Pharmaceutical Technology Editors

In a Sept. 1, 2021 announcement, FDA concluded that the arthritis and ulcerative colitis medicines Xeljanz and Xeljanz XR (tofacitinib) increased the risk of serious heart-related events (such as heart attack and stroke), cancer, blood clots, and death, which was based on a review of a large, randomized safety clinical trial.

The trial compared Xeljanz with tumor necrosis factor (TNF) blockers in patients with rheumatoid arthritis. The results showed an increased risk of blood clots and death with the lower dose of Xeljanz.

The FDA announcement states that the agency will require new and updated warnings for two Janus kinase (JAK) inhibitors, Olumiant (baricitinib) and Rinvoq (upadacitinib), which are in the same drug class as Xeljanz. These drugs have not been studied in trials like Xeljanz in the safety clinical trial. However, since they share mechanisms of action with Xeljanz, Olumiant and Rinvoq may have similar risks as seen in the Xeljanz safety trial.

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FDA will now require new and updated warnings about the increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions.

FDA to Require Additional Warnings for JAK Inhibitors Treating Select Chronic Inflammatory Conditions

SK bioscience (SK) and GlaxoSmithKline (GSK) announced the initiation of a Phase III clinical study of SK’s COVID-19 vaccine candidate, GBP510, in combination with GSK’s pandemic adjuvant following positive interim Phase I/II results in an Aug. 31, 2021 press release. The Phase III clinical study is a randomized, active-controlled global trial that will enroll approximately 4,000 participants. It will evaluate GBP510’s safety and immunogenicity compared to the AstraZeneca/Oxford University COVID-19 vaccine. This will be one of the first global Phase III trials to compare two different COVID-19 vaccine candidates.

Interim Phase I/II data showed that participants who received the adjuvanted vaccine candidate developed strong neutralizing antibody responses, demonstrating a 100% seroconversion rate. No safety concerns have been identified to date in the ongoing study.

Results from the Phase III study are expected in the first half of 2022. The vaccine is then expected to be supplied worldwide through the COVAX facility, pending positive results and regulatory approval.

SK and GSK announce the initiation of a Phase III clinical study of SK’s COVID-19 vaccine candidate, GBP510, in combination with GSK’s pandemic adjuvant.

SK Bioscience and GSK Start Phase III Trial of Adjuvanted COVID-19 Vaccine Candidate

Merck, known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics announced the initiation of the Phase III MOVe-AHEAD clinical trial to evaluate molnupiravir—an investigational oral antiviral therapeutic—for the prevention of COVID-19 infection in a Sept. 1, 2021 press release. The global study is enrolling individuals 18 years of age and older who reside in the same household as someone with laboratory-confirmed SARS-CoV-2 infection with symptoms.

MOVe-AHEAD is a Phase III multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of orally administered molnupiravir compared to placebo in preventing the spread of COVID-19 within households. Approximately 1,332 participants will be enrolled and randomized to receive either 800 mg of molnupiravir or placebo orally every 12 hours for five days. The trial is being conducted globally, including countries such as Argentina, Brazil, Colombia, France, Guatemala, Hungary, Japan, Mexico, Peru, Philippines, Romania, Russia, South Africa, Spain, Turkey, Ukraine, and the United States.

In addition, the safety and efficacy of molnupiravir is being evaluated in part two of the ongoing MOVe-OUT trial, which is a global Phase III, randomized, placebo-controlled, double-blind, multi-site study of non-hospitalized adult patients with laboratory-confirmed mild to moderate COVID-19 and at least one risk factor associated with poor disease outcomes. Data from the study is expected in the second half of 2021.

Merck and Ridgeback Biotherapeutics announced the initiation of the Phase III clinical trial to evaluate an investigational oral antiviral therapeutic for the prevention of COVID-19 infection.

Merck and Ridgeback Biotherapeutics Initiate Phase III Trial to Evaluate Molnupiravir for COVID-19

In the fall of 2021, two of FDA’s vaccine regulators will be leaving, which may potentially impact COVID-19 vaccine regulations—including vaccine recommendations for children under the age of 12 and booster shots recommendations—

according to an Aug. 31, 2021, article in 

. In a Tuesday email to the staff cited in the same article, it was revealed that Marion Gruber, the director of FDA’s vaccines office, will retire in October. Philip Krause, Gruber’s deputy, will leave in November.

 article, their departure could have been in part due to the Biden administration encouraging adults to get a booster vaccine eight months after receiving their second shot. According to anonymous individuals close to the situation referenced in the article, Gruber and Krause believed there was not enough data to justify offering booster shots yet.

According to an Aug. 31, 2021 memo shared with 

, Peter Marks, director of the Center for Biologics Evaluation and Research, FDA, will be the acting head of the vaccine office while FDA searches for a replacement.

Two of FDA’s vaccine regulators will be leaving in the fall of 2021, which has the potential to impact COVID-19 vaccine recommendations for both children under the age of 12 and booster shots.

What Does the Retirement of Two Senior FDA Officials Mean for COVID-19 Vaccine Regulations?

The European Commission (EC) granted conditional marketing authorization on Aug. 26, 2021, to Incyte and MorphoSys for Minjuvi (tafasitamab), a humanized fragment crystallizable region (Fc)-modified cytolytic CD19-targeting monoclonal antibody (mAb), for use in combination with lenalidomide, followed by Minjuvi monotherapy, to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The indication is specifically for DLBCL patients who are not eligible for autologous stem cell transplant (ASCT).

The EC’s decision follows a positive opinion granted by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in June 2021. The conditional approval is based on results from a Phase II study whose results showed best objective response rate of 56.8% (a primary endpoint of the study). The results also showed a complete response rate of 39.5% and a partial response rate of 17.3%. Minjuvi combined with lenalidomide demonstrated a clinically meaningful response and had manageable side effects, according to a company press release.

Under an agreement, Incyte and MorphoSys share global development rights to tafasitamab. Incyte has exclusive commercialization rights to the mAb outside the United States. Tafasitamab is co-marketed by Incyte and MorphoSys under the Monjuvi brand name in the US and is marketed by Incyte under the brand name Minjuvi in the European Union.

Monjuvi in the US is approved in combination with lenalidomide to treat adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for ASCT.

“People living with relapsed or refractory DLBCL in the EU [European Union], have historically had limited treatment options and a poor prognosis. However, with the EC’s approval of Minjuvi, eligible patients now have a new and much needed treatment option,” said Hervé Hoppenot, CEO, Incyte, in the press release. “We will now focus our efforts on working with individual countries in Europe to provide people access to this new treatment.”

“The approval of Minjuvi is a crucial milestone for patients with relapsed or refractory DLBCL in Europe,” said Jean-Paul Kress, CEO, MorphoSys, in the press release. “DLBCL is the most common type of non-Hodgkin lymphoma in adults, and Minjuvi addresses an urgent unmet medical need for the 30–40% of people who do not respond to or relapse, after initial therapy.”

The European Commission has granted marketing authorization to Incyte and MorphoSys for Minjuvi (tafasitamab) in combination therapy with lenalidomide to treat relapsed or refractory DLBCL.

Incyte and MorphoSys Receive EC Approval for Minjuvi in Combination Therapy for Lymphoma

SpringWorks Therapeutics, a clinical-stage biopharmaceutical company, has entered into a sponsored research collaboration with Dana-Farber Cancer Institute (Dana-Farber) to further evaluate the therapeutic potential of nirogacestat, an investigational oral, selective, small-molecule gamma secretase inhibitor (GSI), with anti-B-cell maturation antigen (BCMA) agents, in preclinical models to treat multiple myeloma. Under the agreement, SpringWorks will fund the work and will retain an option to exclusively license any new intellectual property that results from the collaboration, the company announced in an Aug. 30, 2021 press release.

The research will be led by Constantine Mitsiades, MD, PhD, assistant professor of Medicine at Dana-Farber and Harvard Medical School, who will serve as the Principal Investigator. The researchers will use preclinical 

 models from the Mitsiades Lab to simulate the multiple myeloma tumor microenvironment. They will also apply functional genomics approaches to explore determinants of response and mechanisms of resistance to a GSI + BCMA combination therapy.

Inhibition of gamma secretase prevents the cleavage and shedding of BCMA from the surface of multiple myeloma cells. Nirogacestat has been shown to increase the cell surface density of BCMA and to reduce levels of soluble BCMA in preclinical models, and thus is thought to enhance the activity of BCMA-targeted therapies. SpringWorks has entered into clinical collaborations with six industry partners to date to evaluate nirogacestat in combination with BCMA therapies across modalities.

Nirogacestat is in Phase III clinical development for treating rare and often debilitating and disfiguring soft-tissue tumors, including desmoid tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch proteins, that are believed to play a role in activating pathways that contribute to desmoid tumor growth. Gamma secretase has also been shown to directly cleave membrane-bound BCMA, which releases the BCMA extracellular domain (ECD) from the cell surface.

Membrane-bound BCMA can be preserved by inhibiting gamma secretase, which increases target density and reduces levels of soluble BCMA ECD, resulting in potential decoy receptors for BCMA-directed therapies. Nirogacestat has shown an ability to enhance the activity of BCMA-directed therapies, observed in preclinical models of multiple myeloma.

Nirogacestat has received orphan drug designation from FDA for treating desmoid tumors and from the European Commission for treating soft tissue sarcoma. FDA also granted fast track and breakthrough therapy designations for the molecule in the treatment of adult patients with progressive, unresectable, recurrent, or refractory desmoid tumors or deep fibromatosis.

“SpringWorks has demonstrated its commitment to understanding the science and advancing the clinical exploration of GSI + BCMA combination therapies,” said Mitsiades, in the company press release. “I am pleased to collaborate with them towards the goal of improving clinical outcomes for patients with multiple myeloma while simultaneously enabling the advancement of the underlying science.”

“We are delighted to be collaborating with the Mitsiades Lab at Dana-Farber to expand our understanding of nirogacestat’s mechanism of action when combined with BCMA therapies,” said Badreddin Edris, chief operating officer of SpringWorks, in the press release. “Dr. Mitsiades and his colleagues have been at the forefront of developing cutting-edge translational models of multiple myeloma and we believe that this collaboration has the potential to yield novel insights that can help us to further refine our approach to improving outcomes for these patients.”

SpringWorks Therapeutics and the Dana-Farber Cancer Institute will conduct further research into the therapeutic potential of combination therapy with nirogacestat and anti-BCMA agents for multiple myeloma.