SAR446523 Receives FDA Orphan Drug Designation for R/R Myeloma

The FDA has granted orphan drug designation to the GPRC5D-targeted monoclonal antibody SAR446523 as a potential therapeutic option for patients with relapsed or refractory multiple myeloma.¹

SAR446523 is an investigational IgG1-based monoclonal antibody that also features an engineered fragment crystallizable domain intended to enhance antibody-dependent cell-mediated cytotoxicity. The agent is currently being evaluated in a first-in-human phase 1 trial (NCT06630806) in this patient population.

“The orphan drug designation is a significant milestone in our ongoing efforts to develop innovative treatments in multiple myeloma,” Alyssa Johnsen, MD, PhD, global therapeutic area head of Immunology and Oncology Development at Sanofi, stated in a news release. “This underscores our commitment to multiple myeloma, a disease for which we have acquired strong expertise with the development of another widely used and approved immunotherapy treatment.”

What’s Behind the Phase 1 Trial?

The first-in-human study includes both dose-escalation and -optimization portions, and investigators are enrolling patients at least 18 years of age with a documented diagnosis of multiple myeloma who have measurable disease.² All patients must have an ECOG performance status of 0 or 1 and adequate organ and bone marrow function.

In the dose-escalation portion, at least 3 prior lines of therapy are required for enrollment; patients must have disease that is either relapsed or refractory to those prior therapies, or they need to be intolerant to them. Prior exposure to GPRC5D- and BCMA-directed therapy is allowed in this portion of the study.

During dose optimization, at least 3 prior lines of therapy are required, and patients need to be relapsed or refractory to an immunomodulatory drug, proteasome inhibitor, anti-CD38 monoclonal antibody, and anti-BCMA targeting therapy. Intolerance to these treatments also allows patients to enroll. In this portion of the study, prior GPRC5D-directed therapy is not permitted.

In both portions of the study, patients are being excluded if they have primary systemic and localized amyloid light chain amyloidosis; active polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes syndrome; or active plasma cell leukemia. Those with central nervous system involvement or with clinical signs of meningeal involvement of multiple myeloma are also excluded. Other key exclusion criteria comprised systemic therapy within 14 days before the first study treatment, prior treatment with natural killer cell–engaging therapy within 90 days of first study treatment, and significant concomitant illness.

Up to 6 dose levels of SAR446523 are being evaluated during dose escalation with the goal of determining the maximum administered dose, maximum tolerated dose, and recommended dose range for regimens that will be tested in dose optimization.

During dose optimization, patients will be randomly assigned 1:1 to receive SAR446523 at one of the selected doses established in part 1 of the study, with the goal of determining the recommended phase 2 dose.

The incidence of dose-limiting toxicities is the primary end point in dose escalation. Overall response rate (ORR) is serving as the primary end point for dose optimization. Secondary end points include safety (both parts), ORR (dose escalation only), very good partial response or better rate, clinical benefit rate, time to response, progression-free survival, and minimal residual disease status.

The study was initiated in October 2024 and is currently enrolling patients at 9 locations in the United States, Canada, Australia, and Italy. Investigators will enroll an estimated 82 patients, and the estimated primary completion date of the study is November 2028.

References

1. Sanofi’s SAR446523, a GPRC5D monoclonal antibody, earns orphan drug designation in the US for multiple myeloma. News release. Sanofi. July 30, 2025. Accessed August 8, 2025. https://www.sanofi.com/en/media-room/press-releases/2025/2025-07-30-05-00-00-3123737
2. A study to investigate the safety and efficacy of SAR446523 injected subcutaneously in adult participants with relapsed/​refractory myeloma. ClinicalTrials.gov. Updated April 23, 2025. Accessed August 8, 2025. https://clinicaltrials.gov/study/NCT06630806