcell-therapy-for-initial-treatment-of-relapsed-or-refractory-large-bcell-lymphoma-lbcl

BMS Receives EC Approval for Opdivo for recurrent or metastatic ESCC

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BMS Receives EC Approval for Opdivo for recurrent or metastatic ESCC

April 5, 2022: “Bristol Myers Squibb announced that the European Commission has approved Opdivo (nivolumab) in combination with fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) with tumor cell PD-L1 expression ≥ 1%.

The EC’s decision is based on results from the Phase 3 CheckMate -648 trial, in which Opdivo with chemotherapy demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit compared to chemotherapy alone at the pre-specified interim analysis.

The safety profile of Opdivo with chemotherapy was consistent with previously reported studies.

Results from CheckMate -648 were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2021.

“This approval is an important advancement for patients in the EU, especially given the highly aggressive nature of advanced ESCC,” said Ian M. Waxman, M.D., development lead, gastrointestinal cancers, Bristol Myers Squibb.

“Opdivo with chemotherapy is now one of two newly approved Opdivo-based combinations to show superior overall survival benefit compared to chemotherapy alone, offering higher hopes for patients with unresectable advanced, recurrent or metastatic ESCC with tumor cell PD-L1 expression ≥ 1%.

We are eager to introduce this new treatment option to patients in the European Union and potentially improve their survival outcomes.”

The EC has also approved Opdivo in combination with Yervoy (ipilimumab) for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) with tumor cell PD-L1 expression ≥ 1%.

The EC approval allows for the use of Opdivo with fluoropyrimidine- and platinum-based combination chemotherapy for the first-line treatment of adults with unresectable advanced, recurrent or metastatic ESCC with tumor cell PD-L1 expression ≥ 1% in the 27 member states of the European Union, as well as Iceland, Liechtenstein and Norway.

CheckMate -648 Efficacy and Safety Results

Results from CheckMate -648 include:

  • OS in participants with tumor cell PD-L1 expression ≥ 1%. (primary endpoint): Median OS was 15.44 months (95% Confidence Interval [CI]: 11.93, 19.52) for nivolumab with chemotherapy vs. 9.07 months (95% CI: 7.69, 9.95) for chemotherapy (Hazard Ratio [HR] = 0.54; 95% CI: 0.37, 0.80; p= <0.0001).
  • PFS in participants with tumor cell PD-L1 expression ≥ 1%. (primary endpoint): Median PFS was 6.93 months (95% CI: 5.68, 8.34) for nivolumab with chemotherapy vs. 4.44 months (95% CI: 2.89, 5.82) for chemotherapy (HR = 0.65; 95% CI: 0.46, 0.92; p=0.0023)
  • ORR (secondary endpoint): The ORR was 53.2% (95% CI: 45.1, 61.1) for nivolumab with chemotherapy vs. 19.7% (95% CI: 13.8, 26.8) for chemotherapy.
  • Safety (based on pooled data across tumor types): Incidence of Grade 3-5 adverse reactions was 76% for nivolumab with chemotherapy and 62% for chemotherapy alone, with 1.4% fatal adverse reactions attributed to nivolumab in combination with chemotherapy including pneumonia, febrile neutropenia, thrombosis, pneumonitis, diarrhea, and renal failure. Median duration of therapy was 6.44 months (95% CI: 5.95, 6.80) for nivolumab with chemotherapy and 4.34 months (95% CI: 4.04, 4.70) for chemotherapy.

About CheckMate -648

CheckMate -648 is a randomized Phase 3 study evaluating Opdivo plus Yervoy (N=325) or Opdivo with fluorouracil and cisplatin (N=321) against fluorouracil plus cisplatin alone (N=324) in patients with previously untreated, unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma.

The primary endpoints of the trial are overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients with tumor cell PD-L1 expression ≥1% for both Opdivo-based combinations versus chemotherapy. Secondary endpoints of the trial include OS and PFS by BICR in the all-randomized population.

In the Opdivo with chemotherapy arm, patients received treatment with Opdivo 240 mg on Day 1 and Day 15, fluorouracil 800 mg/m²/day on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² on Day 1 of four-week cycle.

Patients received Opdivo for up to 24 months or until disease progression, unacceptable toxicity or withdrawal of consent, and chemotherapy until disease progression, unacceptable toxicity or withdrawal of consent.

In the Opdivo plus Yervoy arm, patients received treatment with Opdivo 3 mg/kg every 2 weeks and Yervoy 1 mg/kg every 6 weeks up to 24 months or until disease progression, unacceptable toxicity or withdrawal of consent.

About Esophageal Cancer

Esophageal cancer is the seventh most common cancer and the sixth leading cause of death from cancer worldwide, with approximately 600,000 new cases and over 540,000 deaths in 2020.

The two most common types of esophageal cancer are squamous cell carcinoma and adenocarcinoma, which account for approximately 85% and 15% of all esophageal cancers, respectively, though esophageal tumor histology can vary by region and country.

Squamous cell carcinoma accounts for approximately 60% of esophageal cancer cases in Europe.

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

Bristol Myers Squibb is inspired by a single vision — transforming people’s lives through science. The goal of the company’s 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 patient’s 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 body’s own immune system to help restore anti-tumor immune response.

By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol Myers Squibb’s 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 Company’s 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.

INDICATIONS

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

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

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

OPDIVO® (nivolumab), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).

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 adult 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 adult 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 adult patients with advanced renal cell carcinoma (RCC).

OPDIVO® (nivolumab) is indicated for the treatment of adult 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 adult 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 adult 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.

OPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

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), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult 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 treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO® (nivolumab) is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).

OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum- containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

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 patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%).

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%).

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 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%).

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, 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%).

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%).

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-Barré 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-Harada–like 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 every 3 weeks, 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.

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.

https://news.bms.com/news/corporate-financial/2022/Bristol-Myers-Squibb-Receives-European-Commission-Approval-for-Opdivo-nivolumab-with-Chemotherapy-as-First-Line-Treatment-for-Patients-with/default.aspx

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