5 FDA Decisions to Watch in Q1

 As of Dec. 22, the FDA had approved at least 88 novel treatments in 2023, for indications ranging from breast and colorectal cancer to Duchenne muscular dystrophy to sickle cell disease. Rare diseases such as Rett syndrome and Friedreich’s ataxia saw their first approvals. Some decisions, like Sarepta’s Elevidys for Duchenne’s, sparked controversy, while others, like Eisai and Biogen’s Leqembi for Alzheimer’s disease, were more straightforward.

How will the FDA follow such a prolific year? BioSpace looks at five decisions to watch in the first quarter of 2024.

Iovance’s Lifileucel

Advanced melanoma

PDUFA: February 24

After a three-month delay due to regulatory resource constraints, tumor-infiltrating lymphocytes (TIL) leader Iovance Biotherapeutics could score the first FDA approval of a TIL therapy for advanced melanoma.

Adoptive cell therapy with TILs is particularly attractive because unlike CAR T cell therapy, TILs come directly from the tumor and so already recognize many targets on cancer cells, said MD Anderson Cancer Center’s Jason Bock, who has consulted for Iovance, in a 2021 review article. While CAR T cells are genetically engineered to recognize one or two targets, a group of TILs retrieved from a tumor could recognize several unique targets, he added.

In the C-144-01 trial, lifileucel elicited a 31% objective response rate at just over three years, with 42% of responses lasting for two years or longer, Iovance reported in November 2022. It’s been a long road for Iovance. In October 2020, the company’s planned Biologics License Application was pushed back when the FDA requested additional data on lifileucel’s potency. Then, in May 2021, the regulator requested even more data. Iovance finally completed a rolling BLA submission in March 2023, which the FDA accepted in May.

If approved, lifileucel would also be the first one-time cell therapy for a solid tumor.

Minerva Neurosciences’ Roluperidone

Schizophrenia (negative symptoms)

PDUFA: February 26

Schizophrenia treatment is finally experiencing a breakthrough after decades of stagnation. Generating much of the excitement is Karuna Therapeutics’ KarXT, which has shown the potential to treat both the positive and negative symptoms of the disease. Currently approved treatments focus only on the positive symptoms such as psychosis. KarXT has been assigned an FDA review date of Sept. 26, 2024, but it’s not the only therapy in development for schizophrenia.

On or before February 26, the FDA is expected to decide on Minerva Neurosciences’ roluperidone, which is specifically intended for the negative symptoms of schizophrenia such as social withdrawal and lack of motivation. By contrast, Karuna is seeking approval for KarXT for the overall treatment of schizophrenia, not negative symptoms specifically.  

According to Minerva’s NDA acceptance announcement, roluperidone has been shown to block serotonin, sigma and α-adrenergic receptors, all of which are involved in the regulation of mood, cognition, sleep and anxiety. It works by avoiding the blockade of dopaminergic receptors while blocking the serotonin receptor subtype 5-HT2A, as well as additional pharmacologic targets, according to the company.

Also in in the running to treat the negative symptoms of schizophrenia is pimavanserin, being developed by Acadia Pharmaceuticals. Pimavanserin is currently being evaluated in Phase III studies, with topline results expected in 2024.

Viatris and Mapi Pharma’s GA Depot

Relapsing multiple sclerosis

PDUFA: March 8

A consistently hot target, multiple sclerosis did not have any novel approvals in 2023; the most recent was TG Therapeutics’ Briumvi (ublituximab-xiiy), which got the FDA’s nod in December 2022 for relapsing forms of multiple sclerosis (RMS).

Another RMS candidate is up for FDA approval on March 8. GA Depot, being developed by Pittsburgh, PA.–based Viatris and Israel–based Mapi Pharma, is a long-acting injected version of the approved Glatiramer Acetate designed to be administered intramuscularly once every four weeks.

In a Phase III, placebo-controlled trial made up of 1,016 RMS patients, GA Depot demonstrated its superiority to other GA products in terms of a preferable schedule and fewer injection site reactions. The study met its primary endpoint, with GA Depot 40 mg showing a statistically significant reduction in annual relapse rate compared to placebo.

Madrigal’s Resmetirom

Nonalcoholic steatohepatitis

PDUFA: March 14

Nonalcoholic steatohepatitis (NASH) patients have been waiting—well, forever—for a targeted treatment for their disease to be approved. That day could come on March 14.

Last September, the FDA accepted Madrigal Pharmaceuticals’ NDA for resmetirom, a thyroid hormone receptor (THR)-β selective agonist that hit both primary endpoints and a key secondary endpoint in its pivotal Phase III trial. In the 52-week trial of more than 950 patients, treatment with resmetirom led to significantly higher levels of NASH resolution and liver fibrosis improvement than did placebo. Patients treated with resmetirom also had reduced levels of liver enzymes, Madrigal reported in December 2022.

The FDA noted in September that it did not intend to hold an advisory committee meeting for the application.

Madrigal’s competitors in the space continue to experience hiccups—or downright failures. In October, shares of  Akero Therapeutics plummeted after its NASH candidate efruxifermin failed to significantly reduce liver fibrosis without worsening disease in a Phase IIb trial, and Intercept Pharmaceuticals failed, for the second time, to secure approval for obeticholic acid (OCA) tablets, leading the company to exit the market in June 2023.

Vertex and CRISPR Therapeutics’ Exa-cel

Transfusion‑dependent beta thalassemia

PDUFA: March 30

On Dec. 8, the FDA approved Vertex and CRISPR Therapeutics’ Casgevy (exa-cel) for sickle cell disease (SCD), making it the first-ever CRISPR-based therapy.

With this approval, Vertex and CRISPR are halfway to their development goal with exa-cel. The other half—an NDA for the gene therapy to treat transfusion‑dependent beta-thalassemia (TDT)—is on the FDA’s docket for March 30.

The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) approved exa-cel, marketed as Casgevy, to treat both SCD and TDT in November, and a European Medicines Agency (EMA) committee endorsed the gene therapy to treat both conditions in December. The European Commission is expected to make a final decision on both indications in February, according to Vertex’s announcement.

Both beta-thalassemia and SCD are genetic conditions that affect the production of beta-globin, a component of hemoglobin, which is used by red blood cells to carry oxygen around the body. Exa-cel works by disabling the gene that silences the expression of the fetal hemoglobin gene, allowing fetal hemoglobin production to resume.

During two global clinical trials of exa-cel, 39 of 42 TDT patients achieved red blood cell transfusion independence for at least 12 months after receiving the gene therapy, according to the MHRA’s announcement. The other three patients saw a 70% drop in the need for transfusions.

Vertex and CRISPR have priced Casgevy at $2.2 million for SCD.

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