Novel GPRC5D mAB Receives FDA Orphan Drug Designation in R/R Myeloma

Sanofi's investigational GPRC5D monoclonal antibody SAR446523 has been granted orphan drug designation by the US FDA for the treatment of relapsed or refractory (R/R) multiple myeloma.¹ This designation highlights the significant unmet medical need in this patient population and underscores the potential of SAR446523 as a novel therapeutic option.

The IgG1-based antibody-dependent cellular cytotoxicity (ADCC)-enhanced monoclonal antibody targets GPRC5D, a protein highly expressed in multiple myeloma plasma cells with minimal expression in healthy tissues, offering a highly specific approach to therapy.

The FDA's orphan drug designation is conferred upon therapies intended to treat rare medical conditions affecting fewer than 200,000 patients in the United States.² This status aims to incentivize the development of drugs for diseases that might otherwise not attract significant investment due to limited patient populations. While a crucial regulatory milestone, it is important for clinicians to note that the safety and efficacy of SAR446523 are still under investigation and have not yet been fully evaluated or approved by any regulatory authority.¹

Multiple myeloma, a malignancy of plasma cells, remains an incurable disease despite advancements in treatment. It is the second most common hematologic malignancy globally, with over 180,000 new diagnoses reported annually. The current landscape of treatment, while improved, still faces challenges, particularly concerning high attrition rates with subsequent therapies and the eventual relapse of most patients who become unresponsive to existing treatments. The 5-year survival rate for newly diagnosed patients is estimated at 62%, emphasizing the urgent need for new and effective therapeutic options, especially for patients who are transplant-ineligible or have exhausted conventional treatments.

SAR446523 is an investigational IgG1-based monoclonal antibody designed to specifically target GPRC5D. Its mechanism involves an engineered fragment crystallizable (Fc) domain, which is designed to enhance ADCC. This enhanced ADCC mechanism aims to improve the efficacy of the treatment by boosting the immune system's ability to identify and eliminate cancer cells.

Currently, SAR446523 is being evaluated in a phase 1, first-in-human clinical study (NCT06630806).³ In part A, the dose-escalation portion, up to 6 dose levels of SAR446523 will be explored to identify the maximum administered dose, maximum tolerated dose, and recommended dose range for part B. Part B, the dose-optimization portion, will identify the recommended phase 2 dose.

Nine locations in the US, Australia, Canada, Israel, and Italy are recruiting patients with a documented diagnosis of multiple myeloma with measurable disease who are refractory to at least 3 prior lines of antimyeloma therapy. Those with an ECOG performance status of 2 or greater, inadequate organ and marrow function, or significant concomitant illness are not eligible for study enrollment. Further, those who received a systemic antimyeloma treatment within 14 days before the first study treatment administration or prior treatment with an NK-cell engaging therapy are not eligible for participation.

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 July 30, 2025. https://tinyurl.com/mtszkx4d

2. Designating an Orphan Product: Drugs and Biological Products. US FDA. Updated August 12, 2024. Accessed July 30, 2025. https://tinyurl.com/5ckfaxtv

3. 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 July 30, 2025. https://clinicaltrials.gov/study/NCT06630806