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Eli’s Jardiance (empagliflozin) becomes first SGLT2 inhibitor to show benefit in HFpEF

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Eli’s Jardiance (empagliflozin) becomes first SGLT2 inhibitor to show benefit in HFpEF

July 6, 2021: The EMPEROR-Preserved phase III trial met its primary endpoint, establishing Jardiance® (empagliflozin) as the first and only therapy to significantly reduce the risk of the composite of cardiovascular death or hospitalization for heart failure in adults, with or without diabetes, who live with heart failure with preserved ejection fraction (HFpEF). 

Boehringer Ingelheim and Eli Lilly and Company announced the topline results.

When added to the EMPEROR-Reduced trial results, these findings demonstrate Jardiance’s efficacy in all forms of heart failure regardless of ejection fraction.

The safety profile was generally consistent with the known safety profile of Jardiance.

“We look forward to presenting the EMPEROR-Preserved results at ESC 2021, which should offer a significant breakthrough in cardiovascular medicine and a new hope for people with HFpEF, which is an increasingly prevalent public health issue. HFpEF has long been the most challenging form of heart failure to treat,” said Professor Stefan Anker, heart failure cardiologist at Charité Berlin, Germany, and EMPEROR-Preserved principal investigator.

“Building on previous results from the EMPA-REG OUTCOME trial, and the EMPEROR-Reduced trial in heart failure with reduced ejection fraction, the EMPEROR-Preserved findings demonstrate that empagliflozin reduces cardiovascular death or hospitalization for heart failure and has the potential to transform the care of people living with heart failure.”

Heart failure poses a significant global disease burden: more than 60 million patients worldwide have heart failure, and half of them have HFpEF.

Heart failure is a leading cause of hospitalization and is becoming increasingly prevalent in Western countries due to aging populations. The risk of death in people with heart failure rises with each hospital admission.

Heart failure with left ventricular preserved ejection fraction occurs when the left ventricle of the heart is unable to fill properly, resulting in less blood being pumped to the body.

“No approved therapies have been clinically proven to improve outcomes specifically for people with HFpEF, leaving a significant unmet medical need in this already prevalent and increasingly common form of heart failure,” said Mohamed Eid, M.D., M.P.H., M.H.A., vice president, Clinical Development & Medical Affairs, Cardio-Metabolism & Respiratory Medicine, Boehringer Ingelheim Pharmaceuticals, Inc. 

“The totality of the data from the EMPEROR-Preserved trial marks a possible new chapter in heart failure, supporting the potential of Jardiance to become the first SGLT2 inhibitor to treat a defined population of adults with heart failure with either preserved or reduced ejection fraction.”

“Jardiance was the first SGLT2 inhibitor to reduce cardiovascular death for people with type 2 diabetes and cardiovascular disease, and we have now reached another important milestone, this time in heart failure,” added Jeff Emmick, M.D., Ph.D., vice president, Product Development, Lilly.

“The EMPEROR-Preserved results offer promise in a type of heart failure that until now has traditionally been very challenging to treat effectively.

The EMPEROR heart failure studies are part of our EMPOWER clinical trial program exploring the effect of Jardiance across a spectrum of cardio-renal-metabolic diseases, aiming to significantly improve outcomes in these highly prevalent conditions that impact many people’s lives.”

The EMPEROR-Preserved trial investigated Jardiance 10 mg compared with placebo. Full results from the EMPEROR-Preserved trial are scheduled for presentation at the European Society of Cardiology (ESC) Congress 2021 on August 27. Boehringer Ingelheim and Lilly plan for regulatory submissions in 2021.

These results add to previous findings from the EMPEROR-Reduced phase III trial, which showed that Jardiance significantly reduced the combined relative risk of cardiovascular death or hospitalization for heart failure by 25% compared to placebo in adults with heart failure with reduced ejection fraction (HFrEF).

Together, these studies demonstrate the benefits of Jardiance for patients across the full heart failure spectrum (including HFrEF and HFpEF).

The EMPEROR-Reduced results formed the basis of the recent approval of a new indication for Jardiance for the treatment of adults with HFrEF by the European Commission. In the U.S., Jardiance is not approved for the treatment of heart failure. 

A supplemental New Drug Application (sNDA) for Jardiance to reduce the risk of cardiovascular death or hospitalization for heart failure in adults with HFrEF has been submitted to the U.S. Food and Drug Administration (FDA), with a decision expected later this year.

Research is ongoing regarding Jardiance’s effects on hospitalization for heart failure and mortality in post-myocardial infarction (heart attack) patients with high risk of heart failure. Jardiance is also currently being investigated in chronic kidney disease.

About the EMPEROR Heart Failure Studies 
The EMPEROR (EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure) heart failure studies are two phase III, randomized, double-blind trials investigating once-daily Jardiance compared with placebo in adults with heart failure with preserved or reduced ejection fraction*, both with and without diabetes, who are receiving current standard of care:

  • EMPEROR-Reduced [NCT03057977] investigated the safety and efficacy of Jardiance in patients with chronic heart failure with reduced ejection fraction (HFrEF).
    • Primary endpoint: time to first event of adjudicated cardiovascular death or adjudicated hospitalization for heart failure
    • Number of patients: 3,730
    • Completion: 2020
  • EMPEROR-Preserved [NCT03057951] investigated the safety and efficacy of Jardiance in patients with chronic heart failure with preserved ejection fraction (HFpEF).
    • Primary endpoint: time to first event of adjudicated cardiovascular death or adjudicated hospitalization for heart failure [Time Frame: up to 38 months]
    • Number of patients: 5,988
    • Completion: 2021

*Ejection fraction is a measurement of the percentage of blood the left ventricle pumps out with each contraction. When the heart relaxes, the ventricle refills with blood.

  • HFrEF occurs when the heart muscle does not contract effectively, and less blood is pumped out to the body compared with a normally functioning heart. 
  • HFpEF occurs when the heart muscle contracts normally but the ventricle does not fill with enough blood, so less blood can enter the heart compared with a normally functioning heart. 

About the EMPOWER program
The Alliance has developed the EMPOWER program to explore the impact of Jardiance on major clinical cardiovascular and renal outcomes in a spectrum of cardio-renal-metabolic conditions.

Cardio-renal-metabolic conditions are the leading cause of mortality worldwide and account for up to 20 million deaths annually.

Through the EMPOWER program, Boehringer Ingelheim and Lilly are working to advance knowledge of these interconnected systems and create care which offers integrated, multi-organ benefits.

Comprised of nine clinical trials and two real-world evidence studies, EMPOWER reinforces the long-term commitment of the Alliance to improve outcomes for people living with cardio-renal-metabolic conditions.

With more than 400,000 adults enrolled worldwide in clinical trials, it is one of the broadest and most comprehensive clinical programs for an SGLT2 inhibitor to date. 

The development program encompasses:

  • EMPEROR-Reduced, in adults with chronic heart failure with reduced ejection fraction to reduce the risk of cardiovascular death or hospitalization due to heart failure
  • EMPEROR-Preserved, in adults with chronic heart failure with preserved ejection fraction to reduce the risk of cardiovascular death or hospitalization due to heart failure
  • EMPULSE, in adults hospitalized for acute heart failure and stabilized to improve clinical and patient reported outcomes
  • EMPACT-MI, to evaluate all-cause mortality and hospitalization for heart failure in adults with and without type 2 diabetes who have had an acute myocardial infarction, with the aim to prevent heart failure and improve outcomes
  • EMPA-KIDNEY, in adults with established chronic kidney disease to reduce the progression of kidney disease and the occurrence of cardiovascular death
  • EMPERIAL-Reduced, in adults with chronic heart failure with reduced ejection fraction to evaluate functional ability and patient-reported outcomes
  • EMPERIAL-Preserved, in adults with chronic heart failure with preserved ejection fraction to evaluate functional ability and patient-reported outcomes
  • EMPA-REG OUTCOME®, in adults with type 2 diabetes and established cardiovascular disease to reduce the risk of major adverse cardiovascular events, including cardiovascular death
  • EMPRISE, two non-interventional studies (U.S. and EU-Asia) of the effectiveness, safety, healthcare utilization and cost of care of empagliflozin in routine clinical practice in adults with type 2 diabetes across the cardiovascular risk continuum

Prioritizing Cardio-Renal-Metabolic Care
Through research and educational initiatives, Boehringer Ingelheim and Lilly are driven to redefine care for people with cardio-renal-metabolic conditions, a group of interconnected disorders that affect more than one billion people worldwide and are a leading cause of death.

The cardiovascular, renal (kidney) and metabolic systems are closely intertwined and share many of the same disease-related pathways. 

Dysfunction in one system may accelerate the onset of dysfunction in others, resulting in the progression of comorbid diseases such as type 2 diabetes, heart failure and chronic kidney disease.

Conversely, improving the health of one system can lead to positive effects across the others and can help reduce the risk for further complications.

Understanding their interconnected nature, we are working to advance treatments that can protect the organs of the cardio-renal-metabolic systems.

It is only through a holistic approach to care that we can truly transform outcomes and restore the harmony between these critical systems.”

https://investor.lilly.com/news-releases/news-release-details/breakthrough-results-jardiancer-empagliflozin-confirm-emperor

Birmingham University and Nonacus partner to develop urine test for bladder cancer

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Birmingham University and Nonacus partner to develop urine test for bladder cancer

July 1, 2021: Nonacus and the University of Birmingham have partnered to develop a non-invasive test for bladder cancer.

The test, which is expected to be available by mid-2022, will use highly sensitive liquid biopsy technology developed by Nonacus, and a panel of biomarkers validated by Dr Rik Bryan and Dr Douglas Ward from the University’s Bladder Cancer Research Centre, to diagnose the disease from urine samples.

Bladder cancer is the seventh most common cancer in the developed world1. In the UK, over 100,000 people a year are referred to hospital clinics that investigate for bladder cancer, usually after passing blood in their urine (haematuria).

The first stage of investigation is usually cystoscopy, which involves inserting a camera into the bladder. Of these 100,000 patients, around 12% are subsequently diagnosed with bladder cancer, normally after a second invasive procedure to extract a biopsy.

Dr Bryan, Director of the Bladder Cancer Research Centre, commented: “While blood visible in the urine should always be investigated, over 80% of people who have a cystoscopy at a haematuria clinic are diagnosed with non-malignant conditions or have no abnormality.

Unfortunately, the remaining 20% will need a further invasive procedure to confirm diagnosis.

What is required is a highly sensitive and specific, non-invasive test that can rapidly determine those who need a biopsy and those who do not, and a urine test is the obvious place to start.”

While the ‘liquid biopsy’ approach is attractive, the low levels of tumour DNA in a background of DNA from normal tissues requires highly sensitive analytical techniques to obtain accurate results.  However, researchers at the University started their work in the knowledge that Nonacus had successfully pioneered commercial non-invasive prenatal tests to identify low-levels of fetal DNA in maternal blood samples. 

Moreover, the company was developing methods to allow confident and sensitive calling of mutations from as little as 10ng of DNA.

The researchers used ‘deep sequencing’ of tumour DNA to identify mutations that are present in the majority of urothelial bladder cancers (UBCs).

Their work, which was funded by Cancer Research UK and an MRC Confidence in Concept grant, involved sequencing 23 genes from tumour samples collected from 956 newly diagnosed, treatment-naïve patients.

This deep sequencing of genes identified 451 unique mutations that were present in over 96% of tumours. 

The researchers also demonstrated that these mutations were identifiable in urine samples collected at the same time as tumour sampling.

As the researchers have shown, mutated DNA in a urine sample can be extracted from cancer cells shed into the urine from the lining of the urinary tract, or can be found as cell-free DNA fragments2.

However, extracting DNA from the cancer cells provides more reliable amounts of DNA for the test, especially when only small volumes of urine may be available.

Coupling the mutation panel with the unique molecular identifiers and the proprietary target capture technology provided by the Nonacus Cell3 Target™ will provide a much more sensitive test than the existing PCR-based approach.

The researchers are already working on validating this combination in a further 600 cases (including non-cancer cases) and they expect to publish data on sensitivity and specificity within six months.

Nonacus intends to launch the new bladder cancer test within 12 months, and the final product will include access to bioinformatics software to help with analysis.

The company expects the test will provide high sensitivity for all stages and grades of disease, and will ensure the test is available worldwide to laboratories, hospitals and clinics.

Promisingly, the original research also determined the influence of the mutations on cancer progression, time to recurrence, and overall and disease-specific survival in patients with non-muscle-invasive bladder cancer (NMIBC), and disease-specific survival in patients with muscle-invasive bladder cancer (MIBC), raising the possibility that the test could be used to stratify patients according to risk.

Chris Sale, CEO of Nonacus, commented: “We expect this partnership to deliver better care and outcomes for patients by reducing the number of invasive procedures, providing earlier diagnosis and speeding up access to treatment for people with bladder cancer.”

Tony Hickson, Chief Business Officer at Cancer Research UK, said: “As funders of much of the world-class, cutting-edge cancer research happening in the UK, we offer unique opportunities to commercial partners looking for early involvement in new discoveries.

Having Nonacus on board to help transform promising findings in the lab into a new non-invasive test to diagnosis bladder cancer is a testament to how commercial collaborations have the potential to transform the lives of patients.

We are looking forward to seeing the next steps as the test is developed and rolled out to the UK and beyond.”

Allen Knight, Chair of Trustees, Action Bladder Cancer UK, said: “This really is very exciting and has the potential to make an incredible difference for patients and for Bladder Cancer treatment.

Currently urine tests do not accurately pick up bladder cancer, and invasive tests are required to confirm a diagnosis.

A urine test that can rapidly determine who needs these tests will be a very welcome development. Many patients, myself included, find cystoscopies very uncomfortable at best, and they can have lasting side effects.

This research could pave the way for routine screening, common in other cancers, but unavailable at present for Bladder Cancer.”

https://nonacus.com/blog-birmingham-university-and-nonacus-partner-to-develop-urine-test-for-bladder-cancer/

FDA Approved Jazz’s Rylaze™ for Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

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FDA Approved Jazz’s Rylaze™ for Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

June 30, 2021: “Jazz Pharmaceuticals announced the U.S. FDA approval of Rylaze™ (asparaginase erwinia chrysanthemi (recombinant)-rywn) for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) in pediatric and adult patients one month and older who have developed hypersensitivity to E. coli-derived asparaginase.

Rylaze is the only recombinant erwinia asparaginase manufactured product that maintains a clinically meaningful level of asparaginase activity throughout the entire duration of treatment, and it was developed by Jazz to address the needs of patients and healthcare providers with an innovative, high-quality erwinia-derived asparaginase with reliable supply.  

“We are excited to bring this important new treatment to patients who are in critical need, and we are grateful to FDA for the approval of Rylaze based on its established safety and efficacy profile.

We are pleased Rylaze was approved before the trial is complete and are diligently working to advance additional clinical trial data.

We are committed to quickly engaging with FDA to evolve the Rylaze product profile with additional dosing options and an IV route of administration,” said Bruce Cozadd, chairman and CEO of Jazz Pharmaceuticals.

“Thank you to our collaborators within the Children’s Oncology Group, the clinical trial investigators, patients and their families, and all of the other stakeholders who helped us achieve this significant milestone.”  

Rylaze was granted orphan drug designation for the treatment of ALL/LBL by FDA in June 2021.

The Biologics Licensing Application (BLA) approval followed review under the Real-Time Oncology Review (RTOR) program, an initiative of FDA’s Oncology Center of Excellence designed for efficient delivery of safe and effective cancer treatments to patients.

The company expects Rylaze will be commercially available in mid-July. 

“The accelerated development and approval of Rylaze marks an important step in bringing a meaningful new treatment option for many ALL patients – most of whom are children – who cannot tolerate E. coli-derived asparaginase medicine,” said Dr. Luke Maese, assistant professor at the University of Utah, Primary Children’s Hospital and Huntsman Cancer Institute.

“Before the approval of Rylaze, there was a significant need for an effective asparaginase medicine that would allow patients to start and complete their prescribed treatment program with confidence in supply.”

Recent data from a Children’s Oncology Group retrospective analysis of over 8,000 patients found that patients who did not receive a full course of asparaginase treatment due to associated toxicity had significantly lower survival outcomes – regardless of whether those patients were high risk or standard risk, slow early responders.2

About Study JZP458-201
The FDA approval of Rylaze, also known as JZP458, is based on clinical data from an ongoing pivotal Phase 2/3 single-arm, open-label, multicenter, dose confirmation study evaluating pediatric and adult patients with ALL or LBL who have had an allergic reaction to E. coli-derived asparaginases and have not previously received asparaginase erwinia chrysanthemi.

The study was designed to assess the safety, tolerability and efficacy of JZP458. The determination of efficacy was measured by serum asparaginase activity (SAA) levels. 

The Phase 2/3 study is being conducted in two parts.

The first part is investigating the intramuscular (IM) route of administration, including a Monday-Wednesday-Friday dosing schedule.

The second part remains active to further confirm the dose and schedule for the intravenous (IV) route of administration.

The FDA approval of Rylaze was based on data from the first of three IM cohorts, which demonstrated the achievement and maintenance of nadir serum asparaginase activity (NSAA) greater than or equal to the level of 0.1 U/mL at 48 hours using IM doses of Rylaze 25 mg/m2.

The results of modeling and simulations showed that for a dosage of 25 mg/m2 administered intramuscularly every 48 hours, the proportion of patients maintaining NSAA ≥ 0.1 U/mL at 48 hours after a dose of Rylaze was 93.6% (95% CI: 92.6%, 94.6%).1

The most common adverse reactions (incidence >15%) were abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding and hyperglycemia.

In patients treated with the Rylaze, a fatal adverse reaction (infection) occurred in one patient and serious adverse reactions occurred in 55% of patients.

The most frequent serious adverse reactions (in ≥5% of patients) were febrile neutropenia, dehydration, pyrexia, stomatitis, diarrhea, drug hypersensitivity, infection, nausea and viral infection.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received Rylaze.

Adverse reactions resulting in permanent discontinuation included hypersensitivity (6%) and infection (3%).

The company will continue to work with FDA and plans to submit additional data from a completed cohort of patients evaluating 25mg/m2 IM given on Monday and Wednesday, and 50 mg/m2 given on Friday in support of a M/W/F dosing schedule.

Part 2 of the study is evaluating IV administration and is ongoing.

The company also plans to submit these data for presentation at a future medical meeting.”

http://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-rylazetm

Vaxzevria induced immunity for at least one year following a single dose

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Vaxzevria induced immunity for at least one year following a single dose

June 28, 2021: A sub-analysis from the Oxford-led COV001 and COV002 trials with Vaxzevria induced strong immune responses following either a prolonged second dose interval of up to 45 weeks or following a third boosting dose.

The results, published by the University of Oxford on the pre-print server of The Lancet, demonstrated that antibody levels remain elevated from baseline for at least one year following a single dose.

An extended interval between the first and second dose of Vaxzevria of up to 45 weeks, resulted in up to an 18 fold increase in antibody response, measured 28 days after the second dose. 

With a 45 week dosing interval between the first and second dose, antibody titres were four times higher than with a 12 week interval, demonstrating that a longer dosing interval is not detrimental but can derive stronger immunity.

In addition, a third dose of Vaxzevria given at least 6 months after a second dose, boosted antibody levels six fold and maintained T cell response. A third dose also resulted in higher neutralising activity against the Alpha (B.1.1.7, ‘Kent’), Beta (B.1.351, ‘South African’) and Delta (B.1.617.2, ‘Indian’) variants.

Both the late second dose and the third dose of Vaxzevria were less reactogenic than the first dose.

Professor Sir Andrew J Pollard, chief investigator and director of the Oxford Vaccine Group at the University of Oxford, said: “This should come as reassuring news to countries with lower supplies of the vaccine, who may be concerned about delays in providing second doses to their populations. There is an excellent response to a second dose, even after a 10 month delay from the first.”

Sir Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “Demonstrating our vaccine generates a robust and durable immune response is important for providing confidence in longer term protection.

We look forward to continuing to partner with the University of Oxford and recommending bodies around the world to further evaluate the impact of these data.”

The analysis included volunteers aged 18 to 55 years who were enrolled in COV001 and COV002 trials and had received either a single dose or two doses of COVID-19 Vaccine AstraZeneca.

Vaxzevria, formerly AZD1222

Vaxzevria was co-invented by the University of Oxford and its spin-out company, Vaccitech.

It uses a replication-deficient chimpanzee viral vector based on a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein.

After vaccination, the surface spike protein is produced, priming the immune system to attack the SARS-CoV-2 virus if it later infects the body.

The vaccine has been granted a conditional marketing authorisation or emergency use in more than 80 countries across six continents, as a two dose regimen given four to 12 weeks apart for adults aged 18 years and over. 

More than 600 million doses of COVID-19 Vaccine AstraZeneca have been supplied to 170 countries worldwide, including more than 100 countries through the COVAX Facility.

In the UK, Vaxzevria is known as COVID-19 Vaccine AstraZeneca.

COV001
COV001 is a single-blinded, randomised, controlled Phase I/II trial to determine safety, immunogenicity and efficacy of the COVID-19 vaccine candidate, AZD1222 in up to 1,077 healthy adults in five trial centres in the United Kingdom.

Participants aged 18-55 years received either a single dose or two-doses of AZD1222 at 5×1010 viral particles or a single dose of a meningococcal conjugate vaccine MenACWY as control vaccine.

Participants had blood samples drawn and clinical assessments for safety as well as immunogenicity at day 0, 28 and will also be followed at day 184 and 364.

In addition, participants enrolled in the Phase I component of the study and in the two dose groups, had visits at 3, 7, 14 and 28 days after each vaccination.

COV002
COV002 is a single-blinded, multi-centre, randomised, controlled Phase II/III trial assessing the safety, efficacy and immunogenicity of AZD1222 in 12,390 participants in the UK.

Trial participants were aged 18 years or over, who were healthy or have medically stable chronic diseases and are at increased risk for being exposed to the SARS-CoV-2 virus. Participants received one or two intramuscular doses of a half dose (~2.5 x1010 viral particles) or full dose (~5×1010 viral particles) of AZD1222 or comparator, meningococcal vaccine MenACWY.

Participants had blood samples drawn and clinical assessments for safety as well as immunogenicity at multiple timepoints up to one year post-vaccination.

Suspected cases presenting with compatible symptoms were tested for virological confirmation by COVID-19 PCR.

In addition, weekly swabbing are done for detection of infection and assessment of vaccine efficacy against infection.

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/vaxzevria-induced-immunity-for-at-least-1-year-following-a-single-dose-and-strong-immune-responses-following-either-a-late-second-dose-or-a-third-dose.html

Nirsevimab shows positive topline results in RSV Phase 2/3 MEDLEY trial

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Nirsevimab shows positive topline results in RSV Phase 2/3 MEDLEY trial

June 28, 2021: In positive topline results from the Phase 2/3 MEDLEY trial, nirsevimab showed a similar safety and tolerability profile compared to palivizumab when administered to preterm infants or those with chronic lung disease (CLD) or congenital heart disease (CHD) entering their first respiratory syncytial virus (RSV) season.

Safety and tolerability were assessed by the occurrence of all treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs).

RSV, a seasonal virus that typically circulates in autumn through spring in temperate regions, is the most common cause of lower respiratory tract infections (LRTI) and the leading cause of hospitalizations in all infants.

“These data for nirsevimab are important as they show a safety and tolerability profile comparable to the only available preventative option against lower respiratory tract infections caused by RSV for preterm infants and those with health conditions,” said Dr. Joseph Domachowske, Professor of Pediatrics and Professor of Microbiology and Immunology at the State University of New York, Upstate Medical Center and MEDLEY trial primary investigator.

“Given the typical RSV season lasts nearly five months, there is a potential advantage to providing a preventative option that could help protect all infants with one dose for the entire season.”

MEDLEY is the third pivotal trial to report positive data for nirsevimab.

In April, Sanofi reported that nirsevimab met its primary endpoint of achieving a statistically significant reduction of LRTI caused by RSV in healthy preterm and term infants in the Phase 3 MELODY trial.

Coupled with recently published Phase 2b trial results, MELODY and MEDLEY results are part of a robust body of evidence demonstrating the potential of nirsevimab to provide RSV protection to all infants.

Results from the MELODY and MEDLEY trials will be presented at forthcoming scientific congresses and, along with the Phase 2b results, will form the basis of global regulatory submissions planned for 2022.

“RSV is the major remaining pediatric infectious disease with no preventative option available to all infants,” said Jean-François Toussaint, Global Head of Research and Development, Sanofi Pasteur.

“We believe nirsevimab has the potential to become an important and innovative routine immunization for all infants – those born prematurely or at term, healthy or with health conditions.”

“RSV is the leading cause of hospitalizations in infants,” said Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca.

“These results, combined with the recent positive efficacy outcome of our MELODY Phase 3 trial and our Phase 2b data, contribute to the body of evidence demonstrating nirsevimab’s potential to protect all infants against RSV with one dose. We look forward to sharing the results with regulators.”

Nirsevimab, being developed in partnership with AstraZeneca, is the first investigational extended half-life monoclonal antibody (mAb) aiming to protect all infants entering their first RSV season, when they are at highest risk for severe RSV disease.

With nirsevimab, the goal is to provide rapid and direct protection to the infant through a single immunization.

Nirsevimab is designed to be administered from birth to infants born during the RSV season or at the season’s start for infants entering their first RSV season.

In contrast to other options for RSV under development, such as maternal immunization, the aim of nirsevimab is to offer protection when needed to all infants entering their first season.

About the Phase 2/3 MEDLEY clinical trial

MEDLEY is a Phase 2/3, randomized, double-blind, palivizumab-controlled trial with the primary objective to evaluate the safety and tolerability of nirsevimab compared to palivizumab when administered to preterm infants entering their first respiratory syncytial virus (RSV) season and children with CLD and CHD entering their first and second RSV season.

Safety is assessed by monitoring the occurrence of TEAEs and TESAEs through 360 days post-dose.

Between July 2019 and May 2021 approximately 925 infants entering their first RSV season were dosed with either nirsevimab or palivizumab.

The evaluation of nirsevimab was carried out earlier than anticipated, based on sufficient enrollment, allowing for the assessment of nirsevimab’s safety and tolerability versus palivizumab in infants followed through their first RSV season.

The trial is ongoing to collect additional safety data in toddlers with CLD or CHD dosed prior to the second season.

Results from the MEDLEY trial will be presented at a forthcoming scientific congress.”

https://www.sanofi.com/en/media-room/press-releases/2021/2021-06-28-08-00-00-2253567

Dupixent® SmPC updated safety profile with moderate-to-severe atopic dermatitis

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Dupixent® SmPC updated safety profile with moderate-to-severe atopic dermatitis

June 28 2021: Long-term safety data from a study of adults with moderate-to-severe atopic dermatitis treated with Dupixent will be added to the Dupixent Summary of Product Characteristics (SmPC) following a positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use.

Data from a single-arm Phase 3 open label extension (OLE) trial showed the long-term safety profile in adults with moderate-to-severe atopic dermatitis treated with Dupixent and observed up to three years was generally consistent with what was observed in the controlled pivotal Phase 3 trials.

The OLE trial assessed the long-term safety of Dupixent 300 mg weekly in adults who had previously participated in Dupixent trials or had been screened for a Phase 3 trial.

The approved Dupixent dose in adults is 300 mg every other week.

Atopic dermatitis is a chronic inflammatory disease of the skin that can be debilitating.

Moderate-to-severe atopic dermatitis is characterized by intense persistent itch and skin lesions that can cover much of the body, resulting in skin dryness, cracking, redness or darkening, crusting and oozing.

Itch is one of the most burdensome symptoms for patients.

Moderate-to-severe atopic dermatitis can also have a substantial emotional and psychosocial impact on patients and their families, causing sleep disturbance, anxiety, depression and feelings of isolation.

Dupixent is the only biologic approved in the EU for children as young as six with severe atopic dermatitis and for adolescents and adults with moderate-to-severe atopic dermatitis who are candidates for systemic therapy.

Dupixent is a fully human monoclonal antibody that inhibits the signaling of the interleukin-4 (IL-4) and interleukin-13 (IL-13) proteins.

IL-4 and IL-13 are key and central drivers of the type 2 inflammation that plays a major role in atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP) and eosinophilic esophagitis (EoE).

Dupixent is not an immunosuppressant and does not require ongoing lab monitoring. Dupixent is currently approved in more than 60 countries, and more than 260,000 patients have been treated globally.

About Dupixent
Dupixent is approved in the EU for children (6-11 years) with severe atopic dermatitis, as well as for adolescents and adults with moderate-to-severe atopic dermatitis who are candidates for systemic therapy; for use in adults and adolescents 12 years and older 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 high dose inhaled corticosteroid (ICS) plus another medicinal product for maintenance treatment; and for adults with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate disease control.”

https://www.sanofi.com/en/media-room/press-releases/2021/2021-06-28-07-00-00-2253546

COVID-19 Update: FDA Authorizes Drug for Treatment of COVID-19

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COVID-19 Update: FDA Authorizes Drug for Treatment of COVID-19

June 24, 2021: “The U.S. FDA issued an emergency use authorization (EUA) for the drug Actemra (tocilizumab) for the treatment of hospitalized adults and pediatric patients (2 years of age and older) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

Actemra is not authorized for use in outpatients with COVID-19.

In clinical trials of hospitalized patients with COVID-19, Actemra in addition to the routine care patients receive for treatment of COVID-19, which included corticosteroid therapy, was shown to reduce the risk of death through 28 days of follow-up and decrease the amount of time patients remained hospitalized.

The risk of patients being placed on ventilators or death through 28 days of follow-up was also decreased.

“Today’s action demonstrates the FDA’s commitment to making new therapies available through every stage of the global COVID-19 pandemic,” said Patrizia Cavazzoni, M.D., director of the FDA’s Center for Drug Evaluation and Research.

“Although vaccines have been successful in decreasing the number of patients with COVID-19 who require hospitalization, providing additional therapies for those who do become hospitalized is an important step in combating this pandemic.”

Actemra is a monoclonal antibody that reduces inflammation by blocking the interleukin-6 receptor. In the case of COVID-19 infection, the immune system can become hyperactive, which may result in worsening of disease.

Actemra does not directly target SARS-COV-2. Actemra is a prescription medication given by intravenous infusion that is FDA-approved for multiple inflammatory diseases, including rheumatoid arthritis.

Under today’s EUA, the FDA is authorizing the emergency use of Actemra for the treatment of certain hospitalized patients with COVID-19.

Actemra is not approved as a treatment for COVID-19.

The issuance of an EUA is different than an FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of available scientific evidence and carefully balances any known or potential risks with any known or potential benefits of the product for use during an emergency.

Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that Actemra may be effective in treating COVID-19 for the authorized population.

And, when used to treat COVID-19 for the authorized population, the known and potential benefits of Actemra outweigh the known and potential risks for the drug.

There are no adequate, approved and available alternative treatments to Actemra for the treatment of COVID-19 in hospitalized adults and pediatric patients (2 years of age or older) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO.

The data supporting this EUA for Actemra are based on four clinical trials. These included one randomized, controlled, open-label, platform trial [Randomised Evaluation of COVID-19 Therapy (RECOVERY)] and three randomized, double-blind, placebo-controlled trials (EMPACTA, COVACTA and REMDACTA).

While all four clinical trials contribute to the FDA’s understanding of Actemra for the treatment of COVID-19, the most important scientific evidence on the potential benefit of Actemra for its authorized use came from the RECOVERY and EMPACTA trials.

In the RECOVERY trial, 4,116 hospitalized patients with severe COVID-19 pneumonia were randomized to receive either Actemra in addition to usual care (2,022 patients) or usual care alone (2,094 patients).

The primary endpoint evaluated death through 28 days of follow-up, and the results of the primary analysis were statistically significant.

The probabilities of death by day 28 were estimated to be 30.7% for patients receiving Actemra and 34.9% for patients receiving usual care alone.

The median time to hospital discharge was 19 days for patients receiving Actemra and more than 28 days for patients receiving usual care alone.

In the EMPACTA trial, 389 hospitalized patients with COVID-19 pneumonia were randomized to receive Actemra (249 patients) or placebo (128 patients).

The primary endpoint evaluated the need for mechanical ventilation or death through 28 days of follow-up.

For patients receiving Actemra, there was an observed reduction in progression to mechanical ventilation or death compared to patients who received placebo, with the primary analysis results being statistically significant.

The proportion of patients who required mechanical ventilation or died by day 28 was estimated to be 12.0% for patients receiving Actemra and 19.3% for patients receiving placebo.

In the COVACTA trial, 452 hospitalized patients with severe COVID-19 pneumonia were randomized to receive Actemra (294 patients) or placebo (144 patients).

The primary endpoint was clinical status through 28 days of follow-up assessed on a 7-category ordinal scale.

While there was no statistically significant difference observed in clinical status on the 7-category ordinal scale at day 28 between treatment groups, the COVACTA trial contributed to the assessment of the safety for Actemra when used for the treatment of COVID-19.

In the REMDACTA trial, 649 hospitalized patients with severe COVID-19 pneumonia were randomized to receive Actemra in combination with remdesivir (430 patients) or placebo in combination with remdesivir (210 patients).

The primary endpoint was time to hospital discharge or “ready for discharge” through 28 days of follow-up.

Additionally, while there were no statistically significant differences observed between treatment groups with respect to time to hospital discharge or “ready for discharge” through 28 days of follow-up, the REMDACTA trial contributed to the assessment of the safety for Actemra when used for the treatment of COVID-19.

Under the EUA, fact sheets that provide important information about using Actemra in treating COVID-19 as authorized must be made available to health care providers and to patients, parents, and caregivers.

These fact sheets include dosing instructions, potential side effects and drug interactions. Common side effects of Actemra observed in the COVID-19 trials include constipation, anxiety, diarrhea, insomnia, hypertension and nausea.

The EUA was issued to Genentech Inc.”

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-treatment-covid-19

International study of rare childhood cancer finds genetic clues

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International study of rare childhood cancer finds genetic clues

June 24, 2021: “In children with rhabdomyosarcoma, or RMS, a rare cancer that affects the muscles and other soft tissues, the presence of mutations in several genes, including TP53, MYOD1, and CDKN2A, appears to be associated with a more aggressive form of the disease and a poorer chance of survival.

This finding is from the largest-ever international study on RMS, led by scientists at the National Cancer Institute’s (NCI) Center for Cancer Research, part of the National Institutes of Health.

The study, published in the Journal of Clinical Oncology on June 24, provides an unprecedented look at data for a large cohort of patients with RMS, offering genetic clues that could lead to more widespread use of tumor genetic testing to predict how individual patients with this childhood cancer will respond to therapy, as well as to the development of targeted treatments for the disease.

“These discoveries change what we do with these patients and trigger a lot of really important research into developing new therapies that target these mutations,” said Javed Khan, M.D., of NCI’s Genetics Branch, who led the study.

“The standard therapy for RMS is almost a year of chemotherapy, radiation therapy, and surgery. These children get a lot of toxic treatments,” said the study’s first author, Jack Shern, M.D., of NCI’s Pediatric Oncology Branch.

“If we could predict who’s going to do well and who’s not, then we can really start to tailor our therapies or eliminate therapies that aren’t going to be effective in a particular patient.

And for the children that aren’t going to do well, this allows us to think about new ways to treat them.”

RMS is the most common type of soft tissue sarcoma in children. In patients whose cancer has remained localized, meaning that it has not spread, combination chemotherapies have led to a five-year survival rate of 70%-80%.

But in patients whose cancer has spread or come back after treatment, the five-year survival rate remains poor at less than 30%, even with aggressive treatment.

Doctors have typically used clinical features, such as the location of the tumor in the body, as well as its size and to what extent it has spread, to predict how patients will respond to treatment, but this approach is imprecise.

More recently, scientists have discovered that the presence of the PAX-FOXO1 fusion gene that is found in some patients with RMS is associated with poorer survival.

Patients are now being screened for this genetic risk factor to help determine how aggressive their treatment should be.

Scientists have also begun using genetic analysis to dig more deeply into the molecular workings of RMS in search of other genetic markers of poorer survival.

In this new study — the largest genomic profiling effort of RMS tumors to date — scientists from NCI and the Institute for Cancer Research in the United Kingdom analyzed DNA from tumor samples from 641 children with RMS enrolled over a two-decade period in several clinical trials.

Scientists searched for genetic mutations and other aberrations in genes previously associated with RMS and linked that information with clinical outcomes.

Among the patterns that emerged, patients with mutations in the tumor suppressor genes TP53, MYOD1, or CDKN2A had a poorer prognosis than patients without those mutations.

Using next-generation sequencing, researchers found a median of one mutation per tumor. Patients with two or more mutations per tumor had even poorer survival outcomes.

In patients without the PAX-FOXO1 fusion gene, more than 50% had mutations in the RAS pathway genes, although RAS mutations did not appear to be associated with survival outcomes in this study.  

The researchers believe that although they have identified the major mutations that may drive RMS development or provide information about prognosis, they have only scratched the surface in defining the genetics of this cancer, with many more mutations yet to be discovered.

They note that more work is needed to identify targeted drugs for those mutations, and future clinical trials could incorporate genetic markers to more accurately classify patients into treatment groups.

Two NCI-sponsored Children’s Oncology Group clinical trials are currently being developed using these markers, and all participants will have their tumors molecularly profiled.

The researchers hope that routine tumor genetic testing for rare cancers, such as RMS, will soon be a standard part of the treatment plan, as it is for more common cancers, such as breast cancer.

“Genetic testing is going to become the standard of care,” said Dr. Shern. “Instead of just the pathologists looking at these tumors, we’re now going to have molecular profiling, and that’s a leap forward.” 

This study was conducted by an international consortium comprised of scientists at NCI and the Children’s Oncology Group in the United States, and the Children’s Cancer and Leukaemia Group and the National Cancer Research Institute’s Young Onset Soft Tissue Sarcoma Subgroup in the United Kingdom.

The data are available at clinomics.ccr.cancer.gov/clinomics/public. The research was supported by NCI and St. Baldrick’s Foundation in Monrovia, California.”

https://www.cancer.gov/news-events/press-releases/2021/childhood-cancer-rhabdomyosarcoma

Treatment With Hepcludex® Was Shown to Achieve Significant Response in Chronic Hepatitis Delta Virus After 24 Weeks

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Treatment With Hepcludex® Was Shown to Achieve Significant Response in Chronic Hepatitis Delta Virus After 24 Weeks

June 24, 2021: Gilead Sciences announced interim results from the Phase 2b and Phase 3 clinical trials evaluating the first-in-class entry inhibitor Hepcludex® (bulevirtide) for the treatment of chronic hepatitis delta virus (HDV).

Findings from the Phase 3 study support the safety and efficacy profile of bulevirtide 2 mg once daily and are being presented today as a late-breaker in the International Liver Congress™ (ILC) 2021 Official Press Program.

Results from the Phase 2b trial show that treatment with bulevirtide alone or in combination with peginterferon alfa-2a, is associated with a significant HDV RNA decline and improvements in biochemical disease activity at Week 24.

The Phase 3 data will be included in the filing of bulevirtide to the U.S. Food and Drug Administration (FDA) later this year.

Bulevirtide has been granted Breakthrough Therapy Designation and Orphan Drug status by the FDA.

Hepcludex has been granted Conditional Marketing Authorization by the European Commission and PRIority MEdicines (PRIME) scheme eligibility by the European Medicines Agency as the first approved treatment in Europe for adults with chronic HDV and compensated liver disease.

“These data represent meaningful progress as we work to address the significant unmet needs of people living with HDV.

This infection presents a public health concern due to its rapid progression, leading to complications including cirrhosis, hepatic decompensation and an increased risk of liver cancer and death,” said Tarik Asselah, Professor of Hepatology at Hôpital Beaujon, Clichy, and at the University Paris, and Head of Viral Hepatitis Team at INSERM UMR1149, France.

“The data presented at ILC support the safety and efficacy of bulevirtide in adults with HDV and confirm the importance of this therapeutic option for people living with chronic HDV.”

Interim results from the Phase 3 MYR301 study indicate that after 24 weeks, the proportion of people with HDV achieving the combined virological and biochemical response was 36.7% with bulevirtide 2 mg, 28% in participants receiving bulevirtide 10 mg and 0% in participants currently under observation who have not received antiviral treatment at this stage of the study.

Treatment for 24 weeks with bulevirtide 2 mg or 10 mg had a superior response (p<0.001) to the no treatment group, with bulevirtide 2 mg for 24 weeks having a numerically higher response rate compared with bulevirtide 10 mg.

Additionally, rapid ALT reduction and normalization were observed in >50% of patients in the bulevirtide 2 mg group compared with the bulevirtide 10 mg or no treatment groups.

These results reinforce the efficacy of bulevirtide for the treatment of HDV.

The safety profile of bulevirtide at 24 weeks from these interim results is consistent with prior reports, and no serious adverse events (AEs), symptomatic elevations in bile salts or AEs leading to discontinuation related to bulevirtide were reported.

Data from the Phase 2b MYR204 study assessing the safety and efficacy of bulevirtide monotherapy or in combination with peginterferon alfa-2a, in people living with HDV will also be presented in an oral session on June 26.

The study evaluating 175 people with chronic HDV randomly allocated people across four groups: peginterferon alfa-2a; bulevirtide 2 mg plus peginterferon alfa-2a; bulevirtide 10 mg plus peginterferon alfa-2a; and bulevirtide 10 mg.

The proportion of participants achieving a combined response after 24 weeks of treatment was higher in those treated with bulevirtide, with the highest response rate seen in the monotherapy group.

Treatment with bulevirtide, both as monotherapy or in combination with peginterferon alfa-2a, was well-tolerated, with mostly mild or moderate AEs and no reported serious AEs or AEs leading to discontinuation of bulevirtide.

The European Commission granted Hepcludex 2 mg Conditional Marketing Authorization; all other dosing and combinations are investigational.

“HDV is the most serious form of chronic viral hepatitis and is associated with rapid progression of serious complications including fibrosis, cirrhosis and liver cancer. Currently, there are very limited treatment options, and people living with HDV typically have a poor prognosis.

These data add to the growing body of evidence demonstrating the potential role for bulevirtide in the treatment of HDV,” said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences.

“We look forward to working closely with global regulators with the goal of bringing bulevirtide to more people living with HDV as quickly as possible.”

Bulevirtide is an investigational agent in the United States and outside of the European Economic Area; in these regions, health authorities have not established the safety and efficacy of bulevirtide.”

https://www.gilead.com/news-and-press/press-room/press-releases/2021/6/treatment-with-hepcludex-bulevirtide-was-shown-to-achieve-significant-response-in-chronic-hepatitis-delta-virus-after-24-weeks

Sandoz announces EU launch of ready-to-dilute generic Pemetrexed forlung cancer

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Sandoz announces EU launch of ready-to-dilute generic Pemetrexed forlung cancer

June 25, 2021: Sandoz announced the launch of generic oncology treatment Pemetrexed in 11 countries across Europe, including Germany, Switzerland, Netherlands, and Spain.

Pemetrexed, as a monotherapy or in combination with cisplatin, is indicated for first-line, second-line and maintenance treatment of patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) other than predominantly squamous cell histology, and for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma.

Globally, 1.8 million people died from lung cancer in 2020 including over 26,000 deaths from mesothelioma, and approximately 2.2 million new cases of lung cancer including 31,000 new cases of mesothelioma were diagnosed.

NSCLC is the most prevalent form of the disease, affecting approximately 85% of those diagnosed with lung cancer.

“At Sandoz, we are committed to using our expertise in product development to enable us to deliver high quality, innovative products that address the needs of patients and healthcare professionals,” said Rebecca Guntern, Head of Sandoz Region Europe.

“By providing Pemetrexed in a ready-to-dilute format and in an additional, higher-strength dosage, we believe that this treatment option will not only be more cost-effective for payers, but patients and physicians will also be able to benefit from the reduced preparation steps required.”

Pemetrexed is a multi-targeted antifolate anti-cancer agent that disrupts crucial folate-dependent metabolic processes essential for cell replication.

It inhibits folate-dependent enzymes critical to the de-novo biosynthesis of nucleotides leading to the disruption of DNA replication.

Patients receive the treatment via a 10-minute intravenous infusion in a hospital setting.

Further launches across Europe are expected throughout the second half of 2021.”

https://www.novartis.com/news/media-releases/sandoz-announces-eu-launch-ready-dilute-generic-pemetrexed-treat-most-prevalent-form-lung-cancer

Lynparza approved in China for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer

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Lynparza approved in China for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer

June 24, 2021: “AstraZeneca and MSD’s Lynparza (olaparib) has been granted conditional approval in China to treat adult patients with germline or somatic BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following treatment that included a new hormonal agent (abiraterone, enzalutamide).

In China, prostate cancer is the sixth most prevalent cancer in men, with approximately 115,000 new patients diagnosed each year and about 7% have germline BRCA mutations.

Prostate cancer patients with these mutations are more likely to have poorer outcomes than those without the mutations.

Around 70% of prostate cancer patients in China have advanced disease at the time of diagnosis, and for those with mCRPC, the median survival is less than two years.

The approval by China’s National Medical Products Administration was based on a subgroup analysis of the PROfound Phase III trial, which showed that Lynparza demonstrated a substantial improvement in radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone or enzalutamide in men with BRCA1/2 mutations.

Continued approval is contingent upon verification and description of clinical benefit in a planned bridging trial with Chinese patients.

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “This approval begins a new era of precision medicine for patients in China with advanced prostate cancer who have historically had a poor prognosis and few treatment options. 

Lynparza more than tripled radiographic progression-free survival in the PROfound trial and is the only PARP inhibitor to show an overall survival benefit compared to treatment with new hormonal agents for men with BRCA-mutated metastatic castration-resistant prostate cancer.”

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: “The approval underscores the critical importance of BRCA testing in men with prostate cancer. We are proud to provide a new personalised treatment option for men with this devastating disease in China, and we will continue to collaborate with the Chinese government and healthcare organisations to bring Lynparza to patients who need it.”

The subgroup analysis from the PROfound Phase III trial showed Lynparza reduced the risk of disease progression or death by 78% (based on a hazard ratio [HR] of 0.22, 95% confidence interval [CI] 0.15-0.32; nominal p<0.0001) and improved rPFS to a median of 9.8 months versus 3.0 with abiraterone or enzalutamide in men with mCRPC with BRCA1/2 mutations.

In addition, Lynparza reduced the risk of death by 37% (HR of 0.63, 95% CI 0.42-0.95) with median OS of 20.1 months versus 14.4 with abiraterone or enzalutamide.

The primary results and OS results from the PROfound Phase III trial were published in The New England Journal of Medicine.

Lynparza is approved in the US to treat men with homologous recombination repair gene-mutated (HRRm) mCRPC and in the EU, Japan and several other countries for BRCA-mutated mCRPC patients based on the PROfound Phase III trial.

In addition, regulatory reviews are ongoing in other countries around the world.

AstraZeneca and MSD are testing Lynparza in additional trials in metastatic prostate cancer, including the ongoing PROpel Phase III trial of Lynparza as a 1st-line treatment for patients with mCRPC in combination with abiraterone versus abiraterone alone. Results are anticipated in the second half of 2021.

Metastatic castration-resistant prostate cancer
Prostate cancer is associated with a significant mortality rate.

Prostate cancer is often driven by male sex hormones called androgens, including testosterone.

In patients with mCRPC, prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.

Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.

Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.

Despite advances in treatment for men with mCRPC, five-year survival is low and extending survival remains a key treatment goal.

PROfound
PROfound is a prospective, multicentre, randomised, open-label, Phase III trial testing the efficacy and safety of Lynparza versus abiraterone or enzalutamide in patients with mCRPC who have progressed on prior treatment that included new hormonal agents (abiraterone or enzalutamide) and have a qualifying tumour mutation in BRCA1/2, ATM or one of 12 other genes involved in the HRRm pathway.

The trial was designed to analyse patients with HRR gene mutations in two cohorts: the primary endpoint was rPFS in those with mutations in BRCA1/2 or ATM genes, and then, if Lynparza showed clinical benefit, a formal analysis was performed of the overall trial population of patients with HRR gene mutations (BRCA1/2, ATM and 12 other HRR gene mutations).

AstraZeneca and MSD announced in August 2019 that the trial met its primary endpoint of rPFS.

BRCA1 and BRCA2
BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells.

When either of these genes is mutated or altered such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable.

As a result, cells are more likely to develop additional genetic alterations that can lead to cancer and confer sensitivity to PARP inhibitors, including Lynparza.

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in HRR, such as mutations in BRCA1 and/or BRCA2.

Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. 

Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in several countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer.

It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer following response to platinum-based chemotherapy.

It is also approved in the US, the EU, and Japan as 1st-line maintenance treatment with bevacizumab for patients with HRD-positive advanced ovarian cancer (BRCAm and/or genomic instability).

In addition, Lynparza is approved in the US, Japan, and several other countries for germline BRCAm, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer.

It is also approved in the US, the EU, Japan, and several other countries to treat germline BRCAm metastatic pancreatic cancer.

In addition, Lynparza is approved in the US for HRR gene-mutated mCRPC (BRCAm and other HRR gene mutations) and in the EU and Japan for BRCAm metastatic castration-resistant prostate cancer.

Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 40,000 patients worldwide. 

Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor.

AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. 

Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.”

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/lynparza-approved-in-china-for-prostate-cancer.html

Merck Announces Phase 3 KEYNOTE-826 Trial Met Dual Primary Endpoints of OS and PFS

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Merck Announces Phase 3 KEYNOTE-826 Trial Met Dual Primary Endpoints of OS and PFS

June 22, 2021: Merck known as MSD outside the United States and Canada announced that the pivotal Phase 3 KEYNOTE-826 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with platinum-based chemotherapy (paclitaxel plus cisplatin or paclitaxel plus carboplatin) with or without bevacizumab, met its primary endpoints of overall survival (OS) and progression-free survival (PFS) for the first-line treatment of patients with persistent, recurrent or metastatic cervical cancer.

Based on an interim analysis conducted by an independent Data Monitoring Committee, KEYTRUDA plus platinum-based chemotherapy with or without bevacizumab demonstrated statistically significant and clinically meaningful improvements in OS and PFS compared to the same platinum-based chemotherapy regimens with or without bevacizumab alone, regardless of PD-L1 status; KEYTRUDA is the first anti-PD-1/PD-L1 therapy to demonstrate this.

The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies. Results will be presented at an upcoming medical meeting and will be submitted to regulatory authorities.

“Despite progress with prevention and screening, cervical cancer continues to be a major health problem, often affecting younger and middle-aged women,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories.

“Women diagnosed with metastatic cervical cancer have a particularly poor prognosis, and there is an urgent need for new treatment options.

KEYNOTE-826 is the first study to show positive results for immunotherapy in first-line persistent, recurrent or metastatic cervical cancer, and we look forward to sharing these findings at an upcoming congress and discussing them with regulatory authorities.

We thank the patients, their caregivers and investigators for their participation in this important study.”

The Phase 3 KEYNOTE-826 trial is also the confirmatory trial for the current accelerated approval for KEYTRUDA in cervical cancer for the second-line treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) as determined by an FDA-approved test.

Merck is rapidly advancing a broad portfolio in women’s cancers with an extensive clinical development program for KEYTRUDA and several other investigational and approved medicines across multiple gynecologic and breast cancers.

About KEYNOTE-826

KEYNOTE-826 is a randomized, triple-blind, Phase 3 trial (ClinicalTrials.gov, NCT03635567) evaluating KEYTRUDA in combination with platinum-based chemotherapy (paclitaxel plus cisplatin or paclitaxel plus carboplatin) with or without bevacizumab compared with placebo in combination with the same platinum-based chemotherapy regimens with or without bevacizumab for the first-line treatment of adult patients with persistent, recurrent or metastatic cervical cancer.

The trial enrolled adults with persistent, recurrent or metastatic squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix who had not been treated with systemic chemotherapy and who were no longer amenable to curative treatment (such as surgery and/or radiation).

The primary endpoints are OS and PFS. The secondary endpoints include objective response rate, duration of response and safety. The study enrolled 617 patients who were randomized to receive:

  • KEYTRUDA (200 mg intravenously) plus investigator’s choice of the one of four platinum-based chemotherapy regimens: paclitaxel (175 mg/m2) plus cisplatin (50 mg/m2) with or without bevacizumab (15 mg/kg); or paclitaxel (175 mg/m2) plus carboplatin Area Under the Curve (AUC) 5 with or without bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately two years); or
  • Placebo plus investigator’s choice of the one of four platinum-based chemotherapy regimens: paclitaxel (175 mg/m2) plus cisplatin (50 mg/m2) with or without bevacizumab (15 mg/kg); or paclitaxel (175 mg/m2) plus carboplatin AUC 5 with or without bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately two years).”

    https://www.merck.com/news/merck-announces-phase-3-keynote-826-trial-met-dual-primary-endpoints-of-overall-survival-os-and-progression-free-survival-pfs-in-patients-with-persistent-recurrent-or-metastatic-cervical-cancer/
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