FDA Action Alert: Mesoblast, Sage/Biogen and Galera
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FDA Action Alert: Mesoblast, Sage/Biogen and Galera

Jul 31, 2023

Published: Jul 31, 2023 By Tristan Manalac

Pictured: FDA sign in front of brown brick buildings/iStock, hapabapa

The FDA has three decision deadlines over the next two weeks, including action dates for therapeutics targeting depression, graft-versus-host disease and a radiotherapy-induced side effect in patients with head and neck cancer.

The FDA has until Aug. 2 to make a decision on Mesoblast’s BLA for remestemcel-L, being proposed for the treatment of steroid-refractory acute graft-versus-host disease (SR-aGVHD) in children.

Designed to be intravenously administered, remestemcel-L is an investigational immunomodulatory therapy that uses culture-expanded mesenchymal stromal cells obtained from the bone marrow of an unrelated donor. Remestemcel-L works by suppressing pro-inflammatory cytokines while simultaneously stimulating anti-inflammatory cytokines, in turn modulating the inflammation that gives rise to SR-aGVHD.

Mesoblast first tried to have remestemcel-L approved in May 2019, with a rolling BLA submission that included data from 309 children across three trials, demonstrating consistent treatment responses. Despite a 9–1 vote in favor of the therapy, the FDA rejected the application in October 2020, requesting at least one more randomized controlled trial to validate the candidate’s efficacy.

In its resubmitted BLA, which the FDA accepted in March 2023, Mesoblast included new data, including long-term survival findings through at least four years and new outcome data for patients with high-risk disease activity. The regulator has granted the resubmission its Priority Review designation, while remestemcel-L had previously already won the FDA’s Fast Track designation.

Remestemcel-L is approved for SR-aGVHD in other countries, including Canada and New Zealand, where it is sold under the brand name Ryoncil.

In one of the summer’s most highly anticipated decisions, the FDA will render its verdict on zuranolone, which Biogen and Sage Therapeutics’ are proposing for the treatment of major depressive disorder (MDD) and postpartum depression (PPD), on or before August 5.

The FDA accepted the NDA for zuranolone in February, and did not choose to convene at advisory committee for the application.

To back its regulatory bid, Biogen and Sage submitted data from the LANDSCAPE and NEST clinical development programs, as well as from a Phase II study in Japan.

LANDSCAPE comprises five studies: MDD-201B, MOUNTAIN, SHORELINE, WATERFALL and CORAL. In February 2022, the partners released positive topline data from CORAL, demonstrating that treatment with zuranolone induced a rapid and significant drop in depressive symptoms.

A couple of months earlier, in December 2021, Biogen and Sage posted promising one-year follow-up data from SHORELINE, showing that three-fourths of patients responded to an initial 14-day regimen, and of these, around 80% needed at most one additional dose of zuranolone over the course of a year.

For PPD, the companies ran the NEST program, which includes two studies dubbed ROBIN and SKYLARK. In June 2022, data from SKYLARK showed that zuranolone met its primary and all secondary endpoints, inducing significant improvements in symptom severity.

Zuranolone is a neuroactive steroid that works by positively modulating GABA-A receptors, which in turn helps to quickly rebalance dysregulated neural networks in people suffering from depression. The drug principally works on brain regions responsible for mood, behavior, cognition and arousal.

The FDA will release its verdict on Galera Therapeutics’ NDA for avasopasem manganese by Aug. 9.

Galera is proposing avasopasem manganese for the treatment of severe oral mucositis (SOM) that arises in patients with head and neck cancer (HNC) as a side effect of radiotherapy. Currently, there are no approved treatments to reduce SOM in this patient population.

Avasopasem manganese previously won the FDA’s Breakthrough Therapy designation and its NDA, which the regulator accepted in February, was granted Priority Review.

Galera supported the candidate’s application with data from two randomized, double-blinded and placebo-controlled trials. In December 2021, the company posted promising topline efficacy data from the Phase III ROMAN study, in which avasopasem manganese met its primary endpoint, significantly reducing radiotherapy-induced SOM. Avasopasem manganese also led to a decrease in the severity of SOM in HNC patients undergoing radiotherapy.

The second study forming part of the NDA is a Phase IIb trial, which also showed improvements in SOM burden following avasopasem manganese treatment. The candidate’s safety profile in both trials was consistent with those commonly observed with cisplatin chemo and radiotherapy, though higher rates of hypotension and nausea were reported.

Avasopasem manganese is a selective dismutase mimetic that works by converting superoxide into hydrogen peroxide, which in turn protects healthy cells while also sensitizing cancer cells to radiation.

Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at [email protected] or [email protected].

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