Regeneron seeking approval of linvoseltamab for RRMM in US, EU

Therapy designed for patients with disease progression despite treatment

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The European Medicines Agency has agreed to review Regeneron Pharmaceuticals’ application seeking approval of its investigational therapy linvoseltamab for adults in Europe with relapsed or refractory multiple myeloma (RRMM), according to a company press release.

A similar application was submitted to the U.S. Food and Drug Administration in December.

Both submissions seek clearance of the antibody-based therapy for RRMM patients whose disease progressed despite at least three prior lines of therapy — specifically, a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.

The two Regeneron applications are backed by positive results from the Phase 1/2 LINKER-MM1 clinical trial (NCT03761108), which is still recruiting in Europe and Korea; the U.S. study sites are no longer actively enrolling patients. Altogether, the study is expected to involve up to 387 people with relapsed or hard-to-treat myeloma.

An ongoing confirmatory Phase 3 trial called LINKER-MM3 (NCT05730036) also is enrolling up to 286 RRMM patients who have received one to four previous lives of therapy at sites globally.

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Linvoseltamab is a bispecific antibody, meaning it has two arms that each interact with a different target. On the other end, its tail contains a specialized region that attracts immune cells.

In patients, one of the antibody arms binds to the CD3 protein on immune T-cells, while the other binds to BCMA, a protein found at high levels on myeloma cells. In doing so, the antibody-based therapy serves as a type of bridge between the two cell types, triggering a cancer-fighting reaction.

LINKER-MM1 was designed to test linvoseltamab in adult RRMM patients who had received at least three prior lines of therapy.

Its now completed Phase 1 portion evaluated the safety and tolerability of various doses of linvoseltamab, given via intravenous, or into-the-vein, infusions. The ongoing Phase 2 dose-expansion phase aims to assess the therapy candidate’s safety and anti-tumor activity.

Participants are receiving linvoseltamab in a step-up dosing protocol, in which the dose and frequency of administration is slowly increased. This is intended to reduce the occurrence of cytokine release syndrome (CRS), a severe type of immune response that can occur with therapeutic antibodies.

Phase 2 participants first receive low dose intravenous infusions of linvoseltamab on day 1 (5 mg) and day 8 (25 mg). The maximum dose (200 mg) is then given weekly from weeks 3-14, and then every other week thereafter. Patients achieving at least a very good partial treatment response after 24 weeks, or about six months, can switch to monthly dosing.

At the end of last year, Regeneron released LINKER-MM1’s Phase 2 findings, covering 117 participants followed for a median of 11 months, or nearly one year. The enrolled patients overall represented a population with a high disease burden and poor prognosis, having received a median of five prior lines of therapy.

The results indicated that overall response rates among these participants increased over time. After a median of 11 months, 71% had achieved at least a partial response, meaning their cancer had at least somewhat shrunk, and 46% saw a complete response — meaning no signs of cancer — or better.

All patients treated with the 200 mg dose experienced at least one adverse event, the most common of which was CRS (46%). Most of these events occurred after the first, low dose of linvoseltamab, and before the first full dose. These side effects were mild in severity, and usually resolved within 24 hours.

Immune effector cell-associated neurotoxicity syndrome (ICANS), another severe immune reaction affecting the brain, occurred in nine patients (8%).

Deaths due to adverse events occurring during dosing or in the following month occurred in 14 patients (12%); in 11, they were attributed to infections.

The confirmatory Phase 3 LINKER-MM3 trial now is comparing the efficacy of linvoseltamab with that of a standard treatment combination of Empliciti (elotuzumab), Pomalyst (pomalidomide), and dexamethasone in RRMM patients.

Additional trials to evaluate linvoseltamab as an earlier line of therapy, meaning at earlier disease stages, are ongoing or planned. These include the LINKER-MM2 trial (NCT05137054), which is testing linvoseltamab in combination with other myeloma therapies in up to 317 previously treated patients. Enrollment is ongoing in the U.S. and Europe.

A Phase 1/2 study called LINKER-MM4 (NCT05828511) aims to evaluate linvoseltamab as a first-line therapy in newly diagnosed multiple myeloma patients. It is recruiting at U.S. sites and seeking an estimated 132 participants.

Studies to assess linvoseltamab’s ability to prevent myeloma development in at-risk patients also are underway or planned. More information about linvoseltamab trials in myeloma patients can be found on the Regeneron website.