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FDA Approves StrataGraft for the Treatment of Adults with Thermal Burns

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FDA Approves StrataGraft for the Treatment of Adults with Thermal Burns

June 15, 2021: “The U.S. FDA approved StrataGraft for the treatment of adult patients with thermal burns containing intact dermal elements (remaining deep skin layers) for which surgical intervention is clinically indicated (also referred to as deep partial thickness burns).

Thermal burns are typically caused by direct contact with an external heat source such as steam, scalding water, hot surfaces or fire.

“Serious burns can be an incredibly difficult injury to treat and can adversely affect more than just the skin.

The goal of burn management is to help the patient return to the highest level of functionality and independence possible, while improving the overall quality of life,” said Peter Marks, M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research.

“This approval provides health care professionals a novel way to treat burn wounds.”

For many deep burns, treatment frequently involves the removal of the damaged, burned skin and replacement with a skin graft.

Skin grafts are often the patient’s own healthy skin taken from their body and moved to the burned area to help it heal.

This procedure, called an autograft, leaves a new wound where the healthy skin was removed.

StrataGraft is produced from two kinds of human skin cells (keratinocytes and dermal fibroblasts) grown together to make a bi-layered construct (a cellularized scaffold).

StrataGraft is for topical application, placed onto the burn by a healthcare provider.

Over time, the patient’s skin cells should grow to replace the skin cells lost as a result of the burn. Treatment with StrataGraft can help avoid or decrease the amount of healthy skin that is needed for grafting.

The effectiveness and safety of StrataGraft are based on two randomized clinical studies involving a total of 101 adult patients with deep partial thickness thermal burns.

In both studies, two deep partial-thickness burn wounds of comparable area and depth on each patient were identified and randomized to receive either a single topical application of StrataGraft or autograft.

The effectiveness is demonstrated by the percentage of StrataGraft treatment sites that achieved a complete wound closure, and the significantly decreased need for autografts at the StrataGraft treatment sites.

Common side effects reported by patients who received StrataGraft in clinical studies were pruritus (itching), blisters, hypertrophic scar, and impaired healing (stalled healing process) at the treatment site. Overall, the safety profile of StrataGraft regarding wound related events, included erythema (redness), swelling, local warmth and wound site infections, was similar to that of autografting in these studies. There were no reports of rejection of StrataGraft in the clinical studies.

The FDA granted StrataGraft regenerative medicine advanced therapy (RMAT), Priority Review and Orphan Drug designations for this indication.

StrataGraft was developed in conjunction with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority.

Since the human keratinocyte cells were grown with mouse cells during initial stages of product development, StrataGraft is formally considered to be a xenotransplantation product (involving tissues or cells belonging to different species). Mouse cells are no longer used in the final manufacturing process. Due to StrataGraft containing cells from human donors and animal-derived materials, and because animal cells were used in early stages of product development, there is a risk of transmission of infectious diseases or agents although at this time transmission of infectious diseases or agents by StrataGraft has not been reported.

The FDA granted approval to Stratatech, a Mallinckrodt company.”

https://www.fda.gov/news-events/press-announcements/fda-approves-stratagraft-treatment-adults-thermal-burns

Updated recommendations for use of Pfizer–BioNTech, Moderna and Janssen vaccines

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Updated recommendations for use of Pfizer–BioNTech, Moderna and Janssen vaccines

June 15, 2021: The interim recommendations  for use of Pfizer-BioNTech BNT162b2, Moderna mRNA–1273 and Janssen Ad26.COV2.S vaccines have been updated to reflect latest evidence.

For further information, see below:Interim recommendations for use of the Pfizer–BioNTech COVID-19 vaccine, BNT162b2, under Emergency Use Listing

Interim recommendations for the use of the Janssen Ad26.COV2.S (COVID-19) vaccine

Interim recommendations for the use of the Janssen Ad26.COV2.S (COVID-19) vaccine

COVID-19 Vaccine AstraZeneca effective against Delta (‘Indian’) variant

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COVID-19 Vaccine AstraZeneca effective against Delta (‘Indian’) variant

June 15, 2021:

Real-world data demonstrated 92% vaccine effectiveness against hospitalisations due to the Delta variant  
 

New data from Public Health England (PHE) demonstrated COVID-19 Vaccine AstraZeneca offers high levels of protection against the Delta variant (B.1.617.2; formerly the ‘Indian’ variant).

Real world data from PHE, published as a pre-print, demonstrated two doses of COVID-19 Vaccine AstraZeneca are 92% effective against hospitalisation due to the Delta variant and showed no deaths among those vaccinated.

The vaccine also showed a high level of effectiveness against the Alpha variant (B.1.1.7; formerly the ‘Kent’ variant) with an 86% reduction of hospitalisations and no deaths reported.

The data suggest that vaccine effectiveness against milder symptomatic disease, although significant, was lower.

Vaccine effectiveness against symptomatic disease was 74% against the Alpha variant and 64% against the Delta variant.

The higher efficacy against severe disease and hospitalisation is supported by recent data showing strong T-cell response to COVID-19 Vaccine AstraZeneca, which should correlate with high and durable protection.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “This real world evidence shows that COVID-19 Vaccine AstraZeneca provides a high level of protection against the Delta variant, which is currently a critical area of concern given its rapid transmission.

The data show that the vaccine will continue to have a significant impact around the world given that it continues to account for the overwhelming majority of supplies to India and the COVAX facility.”

The analysis included 14,019 cases of the Delta variant – 166 of whom were hospitalised – between 12 April and 4 June, looking at emergency hospital admissions in England.

This real world evidenceagainst the Delta variant is based on limited follow up after the second dose which could impact the effectiveness estimate.

The Delta variant is a key contributor to the current wave of infection in the Indian subcontinent and beyond.

It has recently replaced the Alpha variant as the dominant strain in Scotland and is responsible for a notable increase in cases in the United Kingdom.

The WHO Strategic Advisory Group of Experts on Immunization (SAGE) has recommended COVID-19 Vaccine AstraZeneca in countries where new variants, like the Delta variant of concern, are prevalent.

COVID-19 Vaccine AstraZeneca, formerly AZD1222
COVID-19 Vaccine AstraZeneca 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. 

More than 500 million doses of COVID-19 Vaccine AstraZeneca have been supplied to 165 countries worldwide, including more than 100 countries through the COVAX Facility.”

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/covid-19-vaccine-astrazeneca-effective-against-delta-indian-variant.html

U.S. Gov Supply Molnupiravir to Merck for Mild to Moderate COVID-19

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U.S. Gov Supply Molnupiravir to Merck for Mild to Moderate COVID-19

June 9, 2021: “Merck, known as MSD outside the United States and Canada announced it has entered into a procurement agreement with the United States government for molnupiravir (MK-4482).

Molnupiravir is currently being evaluated in a Phase 3 clinical trial, the MOVe-OUT study, for the treatment of non-hospitalized patients with laboratory-confirmed COVID-19 and at least one risk factor associated with poor disease outcomes.

Merck is developing molnupiravir in collaboration with Ridgeback Biotherapeutics.

“Merck is pleased to collaborate with the U.S. government on this new agreement that will provide Americans with COVID-19 access to molnupiravir – an investigational oral therapy being studied for outpatient use early in the course of disease – if it is authorized or approved,” said Rob Davis, president, Merck.

“In addition to this agreement with the U.S. government, we are actively engaged in numerous efforts to make molnupiravir available globally to fulfill Merck’s commitment to widespread access.”

Through the agreement, if molnupiravir receives Emergency Use Authorization (EUA) or approval by the U.S. Food and Drug Administration (FDA), Merck will receive approximately $1.2 billion to supply approximately 1.7 million courses of molnupiravir to the United States government.

Merck has been investing at risk to support development and scale-up production of molnupiravir and expects to have more than 10 million courses of therapy available by the end of 2021.

Merck also plans to submit applications for emergency use or approval to regulatory bodies outside of the U.S. and is currently in discussions with other countries interested in advance purchase agreements for molnupiravir.

Merck is committed to providing timely access to molnupiravir globally and intends to implement a tiered pricing approach based on World Bank data that recognizes countries’ relative ability to finance their public health response to the pandemic.

As part of its access strategy, Merck has also entered into non-exclusive voluntary licensing agreements for molnupiravir with established generic manufacturers to accelerate availability of molnupiravir in 104 low- and middle-income countries (LMICs) following approvals or emergency authorization by local regulatory agencies.

In addition to developing molnupiravir, Merck is contributing to the pandemic response by collaborating with Johnson & Johnson to support the manufacture of its COVID-19 vaccine.

This procurement of molnupiravir will be supported in whole or in part with federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, in collaboration with the DOD Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) under contract number W911QY21C0031.

About Molnupiravir

Molnupiravir (EIDD-2801/MK-4482) is an investigational, orally bioavailable form of a potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2, the causative agent of COVID-19.

Molnupiravir has been shown to be active in several models of SARS-CoV-2, including for prophylaxis, treatment and prevention of transmission, as well as SARS-CoV-1 and MERS.

EIDD-2801 was invented at Drug Innovations at Emory (DRIVE), LLC, a not-for-profit biotechnology company wholly owned by Emory University, and with partial funding support from the U.S. government.

Since licensed by Ridgeback, all funds used for the development of EIDD-2801 by Ridgeback have been provided by Wayne and Wendy Holman and Merck.

The Phase 3 portion (Part 2) of the MOVe-OUT study, evaluating the potential of molnupiravir to reduce the risk of hospitalization or death, is ongoing.

Merck currently anticipates that, pending favorable results from MOVe-OUT, the earliest possible submission for an Emergency Use Authorization for molnupiravir will be in the second half of 2021.

Merck and Ridgeback Biotherapeutics plan to share further findings from the ongoing molnupiravir development program with regulatory agencies as they become available.

For more information on the molnupiravir clinical trial please visit https://merckcovidresearch.com/.

In addition, Merck plans to initiate a clinical program to evaluate molnupiravir for post- exposure prophylaxis in the second half of 2021.”

https://www.merck.com/news/merck-announces-supply-agreement-with-u-s-government-for-molnupiravir-an-investigational-oral-antiviral-candidate-for-treatment-of-mild-to-moderate-covid-19/

BMS and Acceleron Present First Results of Reblozyl® in Adults with NTD Beta Thalassemia

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BMS and Acceleron Present First Results of Reblozyl® in Adults with NTD Beta Thalassemia

June 11, 2021: “Bristol Myers Squibb and Acceleron Pharma announced the first data from the Phase 2 BEYOND study evaluating Reblozyl®(luspatercept-aamt), a first-in-class erythroid maturation agent, plus best supportive care in adult patients with non-transfusion dependent (NTD) beta thalassemia, were presented at the European Hematology Association (EHA) 2021 Virtual Congress as part of its Presidential Symposium.

Results demonstrated that 77.7% of patients treated with Reblozyl achieved a hemoglobin increase (≥1.0 gram/deciliter) compared to 0% of patients in the placebo arm. Changes in patient-reported outcomes also correlated with increases in hemoglobin.

NTD beta thalassemia is a term used to describe patients who do not require lifelong regular red blood cell (RBC) transfusions for survival, although they may require occasional or even frequent transfusions, usually for defined periods of time.

“Patients with non-transfusion dependent beta thalassemia experience chronic anemia and iron overload, which may lead to a range of clinical complications, and treatment options are greatly needed,” said Ali Taher, M.D., Ph.D., FRCP, of American University of Beirut and BEYOND study investigator.

“Results from the BEYOND study show the clinical potential of luspatercept to sustain the elevation of hemoglobin levels in a majority of patients regardless of their baseline hemoglobin status, and improvements were noted in quality of life outcomes in adults with non-transfusion dependent beta thalassemia.”

Reblozyl is the first and only erythroid maturation agent approved in the European Union, United States and Canada to address anemia-associated beta thalassemia and lower-risk myelodysplastic syndromes, representing an important class of therapy for eligible patients.

“We are very encouraged by the magnitude of improvement seen among Reblozyl-treated patients in the BEYOND trial,” said Habib Dable, President and Chief Executive Officer of Acceleron.

“These data further strengthen our confidence in Reblozyl’s potential to become a meaningful option for this important, underserved patient population around the world.”

“The results we are presenting at EHA continue to highlight multiple benefits observed with Reblozyl to treat anemia and achieve transfusion independence, as well as show its potential for patients with non-transfusion dependent disease who face a range of serious, often lifelong health complications,” said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology Development, Bristol Myers Squibb.

“Along with our partners at Acceleron, we are committed to advancing our clinical program for Reblozyl for patients living with anemia-associated blood disorders.”

BEYOND Study Results

BEYOND is a Phase 2, randomized, double-blind, placebo-controlled multi-center study to determine the efficacy and safety of Reblozyl versus placebo in adults with non-transfusion dependent (NTD) beta thalassemia.

Eligible patients were ≥18 years with beta thalassemia or hemoglobin (Hb) E beta thalassemia and received ≤5 red blood cell (RBC) units in the 24 weeks prior to randomization, with mean baseline Hb ≤10.0 gram/deciliter (g/dL).

In the study, 145 patients were randomized 2:1 to receive Reblozyl, 1 milligram/kilogram (titration up to 1.25 mg/kg) or placebo subcutaneously every 3 weeks for ≥48 weeks. Patients in both arms continued to receive best supportive care, including RBC transfusions as indicated and iron chelation therapy. The primary endpoint was achievement of ≥1.0 g/dL mean Hb increase from baseline over a continuous 12-week interval from weeks 13-24 in the absence of RBC transfusions. Secondary endpoints included proportion of patients who remained transfusion free over weeks 1-24, who achieved mean Hb increase of ≥1.5 g/dL from baseline to weeks 13-24, and mean change in NTD beta thalassemia patient-reported outcome tiredness and weakness (NTDT-PRO T/W) domain scores (higher scores reflect worse quality of life; QoL).4

Over a continuous 12-week interval from weeks 13-24 in the absence of RBC transfusions, 74 of 96 (77.1%) patients in the Reblozyl treatment arm achieved the study’s primary endpoint, ≥1.0 g/dL mean Hb increase from baseline, versus 0 of 49 (0%) patients in the placebo arm (P<0.0001).

The primary endpoint was achieved by 40 of 55 (72.7%) patients in the Reblozyl arm with mean baseline Hb of <8.5 g/dL versus 0 (0%) of patients in the placebo arm (P<0.0001), and 34 of 41 patients (82.9%) with mean baseline Hb of ≥8.5 g/dL versus 0 patients (0%) in the placebo arm (P<0.0001).

In a key secondary endpoint of the study, during weeks 13-24, 50 of 96 patients (52.1%) in the Reblozyl arm achieved mean Hb increase of ≥1.5 g/dL compared to baseline versus 0 patients (0%) in the placebo arm (P<0.0001).

89.6% of patients in the Reblozyl arm remained transfusion free at weeks 1-24 versus 67.3% of patients in the placebo arm (P=0.0013).

Improvements in patient-reported QoL outcomes (tiredness and weakness) were also observed to correlate with Hb increases.

The most common treatment-emergent adverse events of any grade occurring in ≥5% of patients were bone pain (36.5% Reblozyl versus 6.1% placebo), headache (30.2% versus 20.4%), and arthralgia (29.2% versus 14.3%). No malignancies or thromboembolic events were reported in patients treated with Reblozyl.

About Beta Thalassemia

Beta thalassemia is an inherited blood disorder caused by a genetic defect in hemoglobin.

It is one of the most common autosomal recessive disorders, and the total annual incidence of symptomatic individuals is estimated at 1 in 100,000 people globally and 1 in 10,000 people in the European Union.

The disease is associated with ineffective erythropoiesis, which results in the production of fewer and less healthy red blood cells (RBCs), often leading to severe anemia—a condition that can be debilitating and can lead to other complications for patients—as well as other serious health issues.

Treatment options for anemia associated with beta thalassemia are limited, consisting mainly of frequent RBC transfusions that have the potential to contribute to iron overload, which can cause serious complications such as organ damage.

Non-transfusion dependent thalassemia is a term used to describe patients who do not require lifelong regular transfusions for survival, although they may experience a range of clinical complications and require occasional or even frequent transfusions, usually for defined periods of time.

About Reblozyl®

Reblozyl (luspatercept-aamt), a first-in-class erythroid maturation agent, promotes late-stage red blood cell maturation in animal models.

Bristol Myers Squibb and Acceleron are jointly developing Reblozyl as part of a global collaboration. Reblozyl is currently approved in the U.S. for the treatment of:

  • anemia in adult patients with beta thalassemia who require regular red blood cell transfusions, and
  • anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

Reblozyl is not indicated for use as a substitute for red blood cell transfusions in patients who require immediate correction of anemia.”

https://news.bms.com/news/corporate-financial/2021/Bristol-Myers-Squibb-and-Acceleron-Present-First-Results-from-Phase-2-BEYOND-Study-of-Reblozylluspatercept-aamt-in-Adults-with-Non-Transfusion-DependentNTDBeta-Thalassemia/default.aspx

ACT Accelerator partnership welcomes commitment of 870 million vaccine doses

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ACT Accelerator partnership welcomes commitment of 870 million vaccine doses

June 13, 2021: G7 leaders donate 870 million vaccine doses for low and low-middle income countries over the next year, vital for reducing virus transmission.

G7 leaders emphasize the importance of all ACT-Accelerator tools to exit the pandemic.

ACT-Accelerator’s funding gap remains significant with an urgent need for funding of tests, treatments and health systems to ensure an end to the pandemic everywhere.

WHO Director General warns of increasing divide in equity to crucial COVID-19 tools.

Total funding committed to the ACT-Accelerator partnership remains US$ 15.1 billion with a gap of over US$16 billion.

At the close of this year’s G7 Leaders’ summit, the Prime Minister of the United Kingdom of Great Britain and Northern Ireland announced a donation of an additional 870 million vaccine doses from attendees, with the majority to be delivered through COVAX, the vaccines pillar of the Access to COVID 19 Tools Accelerator, within the next year.

Attendees included heads of G7 Member States plus Australia, India, South Africa and Republic of Korea, invited as guests.

Leaders confirmed their support for all pillars of the ACT-Accelerator across treatments, tests and strengthening public health systems as well as vaccines (link to the communique).

Additionally, they indicated their intention to work together with the private sector, the G20 and other countries to increase their vaccine contribution over the months to come. Since their G7 Early Leaders’ Summit in February 2021, the G7 has committed one billion doses in total.

Timing is keyWHO Director General, Dr Tedros Adhanom Ghebreyesus, spoke to leaders at their meeting and urged “many other countries are now facing a surge in cases – and they are facing it without vaccines. We are in the race of our lives, but it’s not a fair race, and most countries have barely left the starting line.

We welcome the generous announcements about donations of vaccines and thank leaders. But we need more, and we need them faster”.

Over US$ 16 billion is still needed this year to fully fund the work of ACT-Accelerator, the global partnership of leading international health organizations which is mid-way through its 2020-21 funding need. In additional to vital vaccine research and development and procurement work, ACT-Accelerator needs funds to strengthen health systems and protect health workers administering the tools needed to end the pandemic; tests to detect and contain hotspots, as well as identify new variants that will continue to appear; and treatments to save the lives of those who will continue to catch COVID-19 and suffer.

There is an urgent need for treatments like oxygen which is seeing a surge in demand that is 5 times – and in cases such as India, 10 times – greater than the need before the pandemic.

The funding needed for the ACT-Accelerator will address challenges delivering products where they are most needed, help establish testing for 500 million people in low- and middle-income countries by mid-2021 and help secure the necessary supply of oxygen as well as distribute 165 million doses of treatments including dexamethasone which can save lives of people critically ill with COVID.

Carl Bildt, WHO Special Envoy for the ACT Accelerator, said: “We welcome these commitments but there is still a significant funding gap that must be closed if we are to get the urgently needed treatments, including oxygen, and tests, to low and lower-middle income countries so we aren’t flying blind to where the virus is and how it’s changing.

The time to act is now. We look to the G7 and G20 to fund the work of the ACT Accelerator, the global multilateral solution that can speed up an end to the pandemic. The world needs their political leadership because left to rage anywhere, the virus will remain a threat everywhere.”

“This is an important moment of global solidarity and a critical milestone in the push to ensure those most at risk, everywhere are protected,” said Dr Seth Berkley, CEO of Gavi, the Vaccine Alliance (Gavi). 

“As we strive towards or goal of ending the acute phase of the pandemic, we look forward to working with countries to ensure these doses pledged are quickly turned into doses delivered.”Dr Philippe Duneton, Executive Director of UNITAID, said: “These commitments from G7 leaders are important and welcome.

But it is crucial to remember that right now, COVID-19 patients around the world are dying and suffering due to a lack of oxygen, an essential medicine that is vital for the treatment of COVID-19.

I would urge G7 leaders to act now to ensure that all pillars of the ACT-Accelerator are fully funded – including those focusing on treatments and tests. As recent events in India, Nepal and elsewhere have shown, we need more than vaccines to end this pandemic everywhere.”

Henrietta Fore, Executive Director of UNICEF, said: “The impact of the pandemic in its second year is already far worse than its first. We are seeing significant and devastating outbreaks all over the world – including south Asia, southern Africa and Latin America.
We must continue to sound the alarm.

The longer the virus continues to spread unchecked, the higher the risk of more deadly or contagious variants emerging.

The clearest pathway out of this pandemic is a global, equitable distribution of vaccines, diagnostics and therapeutics, and the overall strengthening of health systems across the globe, because no one will be safe until we are all safe.”

Dr Emma Hannay, Chief Access Officer and ACT-Accelerator Lead for FIND, said: “We thank the G7 for their leadership and continuing drive to ensure R&D and equitable access to diagnostic testing, necessary both for the fight against COVID-19 and to lay the foundations that will prepare the world to guard against future pandemics.”

Dr Richard Hatchett, CEO of CEPI, said: “This is an historic moment – as leaders of some of the wealthiest counties come together to ensure that all parts of the world have access to life saving vaccines.

This pandemic has shown us that we cannot set national against international interests. With a disease like COVID-19 we have to ensure that we get it under control everywhere. 

There is still much to do to get vaccines in arms and ensure our research and development allows us to stay one step ahead of the virus. But for today we give pause and celebrate a watershed moment of political alignment and collaboration”.

Peter Sands, Executive Director of The Global Fund, said: “It is encouraging to see such global collaboration and commitments. However, none of the lifesaving tools to fight COVID-19 will deliver themselves.

We need to make sure that health systems are prepared and that front-line health workers are sufficiently protected to deliver these tools without risking their own lives. This can only happen if the ACT-Accelerator is fully funded.”

https://www.who.int/news/item/13-06-2021-the-act-accelerator-partnership-welcomes-commitment-of-870-million-vaccine-doses-and-calls-for-more-investment-in-all-tools-to-end-the-pandemic

FDA Takes Steps to Increase Availability of COVID-19 Vaccine

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FDA Takes Steps to Increase Availability of COVID-19 Vaccine

June 11, 2021: “Following careful review and deliberation, the U.S. FDA is taking important steps that will allow a critically needed supply of the Janssen (Johnson & Johnson) COVID-19 Vaccine to be made available.

The agency is announcing that it is authorizing for use, under the emergency use authorization (EUA) for the Janssen COVID-19 vaccine, two batches of vaccine drug substance manufactured at the Emergent BioSolutions facility in Baltimore.

Before making this decision, the FDA conducted a thorough review of facility records and the results of quality testing performed by the manufacturer.

Based on this review and considering the current COVID-19 public health emergency, the FDA concluded these batches are suitable for use.

While the FDA is not yet ready to include the Emergent BioSolutions plant in the Janssen EUA as an authorized manufacturing facility, the agency continues to work through issues there with Janssen and Emergent BioSolutions management.

The FDA’s decision to include these two batches of vaccine drug substance in the EUA for the Janssen COVID-19 vaccine means that Janssen vaccine made with this drug substance can be used in the U.S. or exported to other countries.

A condition on any export of these batches, or of vaccine manufactured from these batches, is that Janssen and Emergent agree that the FDA may share relevant information about the manufacture of the batches under an appropriate confidentiality agreement, with the regulatory authorities of the countries in which the vaccine may be used.

The FDA has also revised the letter of authorization for the Janssen vaccine to help facilitate potential export to other countries.

Under the revised letter of authorization, the distribution and administration of exported vaccines must comply with the laws of the recipient countries.

The FDA has determined several other batches are not suitable for use, but additional batches are still under review and the agency will keep the public informed as those reviews are completed.

Additionally, the FDA has extended the expiration dating for the refrigerated Janssen COVID-19 Vaccine after reviewing information submitted by Janssen and determining that the vaccine can be stored at 2-8 degrees Celsius for 4.5 months instead of 3 months.

“These actions followed an extensive review of records, including the production history of the facility and the testing performed to evaluate the quality of the product.

This review has been taking place while Emergent BioSolutions prepares to resume manufacturing operations with corrective actions to ensure compliance with the FDA’s current good manufacturing practice requirements,” said Peter Marks, M.D. Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

“Additionally, the action to extend the shelf life for the refrigerated Janssen vaccine means that jurisdictions that have doses on hand now have additional time to administer vaccine.”

The FDA also will keep the public and our global partners informed as we continue to work expeditiously on this issue and will share information when we are able.”

https://www.fda.gov/news-events/press-announcements/fda-takes-steps-increase-availability-covid-19-vaccine

Modus Therapeutics and Imperial College London collaborates for Malaria drug

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Modus Therapeutics and Imperial College London collaborates for Malaria drug

Jun 11, 2021: Modus Therapeutics Holding AB, a company developing innovative treatments for patients with high unmet medical needs, announces that it has entered a clinical research collaboration with a team led by Professor Kathryn Maitland from Imperial College London, UK.

The project aims at researching the effect of the Company’s proprietary drug sevuparin in patients with severe malaria. 

Modus is currently developing sevuparin in sepsis/septic shock, and other conditions with systemic inflammation, with severe malaria being a further example. These conditions constitute major healthcare problems.

Severe malaria, like sepsis/septic shock, remains an unaddressed medical problem in the parts of the world with endemic malaria.

The condition primarily affects young children infected with the parasites. In severe malaria, the parasitic infection causes a systemic inflammation syndrome that shares similarities with sepsis and other severe conditions resulting in uncontrolled systemic inflammation, which can then progress into shock and multi-organ failure.

The malaria project is funded by a collaborator grant in science from Wellcome (209265/Z/17/Z) to Professor Maitland’s research group at KEMRI-Wellcome Trust Programme, Kilifi Kenya and to the international consortium “Severe Malaria Africa -A consortium for Research and Trials” (SMAART), the goal of which is to identify and research new treatments for severe malaria.

Under the collaboration, Modus will supply sevuparin to a future clinical study in patients with severe malaria. Sevuparin has already shown promising effects on the malaria parasite in patients with uncomplicated malaria and in human samples (Leitgeb et al 2017, Saiwaew et al 2017).

Professor Kathryn Maitland of Imperial College London on the planned clinical study:

“Given the potential of sevuparin to be transformative in improving current outcomes from severe malaria, a large group of specialist doctors in severe malaria research and clinical trials suggested that sevuparin should be tested in children with severe malaria.

All members of the group helped to design this clinical trial (Pan African Trials Registry PACTR202007890194806), which will be conducted on the high dependency ward in Kilifi, Kenya.”

John Öhd, CEO of Modus Therapeutics, commenting on the collaboration said: 

“I am very excited to announce this ground-breaking collaborative effort designed to evaluate the potential of sevuparin as a new treatment for the severe form of malaria.

This work will also provide an important opportunity for Modus to understand more about sevuparin’s potential to tackle disorders involving systemic inflammation in parallel with our lead indication, sepsis.

We are also honored to be able to participate in this work led by Professor Maitland, a world-leader in clinical malaria research and which has the backing of institutions such as Imperial College London and Wellcome.” 

https://www.modustx.com/news/17/58/Modus-Therapeutics-and-Imperial-College-London-Sign-Clinical-Collaboration-Targeting-Severe-Malaria.html

Novartis oral therapy iptacopan shows benefit in PNH

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Novartis oral therapy iptacopan shows benefit in PNH

June 11, 2021: Novartis announced new Phase II data for iptacopan (LNP023), an investigational oral treatment for paroxysmal nocturnal hemoglobinuria (PNH), presented at the 26th Annual Congress of the European Hematology Association (EHA).

In the study (NCT03896152), treatment with 12 weeks of iptacopan monotherapy was generally well tolerated with no unexpected safety findings and resulted in rapid and durable transfusion-free improvement of hemoglobin levels in the majority of patients1.

“Currently, 20-50% of PNH patients treated with standard-of-care anti-C5 therapies remain transfusion-dependent due to persistent extravascular hemolysis, and an additional 20-40% exhibit varying degrees of residual anemia,” said lead author Professor Jun Ho Jang, Division of Hematology-Oncology, Sungkyunkwan University School of Medicine.

“These results show that oral iptacopan blocks both intra- and extravascular hemolysis in patients with hemolytic PNH who have not previously been treated with an anti-C5.

When considered with the findings of the previous Phase II study, these data suggest that iptacopan may provide additional benefits beyond those seen with current standard-of-care therapies, and may potentially change the PNH treatment paradigm.”

All patients completing at least 12 weeks of iptacopan treatment (n=11) achieved the primary endpoint of at least a 60% reduction in their lactate dehydrogenase (LDH) levels, a biomarker of intravascular hemolysis.

Importantly, with the exception of one patient receiving a single red blood cell (RBC) transfusion, all patients remained transfusion-free through 12 weeks of study.

Patients also showed improvement in other biomarkers of hemolysis and a marked increase in the proportion of PNH-type RBCs, indicating overall control of both intra- and extravascular hemolysis.

No serious adverse events or thromboembolic events were reported during the 12-week treatment period and the study yielded no unexpected safety results.

Two participants discontinued iptacopan treatment before completing 12 weeks of treatment: one due to a non-serious headache, the other by physician decision due to worsening of pre-existing neutropenia.

The most common adverse events were headache (31% of patients), abdominal discomfort (15%), blood alkaline phosphatase increase (15%), cough (15%), oropharyngeal pain (15%), pyrexia (raised body temperature; 15%), and upper respiratory infection (15%)1.

“PNH is a rare and life-threatening blood disorder with often debilitating symptoms,” said John Tsai, Head Global Drug Development and Chief Medical Officer, Novartis.

“New treatment options are needed, and these positive results further strengthen the profile of iptacopan as a promising oral monotherapy.

We are excited to continue to explore the potential of iptacopan as new standard-of-care treatment for PNH in the ongoing Phase III study.”

PNH, which is characterized by complement-driven hemolysis, thrombosis and impaired bone marrow function, results in anemia, fatigue and other debilitating symptoms that can impact patients’ quality of life.

Despite treatment with current anti-C5 standard-of-care therapies, a large proportion of PNH patients remain anemic and dependent on transfusions.

In results from the separate open-label Phase II study (NCT03439839), published in The Lancet Haematology, iptacopan improved hematological response and biomarkers of disease activity in PNH patients with active hemolysis despite treatment with the anti-C5 eculizumab.

This benefit was maintained in patients who stopped eculizumab treatmen.

About iptacopan
Iptacopan is an investigational first-in-class, orally administered targeted factor B inhibitor of the alternative complement pathway.

It acts upstream of the C5 terminal pathway, preventing not only intravascular but also extravascular hemolysis in PNH.

In doing so, iptacopan may have a therapeutic advantage over current standard-of-care by targeting a key part of the biology responsible for PNH.

Discovered at the Novartis Institutes for BioMedical Research, iptacopan is currently in development for a number of complement-driven diseases where significant unmet needs exist, including IgAN, C3G, atypical hemolytic uremic syndrome (aHUS), and membranous nephropathy (MN), as well as the blood disorder PNH.

Novartis has initiated a Phase III study of iptacopan as monotherapy in PNH.

Based on disease prevalence and the positive interim data from Phase II studies, iptacopan has received orphan drug designations from the FDA and EMA in C3G and PNH, FDA Breakthrough Therapy Designation in PNH, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN.”

https://www.novartis.com/news/media-releases/novartis-investigational-oral-therapy-iptacopan-lnp023-shows-benefit-monotherapy-treatment-naive-patients-rare-and-life-threatening-blood-disorder-paroxysmal

Roche announces efficacy of Venclexta/Venclyxto in chronic lymphocytic leukaemia

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Roche announces efficacy of Venclexta/Venclyxto in chronic lymphocytic leukaemia

June 2021: Roche announced the latest data from three pivotal phase III studies of Venclexta®/Venclyxto® (venetoclax) – CLL14, MURANO and VIALE-A – to be presented at the European Hematology Association Virtual Congress, June 9-17 (EHA2021).

Long-term follow-up data from the CLL14 and MURANO studies support the primary analysis of Venclexta/Venclyxto in chronic lymphocytic leukaemia (CLL) and the possibility of tailoring treatment approaches based on genetic risk factors.

Furthermore, the latest research shows the potential of minimal residual disease (MRD) as a key measure of disease response in CLL and acute myeloid leukaemia (AML).

“The data from these Venclexta/Venclyxto combinations support our continued commitment to provide valuable therapeutic options for patients with hard-to-treat blood cancers,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development.

“These data also advance our understanding of minimal residual disease, which we believe is a useful endpoint that may help identify patients more quickly who are in need of additional treatment.”

Four-year follow-up analysis of the phase III CLL14 study
This four-year post-hoc analysis of investigator-assessed progression-free survival (PFS) had a median follow-up of 52.4 months (interquartile range: 49.5-56.2 months).

The fixed treatment duration (12 months) study indicated that the chemotherapy-free Venclexta/Venclyxto plus Gazyva/Gazyvaro (obinutuzumab) regimen had an estimated PFS rate of 74.0% vs 35.4% for Gazyva/Gazyvaro plus chlorambucil.

Importantly, the time to next treatment (TTNT) was significantly longer among patients treated with the Venclexta/Venclyxto plus Gazyva/Gazyvaro regimen versus the comparator (four-year TTNT 81.1% vs 59.9%; HR 0.46, 95% CI [0.32-0.65], p<0.0001).

Furthermore, 30 months after the end of treatment, 26.9% of the Venclexta/Venclyxto-treated patients still had undetectable MRD (uMRD) compared with 3.2% of those treated with the comparator. 

Undetectable MRD, sometimes referred to as MRD-negativity, means that no cancer cells could be detected using a specific and highly sensitive test, and is defined as less than one cancer cell in 10,000 leukocytes.

Undetectable MRD is emerging as a measure of disease response that may be useful to consider in treatment decision-making.

Common grade 3-4 adverse events with Venclexta/Venclyxto and Gazyva/Gazyvaro at 28 months follow-up were low white blood cell count and infections.5

Substudy from the phase III MURANO study
Results from this substudy suggested that increased prevalence of certain unfavourable genetic risk factors negatively impacted the MRD response of patients who were retreated with Venclexta/Venclyxto plus MabThera®/Rituxan® (rituximab) after progression on treatment with that regimen.

These data indicate the potential to tailor treatment approaches for patients with previously treated CLL based on genetic risk factors.

Post-hoc analysis of the phase III VIALE-A study
Additionally, a post-hoc analysis from the phase III VIALE-A study suggested the value of continued research to understand the role of MRD monitoring in AML.

In the analysis, patients who achieved a composite complete remission and uMRD following treatment with Venclexta/Venclyxto and azacitidine, a hypomethylating agent, had improved survival outcomes compared with those who were MRD-positive following treatment.

The 12-month estimates for duration of response, overall survival and event-free survival for both groups are listed below:

 Achieved composite complete remission and uMRD (MRD<10-3)Did not achieve composite complete remission and uMRD (MRD≥10-3)
Duration of response81.2% (95% CI 69.3-88.9)46.6% (95% CI 35.6-56.8)
Overall survival94.0% (95% CI 84.7-97.7)67.9% (95% CI 57.6-76.2)
Event-free survival83.2% (95% CI 71.6-90.3)45.4% (95% CI 35.2-55.0)

Adverse events of grade ≥3 (MRD<10-3/MRD≥10-3) were febrile neutropenia (50%/43%), neutropenia (50%/35%), and thrombocytopenia (44%/44%), similar to the overall population.3

Roche is collaborating with regulatory authorities and others in the industry to advance understanding of MRD.

The company continues to investigate Venclexta/Venclyxto in a robust clinical development programme, including in the phase III CRISTALLO trial in previously untreated CLL, which uses MRD as a primary endpoint.

Venclexta/Venclyxto is approved in the US and EU in combination with MabThera/Rituxan for the treatment of adult patients with CLL who have received at least one prior therapy; in combination with Gazyva/Gazyvaro for the treatment of adult patients with previously untreated CLL; and as a monotherapy for the treatment of CLL in the presence of 17p deletion or TP53 mutation in people who are unsuitable for or have failed a B-cell receptor pathway inhibitor.

Venclexta is also approved in the US in combination with azacitidine, decitabine, or low dose cytarabine for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

In the EU, Venclyxto is approved in combination with a hypomethylating agent for the treatment of adult patients with newly diagnosed AML who are ineligible for intensive chemotherapy.

About the CLL14 study
CLL14 [NCT02242942] is a randomised phase III study evaluating the combination of fixed-duration Venclexta®/Venclyxto® (venetoclax) plus Gazyva®/Gazyvaro® (obinutuzumab) compared to Gazyva/Gazyvaro plus chlorambucil in adult patients with previously untreated chronic lymphocytic leukaemia (CLL) and co-existing medical conditions.

Four hundred and thirty-two patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venclexta/Venclyxto alongside six-month duration of Gazyva/Gazyvaro (Arm A) or six-month duration of Gazyva/Gazyvaro alongside 12-month duration of chlorambucil (Arm B).

Arm A started with an initial dosing of Gazyva/Gazyvaro followed by a five-week Venclexta/Venclyxto dose ramp-up to help reduce the risk of tumour burden.

The primary endpoint of the study is investigator-assessed progression-free survival (PFS).

Secondary endpoints included PFS assessed by independent review committee, minimal residual disease status, overall response rate, complete response rate, and safety.

The CLL14 study is being conducted in cooperation with the German CLL Study Group, headed by Michael Hallek, M.D., University of Cologne.

About the MURANO study
MURANO [NCT02005471] is a phase III open-label, international, multicentre, randomised study evaluating the efficacy and safety of fixed-duration Venclexta®/Venclyxto® (venetoclax) in combination with MabThera®/Rituxan® (rituximab) compared to bendamustine in combination with MabThera/Rituxan (BR). All treatments were of fixed duration.

Following a five-week dose ramp-up schedule for Venclexta/Venclyxto, patients on the Venclexta/Venclyxto plus MabThera/Rituxan arm received six cycles of Venclexta/Venclyxto plus MabThera/Rituxan followed by Venclexta/Venclyxto monotherapy for up to two years total.

The study included 389 patients with chronic lymphocytic leukaemia (CLL), with or without 17p deletion, who had been previously treated with at least one line of therapy.

A substudy from 2018 onward enrolled 34 relapsed or refractory CLL patients who progressed after initial treatment to receive Venclexta/Venclyxto plus MabThera/Rituxan as retreatment (n=25) or who crossed over from the BR arm (n=9).

The primary endpoint of the study was progression-free survival.

Secondary endpoints included overall survival, overall response rate and complete response rate (with or without complete blood count recovery).

About the VIALE-A study
VIALE-A [NCT02993523] is a phase III, randomised, double-blind, placebo-controlled multicentre study evaluating the efficacy and safety of Venclexta®/Venclyxto® (venetoclax) plus azacitidine, a hypomethylating agent, compared to placebo with azacitidine, in 431 people with previously untreated acute myeloid leukaemia who are ineligible for intensive chemotherapy.

Two-thirds of patients (n=286) received 400 mg Venclexta/Venclyxto daily, in combination with azacitidine, and the remaining patients (n=145) received placebo tablets in combination with azacitidine.

Patients enrolled in the study had a range of mutational subtypes, including IDH1/2 and FLT3. VIALE-A met its primary and key secondary endpoints.

About Venclexta/Venclyxto
Venclexta®/Venclyxto® (venetoclax) is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein.

In some blood cancers and other tumours, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis.

Venclexta/Venclyxto blocks the BCL-2 protein and works to restore the process of apoptosis.

Venclexta/Venclyxto is being developed by AbbVie and Roche.

It is jointly commercialised by AbbVie and Genentech, a member of the Roche group, in the US and commercialised by AbbVie outside of the US.

Together, the companies are committed to research with Venclexta/Venclyxto, which is currently being studied in clinical trials across several types of blood cancers.

In the US, Venclexta has been granted five Breakthrough Therapy Designations by the U.S. FDA: one for previously untreated chronic lymphocytic leukaemia (CLL), two for relapsed or refractory CLL and two for previously untreated acute myeloid leukaemia.”

https://www.roche.com/media/releases/med-cor-2021-06-11b.ht

BMS Phase 3 Trial Evaluating Breyanzi Vs Chemotherapy in Refractory Lymphoma

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BMS Phase 3 Trial Evaluating Breyanzi Vs Chemotherapy in Refractory Lymphoma

June 10, 2021: “Bristol Myers Squibb announced positive topline results from TRANSFORM, a global, randomized, multicenter Phase 3 study evaluating Breyanzi (lisocabtagene maraleucel) as a second-line treatment in adults with relapsed or refractory large B-cell lymphoma (LBCL) compared to salvage therapy followed by high-dose chemotherapy and hematopoietic stem cell transplant, which is currently considered a gold standard treatment for these patients.

Results of a pre-specified interim analysis conducted by an independent review committee showed the study met its primary endpoint of demonstrating a clinically meaningful and highly statistically significant improvement in event-free survival, as well as key secondary endpoints of complete response rate and progression-free survival compared to standard of care.

Overall survival data were immature at the time of this interim analysis. Safety results were consistent with the known safety profile of Breyanzi for the treatment of LBCL in the third-line setting, and no new safety concerns were identified in this second-line setting.

“We ambitiously designed the TRANSFORM trial to evaluate Breyanzi’s potential in the second-line setting for patients with relapsed or refractory large B-cell lymphoma against the standard of care regimen of high-dose chemotherapy and autologous stem cell transplant,” said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology and Cell Therapy Development, Bristol Myers Squibb.

“These positive interim results build on our commitment to bring CAR T cell therapies into earlier lines and highlight the potential of Breyanzi to transform the treatment paradigm for this difficult-to-treat disease, possibly supplanting the need for patients to undergo current aggressive treatment regimens.”

The results represent the first time a therapy has shown a benefit over standard of care high-dose chemotherapy and stem cell transplant in relapsed or refractory LBCL, and the first time a CD19-directed CAR T cell therapy has demonstrated potential as a second-line therapy in this patient population.

The company will complete an evaluation of the TRANSFORM data and looks forward to sharing the results at an upcoming medical conference, as well as with health authorities.

Bristol Myers Squibb thanks the patients and investigators who are participating in the TRANSFORM clinical trial.

Breyanzi, a CD19-directed CAR T cell therapy,was approved by the U.S. FDA in February 2021 for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. 

Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma.

About TRANSFORM

TRANSFORM (NCT03575351) is a pivotal, global, randomized, multicenter Phase 3 trial evaluating Breyanzi compared to current standard of care regimens, including high-dose chemotherapy (HDCT) and hematopoietic stem cell transplant (HSCT), in adults with large B-cell lymphoma that is primary refractory or relapsed within 12 months of initial therapy and who are eligible for stem cell transplant.

Patients were randomized to receive Breyanzi or standard of care salvage therapy, including rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP), rituximab plus ifosfamide, carboplatin and etoposide (R-ICE), or rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) per the investigators’ choice before proceeding to HDCT and HSCT.

The primary endpoint of the study is event-free survival, defined as time from randomization to death from any cause, progressive disease, failure to achieve complete response or partial response by nine weeks post-randomization, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first.

Complete response rate is a key secondary endpoint. Other efficacy endpoints include progression-free survival, overall survival, overall response rate and duration of response.

All enrolled patients have large B-cell lymphoma and were relapsed or refractory within 12 months from CD20 antibody and anthracycline containing first-line therapy.

About Breyanzi

Breyanzi is a CD-19 directed chimeric antigen receptor (CAR) T cell therapy with a defined composition and 4-1BB costimulatory domain. Breyanzi is administered as a defined composition to reduce variability of the CD8 and CD4 component dose.

The 4-1BB signaling domain enhances the expansion and persistence of the CAR- T cells.

Breyanzi is approved by the U.S.FDA for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Breyanzi is also approved in Japan for relapsed and refractory LBCL, and Marketing Authorization Applications for Breyanzi are currently under review in the European Union, Switzerland and Canada.

Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in earlier lines of treatment for patients with relapsed or refractory LBCL and other types of lymphoma. For more information, visit clinicaltrials.gov.

U.S. FDA-Approved Indication for Breyanzi

BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma.

Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI.

    Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
  • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution or in the absence of CRS.

    Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
  • BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.

Cytokine Release Syndrome (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with BREYANZI. CRS occurred in 46% (122/268) of patients receiving BREYANZI, including ≥ Grade 3 (Lee grading system) CRS in 4% (11/268) of patients.

One patient had fatal CRS and 2 had ongoing CRS at time of death.

The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days).

Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death.

Among patients with CRS, the most common manifestations of CRS include fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%). 

Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI. Sixty-one of 268 (23%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of BREYANZI.

Twenty-seven (10%) patients received tocilizumab only, 25 (9%) received tocilizumab and a corticosteroid, and 9 (3%) received corticosteroids only.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, occurred following treatment with BREYANZI.

CAR T cell-associated neurologic toxicities occurred in 35% (95/268) of patients receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death.

The median time to onset of the first event was 8 days (range: 1 to 46 days).

The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion. Neurologic toxicities resolved in 81 of 95 patients (85%) with a median duration of 12 days (range: 1 to 87 days).

Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy.

Median duration of neurologic toxicity was 15 days (range: 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.

Seventy-eight (78) of 95 (82%) patients with neurologic toxicity experienced CRS. Neurologic toxicity overlapped with CRS in 57 patients.

The onset of neurologic toxicity was after onset of CRS in 30 patients, before CRS onset in 13 patients, same day as CRS onset in 7 patients, and same day as CRS resolution in 7 patients.

Neurologic toxicity resolved in three patients before the onset of CRS. Eighteen patients experienced neurologic toxicity after resolution of CRS.

The most common neurologic toxicities included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), dizziness (6%), and ataxia (6%).

Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, have occurred in patients treated with BREYANZI.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily at a certified healthcare facility during the first week following infusion, for signs and symptoms of CRS and neurologic toxicities.

Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion; evaluate and treat promptly.

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

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

BREYANZI REMS

Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:

  • Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
  • Certified healthcare facilities must have on-site, immediate access to tocilizumab.
  • Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
  • Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer BREYANZI are trained on the management of CRS and neurologic toxicities.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. Infections (all grades) occurred in 45% (121/268) of patients. Grade 3 or higher infections occurred in 19% of patients.

Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 1.5% and 0.4% of patients, respectively. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately.

Administer prophylactic antimicrobials according to standard institutional guidelines.

Febrile neutropenia has been observed in 9% (24/268) of patients after BREYANZI 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 as medically indicated.

Avoid administration of BREYANZI in patients with clinically significant active systemic infections.

Viral reactivation: 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 B cells.

Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI.

Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 31% (84/268) of patients, and included thrombocytopenia (26%), neutropenia (14%), and anemia (3%). Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI. The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14% (37/268) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 21% (56/268) of patients.

Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 32% (85/268) of patients.

Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI 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 BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration.

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

Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients.

The most common nonlaboratory adverse reactions of any grade (≥ 20%) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.”

https://news.bms.com/news/corporate-financial/2021/Bristol-Myers-Squibb-Announces-Positive-Topline-Results-from-Phase-3-TRANSFORM-Trial-Evaluating-Breyanzi-lisocabtagene-maraleucel-Versus-Chemotherapy-Followed-by-Stem-Cell-Transplant-in-Second-line-Relapsed-or-Refractory-Large-B-cell-Lymphoma/default.aspx

Bayer to advance two first-of-its-kind cell and gene therapies for Parkinson’s disease

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Bayer to advance two first-of-its-kind cell and gene therapies for Parkinson’s disease

June 8, 2021: Bayer AG announced that BlueRock Therapeutics (BlueRock), a clinical stage biopharmaceutical company and wholly-owned subsidiary of Bayer AG, successfully administered the first dose of its pluripotent stem cell-derived dopaminergic neurons, named DA01, to a Parkinson’s disease patient in their open-label Phase 1 clinical study.

In parallel a gene therapy program also targeted at providing advanced therapies for Parkinson’s disease is driven forward by Bayer’s wholly-owned clinical-stage adeno-associated virus (AAV) gene therapy company Asklepios BioPharmaceutical, Inc. (AskBio).

This program is currently recruiting and evaluating patients in an ongoing Phase 1b clinical study.

“The potential of BlueRock and AskBio’s clinical candidates to treat Parkinson’s disease could be immense,” said Wolfram Carius, Head of Cell and Gene Therapy at Bayer.

“For the first time, it might be possible to stop and reverse this degenerative disease and truly help patients with their high unmet medical need.

The start of clinical trials represents the beginning towards a truly breakthrough treatment option to dramatically improve the lives of patients.”

Parkinson’s disease is the most common neurodegenerative movement disorder, impacting more than 10 million people worldwide.

It is caused by nerve cell damage in the brain, leading to decreased levels of dopamine (a neurotransmitter involved in processes such as memory or movement).

The disease often starts with a tremor in one hand. Other symptoms include rigidity, cramping and dyskinesias (involuntary, erratic, writhing movements of the face, arms, legs or trunk).

Dopamine substitutes, such as levodopa, are commonly used to mitigate the symptoms of the disease, but their effect diminishes as the disease progresses and there is currently no disease-modifying treatment available.

By targeting the disease at its root cause, cell and gene therapies aim to go beyond symptomatic treatments.

Using authentic dopaminergic neurons, BlueRock aims to re-innervate the affected regions of the human brain and reverse the degenerative process, potentially restoring motor function. BlueRock’s clinical trial will enroll ten patients at sites in the United States of America (US) and Canada.

In this study, patients undergo surgical transplantation of the dopamine-producing cells into the putamen, a deep brain structure affected by Parkinson’s disease.

primary objective of the Phase 1 study (NCT04802733) is to assess the safety and tolerability of DA01 cell transplantation at one-year post-transplant.

The secondary objectives of the study are to assess the evidence of transplanted cell survival and motor effects at one- and two-years post-transplant, to evaluate continued safety and tolerability at two years, and to assess feasibility of transplantation.

AskBio’s approach consists of an AAV that delivers human glial cell line-derived neurotrophic factor (GDNF) gene to the neurons within the putamen, resulting in expression and secretion of GDNF protein in brain regions impacted by Parkinson’s disease.

Long-term experiments using AAV-GDNF showed that sustained expression of GDNF can promote regeneration of midbrain neurons and significant motor recovery in rodents and non-human primate models.

AskBio’s clinical study is currently recruiting and evaluating patients in Phase 1b in the US to assess safety and preliminary efficacy. “

https://media.bayer.com/baynews/baynews.nsf/id/Bayer-to-advance-two-first-of-its-kind-cell-and-gene-therapies-for-Parkinsons-disease?Open&parent=news-overview-category-search-en&ccm=020

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