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FDA Takes Additional Steps to Advance Decentralized Clinical Trials

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FDA Takes Additional Steps to Advance Decentralized Clinical Trials

May 02, 2023: “The U.S. FDA is taking additional steps to support the use of decentralized clinical trials (DCTs) for drugs, biologics and devices, where some or all the trial-related activities occur at locations other than traditional clinical trial sites. 

The agency released a new draft guidance that provides recommendations for sponsors, investigators and other stakeholders regarding the implementation of DCTs to advance medical product development and research.

Examples of decentralized elements include obtaining laboratory tests at a local facility rather than a research medical center or conducting a clinical follow-up visit in the trial participant’s home using telemedicine.

Decentralizing clinical trials will allow some or all trial-related activities to take place at trial participants’ homes or other convenient locations, instead of having them visit research sites.

By reducing barriers to participation, we expect that DCTs will increase the breadth and diversity of participants in clinical trials and improve accessibility for those with rare diseases or mobility challenges.

We anticipate that this approach will facilitate the development of drugs including in areas of medical need, resulting in more treatment options and improved patient outcomes.

This draft guidance builds on agency recommendations issued in 2020, which provided clarity for investigators to facilitate trial decentralization in response to the COVID-19 public health emergency and associated disruptions such as quarantines, site closures and travel limitations.

“The FDA has long considered the benefits of decentralized clinical trials. Advancements in digital health technologies and the COVID-19 pandemic—when in-person visits were limited or unavailable for many trial participants—have accelerated the broader adoption of these activities,” said FDA Commissioner Robert M. Califf, M.D.

“As we seek to improve our evidence generation system, decentralized clinical trials may enhance convenience for trial participants, reduce the burden on caregivers, expand access to more diverse populations, improve trial efficiencies, and facilitate research on rare diseases and diseases affecting populations with limited mobility.”  

While the FDA’s regulatory requirements for investigations of medical products are the same for DCTs and traditional site-based clinical trials, the new draft guidance covers recommendations on topics such as:  

  • design considerations for a DCT;
  • conduct of remote clinical trial visits and clinical trial-related activities in a DCT;
  • use of digital health technologies to remotely acquire data in a DCT;
  • roles and responsibilities of the sponsor and investigators in a DCT;
  • obtaining informed consent (IC) and institutional review board oversight of the IC process in a DCT;
  • determination of the appropriateness of investigational products for use in a DCT;
  • packaging and shipping of investigational products in a DCT; and
  • safety monitoring of trial participants in a DCT.

The FDA expects that clinical trials with decentralized elements will play an important role in addressing public health needs. The FDA is committed to working with sponsors to discuss how decentralized elements may fit into a clinical trial.

https://www.fda.gov/news-events/press-announcements/fda-takes-additional-steps-advance-decentralized-clinical-trials

FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine

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FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine

May 03, 2023: “The U.S. FDA approved Arexvy, the first respiratory syncytial virus (RSV) vaccine approved for use in the United States.

Arexvy is approved for the prevention of lower respiratory tract disease caused by RSV in individuals 60 years of age and older.

“Older adults, in particular those with underlying health conditions, such as heart or lung disease or weakened immune systems, are at high risk for severe disease caused by RSV,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

“Today’s approval of the first RSV vaccine is an important public health achievement to prevent a disease which can be life-threatening and reflects the FDA’s continued commitment to facilitating the development of safe and effective vaccines for use in the United States.”

RSV is a highly contagious virus that causes infections of the lungs and breathing passages in individuals of all age groups. RSV circulation is seasonal, typically starting during the fall and peaking in the winter.

In older adults, RSV is a common cause of lower respiratory tract disease (LRTD), which affects the lungs and can cause life-threatening pneumonia and bronchiolitis (swelling of the small airway passages in the lungs).

According to the U.S. Centers for Disease Control and Prevention, each year in the U.S., RSV leads to approximately 60,000-120,000 hospitalizations and 6,000-10,000 deaths among adults 65 years of age and older. 

The safety and effectiveness of Arexvy is based on the FDA’s analysis of data from an ongoing, randomized, placebo-controlled clinical study conducted in the U.S. and internationally in individuals 60 years of age and older.

The main clinical study of Arexvy was designed to assess the safety and effectiveness of a single dose administered to individuals 60 years of age and older.

Participants will remain in the study through three RSV seasons to assess the duration of effectiveness and the safety and effectiveness of repeat vaccination. Data for a single dose of Arexvy from the first RSV season of the study were available for the FDA’s analysis.  

In this study, approximately 12,500 participants have received Arexvy and 12,500 participants have received a placebo.

Among the participants who have received Arexvy and the participants who have received a placebo, the vaccine significantly reduced the risk of developing RSV-associated LRTD by 82.6% and reduced the risk of developing severe RSV-associated LRTD by 94.1%.

Among a subset of these clinical trial participants, the most commonly reported side effects by individuals who received Arexvy were injection site pain, fatigue, muscle pain, headache and joint stiffness/pain.

Among all clinical trial participants, atrial fibrillation within 30 days of vaccination was reported in 10 participants who received Arexvy and 4 participants who received placebo. 

In two other studies, approximately 2,500 participants 60 years of age and older received Arexvy.

In one of these studies, in which some participants received Arexvy concomitantly with an FDA-approved influenza vaccine, two participants developed acute disseminated encephalomyelitis (ADEM), a rare type of inflammation that affects the brain and spinal cord, seven and 22 days, respectively, after receiving Arexvy and the influenza vaccine. One of the participants who developed ADEM died.

In the other study, one participant developed Guillain-Barré syndrome (a rare disorder in which the body’s immune system damages nerve cells, causing muscle weakness and sometimes paralysis) nine days after receiving Arexvy.

The FDA is requiring the company to conduct a postmarketing study to assess the signals of serious risks for Guillain-Barré syndrome and ADEM.

In addition, although not an FDA requirement, the company has committed to assess atrial fibrillation in the postmarketing study.

This application was granted Priority Review designation. 

The FDA granted approval of Arexvy to GlaxoSmithKline Biologicals.”

https://www.fda.gov/news-events/press-announcements/fda-approves-first-respiratory-syncytial-virus-rsv-vaccine

Bayer and Cat Creek Energy Sign Landmark Renewable Energy Deal

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Bayer and Cat Creek Energy Sign Landmark Renewable Energy Deal

May03,2023: “Bayer, a global enterprise with core competencies in the life science fields of health care and nutrition, and Cat Creek Energy (CCE), a renewable energy Independent Power Producer announced a long-term Structured Renewable Energy Credit (REC) Purchase Agreement that will satisfy Bayer´s renewable electricity needs and lead to the construction by CCE of multiple variable renewable energy resources plus energy storage facilities in Idaho.

The renewable energy projects will generate 1.4 terawatt hours of clean electricity annually.

“The innovative agreement with CCE marks one of the biggest single renewable energy deals in the United States.

It will secure 40 percent of Bayer’s global and 60 percent of Bayer´s U.S.-purchased electricity demand out of renewable sources, while meeting Bayer’s ambitious quality criteria for renewable electricity,” said Werner Baumann, CEO of Bayer AG.

The project will realize 1.4 terawatt hours of power, an amount equal to the energy consumption of 150,000 households. In terms of CO2, the deal enables Bayer to reduce annual emissions by 370,000 tons.

That’s roughly equivalent to the emissions of 270,000 mid-sized cars, or the amount that 31.7 million trees are capable of binding annually.

In accordance with the United Nations Sustainable Development Goals and the Paris Agreement to limit global warming to 1.5 degrees Celsius by 2050, Bayer aims to continuously reduce greenhouse gas (GHG) emissions within the company and along its entire value chain.

The company aims to become climate neutral in its own operations in 2030. A key strategy to achieving Bayer’s reduction targets is to purchase 100 percent sustainable renewable electricity by 2030.

These reduction targets have been approved by the Science Based Targets, an initiative that drives ambitious climate action in the private sector by enabling organizations to set science-based emissions reduction targets.

Additionally, Bayer is committed to the highest standards for sustainable renewable electricity based on guidelines from the World Wide Fund for Nature (WWF), including the proximity of renewable energy production facilities to Bayer sites.

For Idaho, the renewable plus energy storage projects will continue the state’s conversion to clean reliable energy by 2045.

For rural communities, the result will be over $1.5 billion in new electrical infrastructure, the creation of hundreds of jobs, and contribution of millions of dollars in year-over-year tax revenues contributed for counties and schools where the projects are built.

Construction will commence in the third quarter of this year.

“As an innovation driven company, Bayer recognizes the need to introduce renewable energy solutions that are healthier for the planet and healthier for humans,” said Bayer EVP of Public Affairs, Science, Sustainability and HSE Matthias Berninger.

“This project with Cat Creek Energy is exciting because it catapults our energy goal target fulfilments while also supporting Idaho, a state many of our employees call home.”

“I appreciate Bayer’s alignment with the CCE vision and efforts to build out our multi-technology 1,760 MW platform,” said fourth generation Idaho rancher and president of Cat Creek Energy John Faulkner.

“We admire Bayer’s commitment to find projects near its Idaho facility, which has the highest electricity use within Bayer in the United States, signifying a major milestone in their global energy goals.” 

Energy storage is a vital technological component in the successful transition to clean energy.

As CCE continues its Large Volume Long Duration storage development through its Pumped Storage Hydro project, the installations under the Agreement allow for battery storage of 160 MW nameplate capacity to support and strengthen regional transmission grid integrity and reliability.’

https://www.bayer.com/media/en-us/bayer-and-cat-creek-energy-sign-landmark-renewable-energy-deal/

Sandoz to exclusively commercialize six products in the US, reinforcing global leadership position in off-patent medicines

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Sandoz to exclusively commercialize six products in the US, reinforcing global leadership position in off-patent medicines

May 4, 2023: “Sandoz, a global leader in generic pharmaceuticals and biosimilars, announced that it has signed a distribution and collaboration agreement with Adalvo for exclusive Sandoz rights to commercialize six products in the US across key therapeutic areas, including antifungal/antibiotic, oncology and pulmonary.

“Sandoz is putting patients first by securing the rights to bring more affordable, equally effective treatments for a range of disorders that collectively affect millions of people in the US every year,” said Keren Haruvi, President, Sandoz Inc. “This agreement also helps advance our ambition to be the world’s largest and most valued generics company.”

These products, which are slated for near- to mid-term launches beginning in 2024, have a total addressable market size of approximately USD 3 bn, further advancing the Sandoz product pipeline in the key US generics market.

The agreement also demonstrates the unwavering Sandoz commitment to pioneering patient access to critical medicines in areas of greatest unmet need.

In addition to building out the Sandoz US offering in these key areas, the antibiotic products would also underpin the Sandoz strategy of combatting the global spread of antimicrobial resistance (AMR) by driving responsible access to a broad range of appropriate treatments.”

https://www.novartis.com/news/media-releases/sandoz-exclusively-commercialize-six-products-us-reinforcing-global-leadership-position-patent-medicines

XTANDI® plus Leuprolide Reduced the Risk of Metastasis by 58% in Non-Metastatic Hormone-Sensitive Prostate Cancer versus Placebo plus Leuprolide

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XTANDI® plus Leuprolide Reduced the Risk of Metastasis by 58% in Non-Metastatic Hormone-Sensitive Prostate Cancer versus Placebo plus Leuprolide

April 29, 2023: “Astellas Pharma Inc. and Pfizer Inc. announced that XTANDI® (enzalutamide) plus leuprolide significantly reduced the risk of metastasis or death by 58% versus placebo plus leuprolide (Hazard Ratio [HR]: 0.42; 95% Confidence Interval [CI], 0.30–0.61; P<0.0001), as assessed by the primary endpoint of metastasis-free survival (MFS), in men with non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as non-metastatic castration-sensitive prostate cancer or nmCSPC) with high-risk biochemical recurrence (BCR).

These data from the Phase 3 EMBARK trial, which evaluated patients across three study arms (XTANDI plus leuprolide [n=355], placebo plus leuprolide [n=358], or XTANDI monotherapy [n=355]), were presented as a plenary session during the 2023 American Urological Association Annual Meeting (Saturday, April 29 at 9:45 a.m. CT). 

The overall safety profile was consistent with the known safety profile of each of the medicines.

The most common adverse events in those treated with XTANDI plus leuprolide were fatigue, hot flush, and arthralgia and in those treated with XTANDI monotherapy were fatigue, gynecomastia, and arthralgia.

“There are patients with localized prostate cancer who undergo prostatectomy or radiation therapy in an attempt to cure their disease, but, unfortunately, some patients will develop BCR,” said Neal Shore, M.D., F.A.C.S., U.S. Chief Medical Officer of Urology and Surgical Oncology, GenesisCare, Director, Carolina Urologic Research Center, and Primary Investigator for the EMBARK study.

“Importantly, some patients with BCR are at very high risk for developing metastatic disease, which can lead to a cascade of therapeutic interventions.

The clinical goal of BCR therapy is to delay cancer progression and avoid metastatic disease.

The MFS results from the EMBARK study demonstrate that this intervention with XTANDI plus leuprolide was statistically significant for patients with high-risk BCR.” 

“The EMBARK study is a Phase 3 trial exploring the potential of enzalutamide in patients with non-metastatic hormone-sensitive prostate cancer with high-risk BCR,” said Stephen J. Freedland, M.D., Director of the Center for Integrated Research in Cancer and Lifestyle and the Warschaw Robertson Law Families Chair in Prostate Cancer at Cedars-Sinai Cancer and Co-Principal Investigator of the Clinical Trial.

“If approved, we hope to bring a new option to men earlier in the course of their disease.”  

Consistent with the study’s primary endpoint, statistically significant and clinically meaningful improvements were also observed in the trial’s key secondary endpoints in both the XTANDI combination and monotherapy arms.

Specifically, the XTANDI monotherapy arm demonstrated that treatment with XTANDI reduced the risk of metastasis or death by 37% versus leuprolide plus placebo (HR: 0.63; 95% CI, 0.46–0.87; P=0.0049), meeting its MFS endpoint.

Treatment with XTANDI plus leuprolide and XTANDI monotherapy reduced the risk of PSA progression by 93% (HR: 0.07; 95% CI, 0.03–0.14; P<0.0001) and 67% (HR: 0.33; 95% CI, 0.23–0.49; P<0.0001), respectively, versus placebo plus leuprolide.

The progression risk in starting a new antineoplastic therapy was reduced by 64% in those treated with XTANDI plus leuprolide (HR: 0.36; 95% CI, 0.26–0.49; P<0.0001) and 46% in those treated with XTANDI monotherapy (HR: 0.54; 95% CI, 0.41–0.71; P<0.0001) versus placebo plus leuprolide.

A positive trend in the key secondary endpoint of overall survival (OS) was also observed in the XTANDI combination arm at the time of the analysis, but these data were not yet mature. Patients in the trial will be followed for a subsequent final OS analysis. 

Detailed results from the trial will be submitted for peer-reviewed publication. Additionally, the EMBARK data will be discussed with regulatory authorities, including the U.S. Food and Drug Administration (FDA), to support a potential regulatory submission for XTANDI in this indication in 2023.

About EMBARK
The Astellas- and Pfizer-led Phase 3, randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,068 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as non-metastatic castration-sensitive prostate cancer or nmCSPC) with high-risk biochemical recurrence (BCR) at sites in the United States, Canada, Europe, South America and the Asia-Pacific region.

Patients who were considered to experience high-risk BCR had a prostate-specific antigen doubling time (PSA-DT) ≤ 9 months; serum testosterone ≥ 150 ng/dL (5.2 nmol/L); and screening PSA by the central laboratory ≥ 1 ng/mL if they had a radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer, or at least 2 ng/mL above the nadir if they had radiotherapy only as primary treatment for prostate cancer.

Patients in the EMBARK trial were randomized to receive enzalutamide 160 mg daily plus leuprolide (n=355), enzalutamide 160 mg as a monotherapy (n=355), or placebo plus leuprolide (n=358). Leuprolide 22.5 mg was administered every 12 weeks. 

The primary endpoint of the trial was metastasis-free survival (MFS) for enzalutamide plus leuprolide versus placebo plus leuprolide. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death.

For more information on the EMBARK trial (NCT02319837) go to www.clinicaltrials.gov.

XTANDI, either in combination with leuprolide or as a monotherapy, has not been approved by any regulatory agency for the treatment of patients with nmHSPC with high-risk BCR. 

About Non-Metastatic Hormone-Sensitive Prostate Cancer with High-Risk Biochemical Recurrence
In non-metastatic hormone- (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC), no evidence of the cancer spreading to distant parts of the body (metastases) is detectable with conventional radiological methods (CT/MRI), and the cancer still responds to medical or surgical treatment designed to lower testosterone levels.

Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience a biochemical recurrence (BCR) within 10 years.

About 9 out of 10 men with high-risk BCR will develop metastatic disease, and 1 in 3 will die as a result of the recurrence.

The EMBARK trial focused on men with high-risk BCR. Per the EMBARK protocol, patients with nmHSPC and high-risk BCR are those initially treated by radical prostatectomy or radiotherapy, or both, with a prostate-specific antigen doubling time (PSA-DT) ≤ 9 months. High-risk BCR patients with a PSA-DT of ≤ 9 months have a higher risk of metastases and death.5

About XTANDI® (enzalutamide)
XTANDI (enzalutamide) is an androgen receptor signaling inhibitor.

XTANDI has received regulatory approvals in one or more countries around the world for use in men with metastatic hormone-sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC), and non-metastatic castration-resistant prostate cancer (nmCRPC).

XTANDI is currently approved for one or more of these indications in more than 100 countries, including in the United States, European Union and Japan. One million patients have been treated with XTANDI globally.6

U.S. Important Safety Information
XTANDI (enzalutamide) is indicated in the U.S. for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Warnings and Precautions

Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure.

It is unknown whether anti-epileptic medications will prevent seizures with XTANDI.

Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space-occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection.

Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Permanently discontinue XTANDI in patients who develop a seizure during treatment. 

Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in patients receiving XTANDI.

PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension.

A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES. 

Hypersensitivity: Reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in seven randomized clinical trials.

Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions. 

Ischemic Heart Disease: In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%).

Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% on placebo.

events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease. 

Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo.

Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo. 

Embryo-Fetal Toxicity: The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female.

Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. 

Adverse Reactions (ARs): In the data from the four randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension.

In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients.

In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI treated patients.

In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients.

Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients. 

In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients.

Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. 

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia. 

Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.  

Drug Interactions 

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI.

If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If coadministration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs.

If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.”

https://www.pfizer.com/news/press-release/press-release-detail/xtandir-enzalutamide-plus-leuprolide-reduced-risk

Update on FDA Advisory Committee vote on Lynparza plus abiraterone for metastatic castration-resistant prostate cancer

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Update on FDA Advisory Committee vote on Lynparza plus abiraterone for metastatic castration-resistant prostate cancer

April 28, 2023: “The Food and Drug Administration’s Oncologic Drugs Advisory Committee (ODAC) has recognised a favourable benefit risk profile for AstraZeneca and MSD’s Lynparza (olaparib) plus abiraterone and prednisone or prednisolone for the treatment of adult patients with BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC) based on the PROpel Phase III trial.

The Committee voted 11 to 1, with 1 abstaining, that the indication should be limited to patients whose tumours have a BRCA mutation.

In August 2022, the FDA accepted the supplemental New Drug Application (sNDA) for Lynparza based on positive results from the pivotal PROpel trial, also published in NEJM Evidence.

The ODAC provides the FDA with independent, expert advice and recommendations on marketed and investigational medicines for use in the treatment of cancer.

The FDA is not bound by the Committee’s guidance but takes its advice into consideration. AstraZeneca and MSD will continue to work with the FDA as it completes its review of the application.

Neal Shore, Chief Medical Officer of Urology and Surgical Oncology for Genesis Care, US and PROpel trial investigator, said: “Today’s recommendation by the ODAC is disappointing news for clinicians and prostate cancer patients alike.

Preventing or delaying radiographic progression is an important clinical endpoint in assessing oncologic treatment and is very relevant to patients, their caregivers and their families. It is essential that physicians and patients have an opportunity to choose treatment with the goal of optimising cancer care outcomes.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: “Novel treatment options are urgently needed for patients with metastatic castration-resistant prostate cancer.

While we are pleased with the recognition of the benefit of Lynparza plus abiraterone for patients with BRCA-mutated metastatic castration-resistant prostate cancer, we are disappointed with the outcome of today’s ODAC meeting.

We strongly believe in the results of the PROpel trial, which demonstrated the clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status.”

Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, MSD Research Laboratories, said “With the incidence and mortality of prostate cancer set to double in the coming decades, it is critical that we bring new treatment options with the potential to reduce the risk of disease progression or death to patients at the earliest possible moment in their care.

While we are pleased that the ODAC recommended Lynparza for patients with metastatic castration-resistant prostate cancer who have BRCA mutations, we believe in the potential of Lynparza plus abiraterone for a broad range of patients with metastatic castration-resistant prostate cancer, based on the results of PROpel. We look forward to the outcome of the FDA’s review of the application.”

Results from the PROpel trial showed a statistically significant and clinically meaningful 34% reduction in the risk of radiographic disease progression or death with Lynparza plus abiraterone with prednisone or prednisolone, versus abiraterone alone in patients with mCRPC (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.001). Median radiographic progression-free survival (rPFS) was 24.8 months and 16.6 months, respectively.

Further results from the final prespecified overall survival (OS) analysis presented at ASCO Genitourinary Cancers Symposium 2023 showed Lynparza plus abiraterone and prednisone or prednisolone demonstrated median OS of 42.1 months versus 34.7 months for abiraterone plus placebo.

This result represents a 7.4-month absolute difference in median OS versus a standard of care (47.9% maturity, HR of 0.81, 95% CI 0.67-1.00; p=0.0544).

While this numerical increase in median OS did not achieve statistical significance, it builds on the meaningful survival gains achieved for patients in this setting treated with abiraterone alone, a current standard of care.

In exploratory analyses of the BRCAm subgroup, Lynparza plus abiraterone demonstrated improvements in both rPFS (HR of 0.23, 95% CI, 0.12-0.43) and OS (HR of 0.29, 95% CI, 0.14-0.56).

In the non-BRCAm subgroup, Lynparza plus abiraterone also showed improvements in rPFS (HR of 0.76, 95% CI, 0.61-0.94), and a modest trend for OS (HR of 0.91, 95% CI, 0.73-1.13).

The safety and tolerability of Lynparza plus abiraterone in PROpel was in line with that observed in prior clinical trials and the known profiles of the individual medicines.

Lynparza in combination with abiraterone and prednisone or prednisolone is approved in the EU and several other countries for the treatment of adult patients with mCRPC based on the PROpel trial.”

https://www.astrazeneca.com/media-centre/press-releases/2023/odac-vote-on-lynparza-combo-in-prostate-cancer.html

EMA validates marketing authorisation application for Jemperli plus chemotherapy for dMMR/MSI-H primary advanced or recurrent endometrial cancer

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EMA validates marketing authorisation application for Jemperli plus chemotherapy for dMMR/MSI-H primary advanced or recurrent endometrial cancer

April 25, 2023: “GSK announced that the EMA validated the Company’s Type II Variation for a potential new indication for Jemperli (dostarlimab) in combination with chemotherapy for the treatment of adult patients with a type of gynaecological cancer known as mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer.

As a result, the EMA’s Committee for Medicinal Products for Human Use will begin the formal review process to make a recommendation to the European Commission regarding marketing authorisation for the potential new indication.

The regulatory submission is based on the interim results of the RUBY/ENGOT-EN6/GOG3031/NSGO phase III trial.

The trial met its primary endpoint of investigator-assessed progression-free survival (PFS), showing a statistically significant and clinically meaningful benefit versus placebo plus chemotherapy in patients treated with dostarlimab plus carboplatin-paclitaxel in the dMMR/MSI-H population.

In addition, the safety and tolerability profile of dostarlimab in combination with carboplatin-paclitaxel was generally consistent with the known safety profiles of the individual agents.

The results were presented on 27 March 2023 at a European Society for Medical Oncology Virtual Plenary and the Society of Gynecologic Oncology Annual Meeting and simultaneously published in The New England Journal of Medicine.

Hesham Abdullah, Senior Vice President, Global Head of Oncology Development, GSK said: “New treatment options are urgently needed for patients with primary advanced or recurrent endometrial cancer. With this initial filing, we are accelerating the submission of a potential new indication for dostarlimab in the patient population that demonstrated the strongest treatment effect in the RUBY phase III trial.

These patients currently face significant unmet medical needs, and this combination could change the treatment paradigm for this condition. The RUBY phase III trial continues to follow patients for the dual-primary endpoint of overall survival in the intent-to-treat population.”

GSK expects US regulatory filing review based on the RUBY phase III trial results to occur in the first half of 2023.

About endometrial cancer
Endometrial cancer is found in the inner lining of the uterus, known as the endometrium.

Endometrial cancer is the most common gynaecologic cancer in developed countries, with approximately 417,000 new cases reported each year worldwide, and incidence rates are expected to rise by almost 40% by 2040.

Approximately 15-20% of patients with endometrial cancer will be diagnosed with advanced disease at the time of diagnosis.

About RUBY
RUBY is a two-part global, randomised, double-blind, multicentre phase III trial of patients with primary advanced or recurrent endometrial cancer.

Part 1 is evaluating dostarlimab plus carboplatin-paclitaxel followed by dostarlimab versus carboplatin-paclitaxel plus placebo followed by placebo.

Part 2 is evaluating dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib versus placebo plus carboplatin-paclitaxel followed by placebo.

The primary endpoints in Part 1 are investigator-assessed PFS based on the Response Evaluation Criteria in Solid Tumours v1.1 and overall survival (OS).

The statistical analysis plan included pre-specified analyses of PFS in the dMMR/MSI-H and intent-to-treat populations and OS in the overall population. Pre-specified exploratory analyses of PFS in the mismatch repair proficient/microsatellite stable population and OS in the dMMR/MSI-H populations were also performed.

RUBY Part 1 included a broad population, including histologies often excluded from clinical trials and had approximately 10% of patients with carcinosarcoma and 20% with serous carcinoma.

In Part 2, the primary endpoint is investigator-assessed PFS. Secondary endpoints in Part 1 and Part 2 include PFS per blinded independent central review, overall response rate, duration of response, disease control rate, patient-reported outcomes, and safety and tolerability.

About Jemperli (dostarlimab)
Jemperli is a programmed death receptor-1 (PD-1)-blocking antibody that binds to the PD-1 receptor and blocks its interaction with the PD-1 ligands PD-L1 and PD-L2.

Jemperli is not approved anywhere in the world for use in combination with standard-of-care chemotherapy (carboplatin-paclitaxel) followed by dostarlimab for primary advanced or recurrent endometrial cancer.

In the US, Jemperli is approved for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by a US FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and are not candidates for curative surgery or radiation. 

Jemperli is also indicated in the US for patients with dMMR recurrent or advanced solid tumours, as determined by a US FDA-approved test, that have progressed on or following prior treatment and have no satisfactory alternative treatment options.

The latter indication is approved in the US under accelerated approval based on tumour response rate and durability of response.

Continued approval for this indication in solid tumours may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Jemperli was discovered by AnaptysBio, Inc. and licensed to TESARO, Inc., under a collaboration and exclusive license agreement signed in March 2014.

The collaboration has resulted in three monospecific antibody therapies that have progressed into the clinic. These are: Jemperli (GSK4057190), a PD-1 antagonist; cobolimab, (GSK4069889), a TIM-3 antagonist; and GSK4074386, a LAG-3 antagonist.

GSK is responsible for the ongoing research, development, commercialisation, and manufacturing of each of these medicines under the agreement.

Important Information for Jemperli in the EU

Indication 
Jemperli is indicated as monotherapy for treating adult patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.

Refer to the Jemperli EMA Reference Information for a full list of adverse events and the complete important safety information in the EU.

GSK in oncology
GSK is committed to maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, tumour cell targeting therapies and synthetic lethality.

Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, and antibody-drug conjugates, either alone or in combination.”

https://www.gsk.com/en-gb/media/press-releases/european-medicines-agency-validates-marketing-authorisation-application-for-jemperli-dostarlimab/

FDA Authorizes Changes to Simplify Use of Bivalent mRNA COVID-19 Vaccines

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FDA Authorizes Changes to Simplify Use of Bivalent mRNA COVID-19 Vaccines

April 18, 2023: “The U.S. FDA amended the emergency use authorizations (EUAs) of the Moderna and Pfizer-BioNTech COVID-19 bivalent mRNA vaccines to simplify the vaccination schedule for most individuals.

This action includes authorizing the current bivalent vaccines (original and omicron BA.4/BA.5 strains) to be used for all doses administered to individuals 6 months of age and older, including for an additional dose or doses for certain populations.

The monovalent Moderna and Pfizer-BioNTech COVID-19 vaccines are no longer authorized for use in the United States.

What You Need to Know:

  • Most individuals, depending on age, previously vaccinated with a monovalent Coronavirus treatment: List of Vaccines and drugs in the pipeline for COVID-19 vaccine who have not yet received a dose of a bivalent vaccine may receive a single dose of a bivalent vaccine. 
  • Most individuals who have already received a single dose of the bivalent vaccine are not currently eligible for another dose.

    The FDA intends to make decisions about future vaccination after receiving recommendations on the fall strain composition at an FDA advisory committee in June.
  • Individuals 65 years of age and older who have received a single dose of a bivalent vaccine may receive one additional dose at least four months following their initial bivalent dose. 
  • Most individuals with certain kinds of immunocompromise who have received a bivalent COVID-19 vaccine may receive a single additional dose of a bivalent COVID-19 vaccine at least 2 months following a dose of a bivalent COVID-19 vaccine, and additional doses may be administered at the discretion of, and at intervals determined by, their healthcare provider.
  • However, for immunocompromised individuals 6 months through 4 years of age, eligibility for additional doses will depend on the vaccine previously received.
     
  • Most unvaccinated individuals may receive a single dose of a bivalent vaccine, rather than multiple doses of the original monovalent mRNA vaccines. 
  • Children 6 months through 5 years of age who are unvaccinated may receive a two-dose series of the Moderna bivalent vaccine (6 months through 5 years of age) OR a three-dose series of the Pfizer-BioNTech bivalent vaccine (6 months through 4 years of age).

    Children who are 5 years of age may receive two doses of the Moderna bivalent vaccine or a single dose of the Pfizer-BioNTech bivalent vaccine.
     
  • Children 6 months through 5 years of age who have received one, two or three doses of a monovalent COVID-19 vaccine may receive a bivalent vaccine, but the number of doses that they receive will depend on the vaccine and their vaccination history.

“At this stage of the pandemic, data support simplifying the use of the authorized mRNA bivalent COVID-19 vaccines and the agency believes that this approach will help encourage future vaccination,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

“Evidence is now available that most of the U.S. population 5 years of age and older has antibodies to SARS-CoV-2, the virus that causes COVID-19, either from vaccination or infection that can serve as a foundation for the protection provided by the bivalent vaccines.

COVID-19 continues to be a very real risk for many people, and we encourage individuals to consider staying current with vaccination, including with a bivalent COVID-19 vaccine.

The available data continue to demonstrate that vaccines prevent the most serious outcomes of COVID-19, which are severe illness, hospitalization, and death.”

Available data show that almost all of the U.S. population 5 years of age and older now have antibodies as a result of either vaccination or infection against SARS-CoV-2.

The use of bivalent COVID-19 vaccines for all doses administered to individuals 6 months of age and older is supported by the data described below, as well as post-marketing data, including real-world data, with the monovalent and bivalent mRNA COVID-19 vaccines, which have been administered to millions of people, including young children.

A second bivalent dose for individuals 65 years of age and older is supported by data showing the waning of immunity in this population over time and its restoration by an additional dose.  Additionally, based on evidence from studies conducted previously, immunocompromised individuals may require additional doses.

Moderna COVID-19 Vaccine, Bivalent

The safety and effectiveness of Moderna COVID-19 Vaccine, Bivalent is based on FDA’s previous analyses of clinical trials data of monovalent Moderna COVID-19 Vaccine in individuals 6 months of age and older and an investigational bivalent Moderna COVID-19 vaccine (original and omicron BA.1) in individuals 18 years of age and older. 

In addition, effectiveness of a single dose is supported by the FDA’s analysis of immune response data from clinical studies in which 145 individuals 6 years of age and older who had evidence of prior SARS-CoV-2 infection and 1,376 individuals 6 years of age and older without evidence of prior SARS-CoV-2 infection had received two doses of monovalent Moderna COVID-19 Vaccine.

The immune response after one dose of vaccine among participants with evidence of prior infection was comparable to the immune response after two doses among participants without evidence of prior infection.

The data accrued with the investigational bivalent Moderna COVID-19 vaccine (original and omicron BA.1) and with the monovalent Moderna COVID-19 Vaccine are relevant to the Moderna COVID-19 Vaccine, Bivalent because these vaccines are manufactured using the same process.

Pfizer-BioNTech COVID-19 Vaccine, Bivalent

The safety and effectiveness of Pfizer-BioNTech COVID-19 Vaccine, Bivalent is based on the FDA’s previous analyses of clinical trials data of monovalent Pfizer-BioNTech COVID-19 Vaccine for use in individuals 6 months of age and older, an investigational bivalent Pfizer-BioNTech COVID-19 vaccine (original and omicron BA.1) in individuals greater than 55 years of age, as well as safety data with Pfizer-BioNTech COVID-19 Vaccine, Bivalent (original and omicron BA.4/BA.5) in individuals 6 months of age and older and immune response data in individuals 6 months through 4 years of age.  

In addition, effectiveness of a single dose is supported by observational data from England on the effectiveness of one dose of monovalent Pfizer-BioNTech COVID-19 Vaccine.

Among individuals 12 to 17 years of age who had received only one dose of Pfizer-BioNTech COVID-19 Vaccine, those who had evidence of previous infection with alpha, delta or omicron variants had increased protection against symptomatic omicron infection compared with those with no evidence of previous infection. 

The data accrued with the investigational Pfizer-BioNTech bivalent COVID-19 vaccine (original and omicron BA.1) and with the monovalent Pfizer-BioNTech COVID-19 Vaccine are relevant to the Pfizer-BioNTech COVID-19 Vaccine, Bivalent because these vaccines are manufactured using the same process.

With today’s authorizations, the fact sheets have been updated and consolidated for the Moderna COVID-19 Vaccine, Bivalent and the Pfizer-BioNTech COVID-19 Vaccine, Bivalent.

Each vaccine now has one fact sheet for healthcare providers and one fact sheet for recipients and caregivers, rather than different fact sheets for the various authorized age groups. 

Vaccines and Related Biological Products Advisory Committee

Today’s authorizations follow discussions that occurred during a meeting with the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Jan. 26.

At that time, by a unanimous vote, the committee recommended harmonizing the strain composition of COVID-19 vaccines used in the U.S. There was also support for simplifying the vaccine dosing schedule. 

In June, the FDA will hold a meeting of its VRBPAC to discuss the strain composition of the COVID-19 vaccines for fall of 2023. Much like the FDA does yearly with the influenza vaccines, the agency will seek input from the committee on which SARS-CoV-2 variants and lineages are most likely to circulate in the upcoming year.

Once the specific strains are selected for the COVID-19 vaccines, the FDA expects manufacturers to make updated formulations of the vaccines for availability this fall.

The amendments to the EUAs were issued to ModernaTX Inc. and Pfizer Inc.”

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-changes-simplify-use-bivalent-mrna-covid-19-vaccines

Bayer’s New data from pivotal studies with aflibercept 8 mg

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Bayer’s New data from pivotal studies with aflibercept 8 mg

April 17, 2023: “Bayer and its collaborator Regeneron will present new clinical data analyses for the investigational formulation aflibercept 8 mg at the Annual Meeting of The Association for Research in Vision and Ophthalmology (arvo.org) 2023, in New Orleans, Louisiana, 23-27 April 2023.

The data will highlight Bayer’s commitment to advancing the unmet need of extended treatment intervals in exudative retinal disease.

New subgroup and further analyses of the pivotal studies PULSAR, PHOTON and CANDELA will provide further insights into durability results of extended treatment intervals, patient characteristics as well as efficacy and safety of aflibercept 8 mg versus aflibercept 2 mg (EyleaTM) in patients with neovascular (wet) age-related macular degeneration (nAMD) and diabetic macular degeneration (DME).

The following new abstracts for aflibercept 8 mg will be presented at ARVO 2023:

The pooled safety analysis compares the safety of aflibercept 8 mg with aflibercept 2 mg across the clinical trial program which includes data from the phase II trial CANDELA in nAMD and the pivotal phase II/III trial PHOTON in DME and the phase III trial PULSAR in nAMD.

· Pooled Safety Analysis of Aflibercept 8 mg in the CANDELA, PHOTON, and PULSAR Trials

o Poster presentation # 3724 – C0501

o April 25, 2023; 15.30-17.15 EST

The analysis of the phase III trial PULSAR reports safety and tolerability outcomes of aflibercept 8 mg every 12 or 16 weeks versus aflibercept 2 mg every 8 weeks through to week 48.

· Tolerability and safety of intravitreal aflibercept 8 mg in the phase III PULSAR trial of patients with neovascular (wet) age-related macular degeneration

o Poster presentation # 278 – C0115

o April 23, 2023; 8.00-9.45 EST

The post-hoc analysis of the phase III trial PULSAR describes baseline characteristics of patients maintained on their original randomized dosing regimens of aflibercept 8 mg every 12 or 16 weeks or aflibercept 2 mg every 8 weeks versus those who had shortened intervals according to prespecified dose regimen modification criteria denoting disease activity.

· Baseline disease characteristics in patients maintaining q12 and q16 dosing with aflibercept 8 mg versus patients with shortened treatment intervals: A Phase 3 PULSAR post hoc analysis

o Poster presentation # 2238-C0192

o April 24, 2023; 15.15-17.00 EST

In a subgroup analysis from the phase III trial PULSAR the treatment effect on the primary endpoint in patients with treatment-naïve nAMD was determined for clinically relevant subgroups by baseline BCVA, central retinal thickness (CRT) or lesion type.

· Subgroup analyses from the Phase 3 PULSAR trial of aflibercept 8 mg in patients with treatment-naïve neovascular age-related macular degeneration

o Poster presentation # 2239 – C0191

o April 24, 2023; 15.15-17.00 EST

The analysis of the PHOTON trial evaluates baseline clinical characteristics of patients with diabetic macular edema (DME) who received intravitreal aflibercept 8 mg and maintained their randomized dosing intervals versus those whose intervals were shortened after meeting prespecified criteria through Week 48.

· Baseline Disease Characteristics of Patients Who Maintained 12- and 16-Week Aflibercept 8 mg Dosing Versus Patients with Shortened Treatment Intervals Through Week 48 in the Phase 2/3 PHOTON Trial

o Podium presentation

o April 25, 2023; 12.15-12.30 EST

The analysis of the PHOTON trial evaluates the treatment effects of aflibercept 8 mg versus 2 mg at Week 48 in patients with diabetic macular edema (DME) by baseline demographics.

· Intravitreal Aflibercept 8 mg for Diabetic Macular Edema: Week 48 Efficacy Outcomes by Baseline Demographics in the Phase 2/3 PHOTON Trial

o Poster presentation # 2707 – B0529

o April 25, 2023; 8.45-10.30 EST

Aflibercept 8 mg is being jointly developed by Bayer and Regeneron. Regeneron maintains exclusive rights to Eylea and aflibercept 8 mg in the United States. Bayer has licensed the exclusive marketing rights outside the United States, where the companies share equally the profits from sales of Eylea.

Aflibercept 8 mg is investigational, and its safety and efficacy have not yet been evaluated by any regulatory authority.

About aflibercept 8 mg
Aflibercept 8 mg has been developed with the aim to increase intervals between injections without compromising vision gains.

Aflibercept 8 mg was investigated in neovascular (wet) age-related macular degeneration (PULSAR) and diabetic macular edema (PHOTON) to evaluate efficacy and safety compared to Eylea (aflibercept 2 mg).

About PULSAR, PHOTON and CANDELA
PULSAR and PHOTON are double-masked, active-controlled pivotal trials. Both trials were conducted in multiple centers globally with similar designs and endpoints.

The Phase III PULSAR trial in nAMD and Phase II/III PHOTON trial in DME evaluated the efficacy and safety of aflibercept 8 mg with 12- and 16-week dosing regimens versus Eylea (aflibercept 2 mg) dosed every 8 weeks, following initial monthly doses, with the primary endpoint of non-inferiority in terms of best corrected visual acuity (BCVA) at week 48.

Patients in both clinical trials were randomized at baseline and assigned to the three different arms.

Across both studies, 1,164 patients were treated with aflibercept 8 mg. All patients in the aflibercept 8 mg arms were continuously evaluated under stringent, clinically relevant, patient focused dose regimen modification (DRM) criteria starting from week 16 throughout the study.

In the first year, patients in the aflibercept 8 mg groups could have their dosing intervals shortened down to an every 8-week interval if DRM criteria for disease progression were observed.

Intervals could not be extended until the second year of the study, with those results still to be assessed.

Patients in all Eylea groups maintained a fixed 8-week dosing regimen throughout their participation in the trials.

CANDELA was a Phase II trial investigating aflibercept 8 mg with regards to safety and efficacy and to determine if aflibercept 8 mg provides longer durability compared to Eylea (aflibercept 2 mg) in patients with nAMD.

About nAMD and DME
Neovascular (wet) age-related macular degeneration (nAMD) is an eye disease that progresses rapidly and if left untreated can lead to vision loss in as little as three months.

nAMD is one of the leading causes of irreversible blindness and vision impairment around the world.

nAMD may affect people as they age. It occurs when abnormal blood vessels grow and leak fluid under the macula, the part of the eye responsible for sharp central vision and seeing fine detail.

This fluid can damage and scar the macula, which can cause vision loss. 196 million people worldwide are living with AMD – it is anticipated that this figure will increase to 288 million by 2040.

Diabetic macular edema (DME) is a common complication in eyes of people living with diabetes. DME occurs when high levels of blood sugar lead to damaged blood vessels in the eye that leak fluid into the macula.

This can lead to vision loss and, in some cases, blindness. Globally, 146 million people are currently living with diabetic retinopathy (DR), which can develop into a more serious condition which is diabetic macular edema (DME).”

https://www.bayer.com/media/en-us/new-data-from-pivotal-studies-with-aflibercept-8-mg/#

BMS Submits Application for Abecma® for Relapsed or Refractory Multiple Myeloma

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April 17, 2023: “Bristol-Myers Squibb announced that the company has submitted the supplemental New Drug Application for the manufacturing and marketing approval of an additional indication for Abecma® (idecabtagene vicleucel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell immunotherapy, for patients with relapsed or refractory multiple myeloma (RR/MM) who have received at least two prior regimens, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

The application is based on the interim analysis from KarMMa-3 (BB2121-MM-003), a global phase 3 study that evaluated the efficacy and safety of Abecma® in subjects with relapsed or refractory multiple myeloma who had received two to four prior regimens, including an immunomodulatory agent, a proteasome inhibitor, and daratumumab.

Multiple myeloma is a disease in which plasma cells—differentiated B cells—transform into cancerous myeloma cells, which grow primarily in the bone marrow. Plasma cells produce antibodies that protect the body from invasive foreign substances, such as bacteria and viruses.

When transforming into cancerous myeloma cells, however, plasma cells continue to produce monoclonal immunoglobulin (M protein) that is not capable of attacking the foreign substances.

The increase in myeloma cells and M protein causes a variety of clinical manifestations, including hematopoietic disorders (mainly anemia), kidney damage, and osteolytic lesions.

Despite advances in treatment, multiple myeloma repeatedly recurs after initial response to treatment, with increased malignancy with an increasing number of therapies, ultimately progressing to a refractory state. 

In patients with RR/MM treated with the three major drug classes, including proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibodies, the prognosis is poor regardless of the number of prior therapies, and treatment options are limited.

In recent years, there has also been an increase in the use of anti-CD38 antibodies in combination with immunomodulatory agents or proteasome inhibitors for the initial treatment or at the first relapse.

Thus, there is a need for drugs with novel mechanisms of action, highly effective in patients with multiple myeloma who have relapsed or are refractory to these treatments, irrespective of the number of lines of therapy received.

Commenting on the application acceptance, Makoto Sugita, Bristol Myers Squibb’s head of R&D in Japan, said, “We participate in almost global studies conducted by BMS, undertaking simultaneous development and submission, in order to bring new treatment options as quickly as possible to patients in Japan suffering from serious diseases.

We are pleased that we achieved nearly simultaneous filing with the United States and the European Union for approval of Abecma® for use in earlier lines of treatment.

We hope to be able to offer the option of CAR T cell therapy to patients with relapsed or refractory multiple myeloma in Japan in their earlier treatment stages at the same time as the U.S. and Europe.”

About KarMMa-3 (Study BB2121-MM-003)
KarMMa-3 (BB2121-MM-003) is a pivotal, Phase 3, open-label, global, randomized, controlled trial evaluating Abecma compared to standard regimens in patients with relapsed and refractory multiple myeloma who have received two to four prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and daratumumab and were refractory to the last treatment regimen.

Patients were randomized to receive Abecma or standard regimens that consisted of combinations that included daratumumab, pomalidomide, and dexamethasone (DPd), daratumumab, bortezomib, and dexamethasone (DVd), ixazomib, lenalidomide, and dexamethasone (IRd), carfilzomib and dexamethasone (Kd) or elotuzumab, pomalidomide and dexamethasone (EPd) chosen by investigators based on their most recent treatment regimen.

The primary endpoint evaluated in this study is progression-free survival, defined as time from randomization to the first documentation of progressive disease or death due to any cause, whichever occurs first.

Key secondary endpoints include overall response rate and overall survival.

About Abecma
Abecma is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell immunotherapy. 

Abecma recognizes and binds to BCMA on the surface of multiple myeloma cells, which leads to the proliferation of CAR T cells and cytokine release, resulting in the dissolution and death of BCMA-expressing cells.

In Japan, Abecma was approved for manufacturing and marketing on January 20, 2022, and indicated for patients with relapsed or refractory multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody.

Overseas, in the United States, Abecma was approved in March 2021 for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

In the EU, Abecma was approved for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.

In addition, Abecma has been approved for production and marketing in Canada, Switzerland, Great Britain, and Israel.

Based on the interim results of the KarMMa-3 study, applications for the earlier use of Abecma have been filed in the United States, in the EU and in Japan.

Abecma U.S. FDA-Approved Indication

ABECMA (idecabtagene vicleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. 

U.S. Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders.
    Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
  • Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA.
    Provide supportive care and/or corticosteroids as needed.
  • Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
  • Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA.
  • ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS

WARNINGS AND PRECAUTIONS:
Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA in 85% (108/127) of patients. Grade 3 or higher CRS occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient.

The median time to onset of CRS, any grade, was 1 day (range: 1 – 23 days) and the median duration of CRS was 7 days (range: 1 – 63 days). The most common manifestations included pyrexia, hypotension, tachycardia, chills, hypoxia, fatigue, and headache.

Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome, and HLH/MAS.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension.

CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap.

In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Fifty four percent (68/127) of patients received tocilizumab (single dose: 35%; more than 1 dose: 18%).

Overall, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS.

All patients that received corticosteroids for CRS received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of CRS and monitor patients for signs or symptoms of CRS for at least 4 weeks after ABECMA infusion.

At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic Toxicities: Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death.

Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 – 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median time to resolution of 5 days (range: 1 – 61 days).

The median duration of neurotoxicity was 6 days (range: 1 – 578) in all patients including 3 patients with ongoing neurotoxicity.

Thirty-four patients with neurotoxicity had CRS with onset in 3 patients before, 29 patients during, and 2 patients after CRS. The most frequently reported manifestations of CAR T cell-associated neurotoxicity include encephalopathy, tremor, aphasia, and delirium.

Grade 4 neurotoxicity and cerebral edema in 1 patient, Grade 3 myelitis, and Grade 3 parkinsonism have been reported with ABECMA in another study in multiple myeloma.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of neurologic toxicities and monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after ABECMA infusion and treat promptly.

Rule out other causes of neurologic symptoms. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms occur at any time.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient developed fatal multi-organ HLH/MAS with CRS and another patient developed fatal bronchopulmonary aspergillosis with contributory HLH/MAS. Three cases of Grade 2 HLH/MAS resolved.

All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4 – 9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity.

The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia.

HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional guidelines.

ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS.
Further information is available at www.AbecmaREMS.com or 1-888-423-5436.

Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.

Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients.

Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines.

Febrile neutropenia was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care.

Viral Reactivation: CMV infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: In the clinical study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months.

Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support.

Hypogammaglobulinemia: Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA.

Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage appropriately per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

The safety of immunization with live viral vaccines during or after ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.

Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion.

Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions: The most common nonlaboratory adverse reactions include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.”

https://investors.bms.com/iframes/press-releases/press-release-details/2023/Bristol-Myers-Squibb-Submits-Application-for-Abecma–a-CAR-T-Cell-Therapy-for-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma-Who-Have-Received-at-Least-Two-Prior-Therapies-/default.aspx

FDA Approves Cell Therapy for Patients with Blood Cancers to Reduce Risk of Infection Following Stem Cell Transplantation

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FDA Approves Cell Therapy for Patients with Blood Cancers to Reduce Risk of Infection Following Stem Cell Transplantation

April 17, 2023: “The U.S. FDA approved Omisirge (omidubicel-onlv), a substantially modified allogeneic (donor) cord blood-based cell therapy to quicken the recovery of neutrophils (a subset of white blood cells) in the body and reduce the risk of infection.

The product is intended for use in adults and pediatric patients 12 years and older with blood cancers planned for umbilical cord blood transplantation following a myeloablative conditioning regimen (treatment such as radiation or chemotherapy). 

“Today’s approval is an important advance in cell therapy treatment in patients with blood cancers,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

“Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation.

This approval reflects the FDA’s continued commitment to supporting development of innovative therapies for life-threatening cancers.”

Blood cancers are a form of cancer caused by uncontrolled growth of cells in the blood, disrupting the ability of blood cells to perform their normal functions.

This abnormal cell growth often begins in the bone marrow, which is made up of stem cells that form into different types of blood cells with specific functions in the body. Blood cancers represent about 10% of all cases of cancer each year in the U.S. Blood cancers can be fatal, with varying survival rates based on multiple factors including the specific type of blood cancer diagnosed.

This type of cancer can also cause serious and damaging effects to the body and lead to symptoms such as fatigue, bone and joint pain, night sweats, infections, weakness, weight loss and fever. 

Stem cell transplantation is a common treatment for blood cancers. It involves putting healthy stem cells into the body to help restore the normal production and function of blood cells.

One source of healthy stem cells is umbilical cord blood. Generally, before receiving this kind of transplant, the patient will undergo a course of treatments to remove their own stem cells and prepare the body for the new stem cells.

This process may include undergoing therapies such as radiation or chemotherapy, both of which may weaken an individual’s immune system. As a result, a frequent and serious risk of this treatment is the occurrence of severe and sometimes deadly infections.

Omisirge, administered as a single intravenous dose, is composed of human allogeneic stem cells from umbilical cord blood that are processed and cultured with nicotinamide (a form of vitamin B3). Each dose is patient-specific, containing healthy stem cells from an allogeneic pre-screened donor, meaning it comes from a different individual rather than using the patient’s own cells. 

The safety and effectiveness of Omisirge was supported by a randomized, multicenter study comparing transplantation of Omisirge to transplantation of umbilical cord blood, in subjects between the ages of 12 and 65 years. The study enrolled a total of 125 subjects.

All subjects in the study had confirmed blood cancers. The efficacy of Omisirge was based on the amount of time needed for recovery of the subject’s neutrophils (a type of white blood cell that helps protect the body from infections) and the incidence of infections following transplantation.

Eighty-seven percent of subjects who were randomized to receive Omisirge achieved neutrophil recovery with a median of 12 days following treatment with the product, compared to 83% of subjects who were randomized to receive umbilical cord blood transplantation and who achieved neutrophil recovery with a median of 22 days.

Bacterial or fungal infections by 100 days following transplantation were seen in 39% of subjects receiving Omisirge versus 60% of subjects in the control group who received umbilical cord blood.

Treatment with Omisirge has the potential to cause severe side effects, which must be considered in assessing the risks and benefits of using this product.

Similar to all approved umbilical cord products, the label carries a Boxed Warning for infusion reactions, graft versus host disease (GvHD – a condition that occurs when donor bone marrow or stem cells attack the graft recipient), engraftment syndrome (characterized by a noninfectious fever and rash), and graft failure (occurs when new cells do not produce white blood cells, red blood cells and platelets). 

The most common adverse reactions associated with Omisirge included infections, GvHD, and infusion reactions.

Patients who receive Omisirge should be monitored for signs and symptoms of infusion reactions, GvHD, engraftment syndrome, graft failure, transmission of serious infections or rare genetic diseases from the donor cells, as well as life-long for secondary malignancies (cancers that can spread from the original site or emerge following treatment). 

This application received Priority Review, Breakthrough Therapy and Orphan designations. 

The FDA granted regular approval of Omisirge to Gamida Cell Ltd.”

https://www.fda.gov/news-events/press-announcements/fda-approves-cell-therapy-patients-blood-cancers-reduce-risk-infection-following-stem-cell

Update to contractual arrangements between AstraZeneca, Swedish Orphan Biovitrum AB and Sanofi

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Update to contractual arrangements between AstraZeneca, Swedish Orphan Biovitrum AB and Sanofi

April 11, 2023: “AstraZeneca, Swedish Orphan Biovitrum AB (publ) (Sobi) and Sanofi have updated and simplified their contractual arrangements relating to the development and commercialisation of nirsevimab in the US.

Given the upcoming launch of nirsevimab in the US and other markets, simplification of the prior arrangements clarifies the roles and responsibilities of relevant parties.  

Under the updated arrangements, Sobi has entered into a direct relationship with Sanofi, replacing the previous participation agreement with AstraZeneca entered into in November 2018.

Under the previous agreement, from the day of the transaction with Sobi, AstraZeneca had to provision the risk adjusted value of the discounted cash flow of future payments to be made to Sobi as a liability.

As a result of this simplification agreement, Sanofi will pay royalties to Sobi as US nirsevimab sales arise, and the liability related to future obligations is eliminated.

AstraZeneca will record a gain of $0.7 billion, to be recognised in Core Other operating income in 2023. This does not impact AstraZeneca’s financial guidance for 2023.

Notes

About nirsevimab
Nirsevimab is a single dose long-acting antibody, developed and commercialised in partnership by AstraZeneca and Sanofi using AstraZeneca’s YTE technology.

It is designed to protect infants entering or during their first respiratory syncytial virus (RSV) season and for children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.

Nirsevimabhas been developed to offer newborns and infants direct RSV protection via an antibody to help prevent lower respiratory tract disease (LRTD) caused by RSV.Monoclonal antibodies do not require the activation of the immune system to help offer timely, rapid and direct protection against disease.

In November 2022, Beyfortus was approved by the European Commission and by the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Sanofi Alliance
In March 2017, AstraZeneca and Sanofi announced an agreement to develop and commercialise nirsevimab.

Under the terms of the agreement, AstraZeneca leads development and manufacturing activities, and Sanofi leads commercialisation activities and records revenue.

Under the terms of the global agreement, Sanofi made an upfront payment of €120m, has paid a development milestone of €30m and will pay further milestones subject to achievement of certain development and sales-related milestones.

The two companies share costs and profits. Revenue from the agreement is reported as Alliance Revenue and Collaboration Revenue in the Company’s financial statements.”

https://www.astrazeneca.com/media-centre/press-releases/2023/update-to-arrangements-with-sobi-and-sanofi.html

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