FDA declines linvoseltamab decision for RRMM due to facility issue
Agency letter to Regeneron notes problem with third-party manufacturer
The U.S. Food and Drug Administration (FDA) has rejected Regeneron Pharmaceuticals’ application for approval of linvoseltamab to treat adults with relapsed or refractory multiple myeloma (RRMM), and at least three prior lines of therapy, due to an issue at a manufacturing site.
In a complete response letter to the company, the agency cited an issue related to a third-party fill/finish manufacturer during a pre-approval inspection, according to a Regeneron press release. The FDA noted no concerns regarding linvoseltamab’s safety or efficacy in its letter. (Fill/finish refers to a key manufacturing stage for pharmaceuticals, in which a treatment is filled into its container, sealed, and packaged for distribution.)
The unnamed manufacturer has informed Regeneron that steps have been taken to fix the issue, which was not directly related to linvoseltamab production. The facility anticipates a follow-up FDA inspection in the next few months, the release stated.
Regeneron reported that it is working with both the manufacturer and the FDA to move ahead with linvoseltamab’s review and possible approval. If approved, it plans to make the treatment available as soon as possible.
Linvoseltamab is designed to prime T-cells to kill myeloma cells
Regeneron’s U.S. application for linvoseltamab was granted priority review by the FDA earlier this year, a status designed to shorten the time to an approval decision from 10 months to six months.
Regulatory agencies in the European Union currently are reviewing a similar linvoseltamab application. Both requests seek the therapy’s clearance for RRMM patients whose disease has progressed after treatment with a proteasome inhibitor, an immunomodulator, and a CD38 inhibitor as part of three or more previous lines of therapy.
Multiple myeloma develops when plasma cells, a type of white blood cell, turn abnormal and outgrow healthy plasma cells in the bone marrow, forming tumors in various bones. Available disease therapies work to slow cancer progression, but most patients need additional lines of therapy as the cancer advances.
Linvoseltamab is a bispecific antibody that comprises two parts: one part attaches to a protein called BCMA at the surface of myeloma cells, and the other to the CD3 protein at the surface of immune T-cells. When linvoseltamab bridges these two cells, it primes T-cells to attack and kill the myeloma cells.
Regulatory applications seeking the therapy’s approval drew on data from LINKER-MM1 (NCT03761108), an international Phase 1/2 study that is evaluating linvoseltamab’s safety and efficacy in up to 387 adults. All enrolled had at least three prior therapy lines, including a proteasome inhibitor, an immunomodulator, and a CD38 inhibitor.
The trial’s completed Phase 1 portion assessed linvoseltamab for side effects across nine different doses given as intravenous (into-the-vein) infusions. In the ongoing Phase 2 portion, which may still be recruiting patients at sites in Europe, Japan, and Korea, all enrolled are receiving either a low dose (50 mg) or a high dose (200 mg) of the therapy.
In Phase 2, the trial’s main goal part is to assess the rate of response over up to five years.
In Phase 2 of trial, nearly 50% of 117 patients had a complete response
Data covering 117 patients treated at high dose and followed for a median of 14 months, or just over one year, showed that 70.9% responded to the therapy, with 49.6% achieving a complete response (no signs of cancer) or better.
Responses in this patient group occurred early and deepened with time, with response lasting a median of 29.4 months, or nearly 2.5 years. The probability of maintaining a response at one year was of 80.9% for patients experiencing a partial or better response. This probability rose to 95% among those who had achieved a complete or better response, the company reported.
Common adverse events with linvoseltamab included an overactive immune response called cytokine release syndrome (46%), low numbers of certain immune cells (neutropenia, 42.7% at high dose; 28.8% at 50 mg dose), and anemia or low red blood cell counts (38.5%). Infections were reported in 74.4% of patients, with their frequency and severity declining over time.
The LINKER-MM1 trial is due to conclude in 2032.
Meanwhile, the confirmatory Phase 3 LINKER-MM3 trial (NCT05730036) is testing linvoseltamab against a standard treatment combination in up to 286 RRMM patients previously given one to four therapy lines. The standard combo comprises Empliciti (elotuzumab), pomalidomide (sold as Pomalyst, with generics available), and dexamethasone. The study, which started in September, is enrolling eligible adults at more than 100 sites around the world.
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