FDA Issues Complete Response Letter to Regeneron’s Odronextamab Based on Confirmatory Trial Enrollment Status

Image credit: Araki Illustrations | stock.adobe.com

The FDA has issued a complete response letter (CRLs) to Regeneron’s Biologics License Application (BLA) for odronextamab in the treatment of relapsed/refractory (R/R) follicular lymphoma (FL) and for R/R diffuse large B-cell lymphoma (DLBCL) following two or more prior lines of systemic therapy. The CRL was based on the enrollment status of the confirmatory trials, but the FDA did not cite approvability issues related to the drug’s efficacy or safety, trial design, labeling, or manufacturing, according to Regeneron.¹

The agency previously granted priority review to the BLA for odronextamab based on findings from the Phase 1 ELM-1 trial (NCT02290951) and the pivotal Phase II ELM-2 trial (NCT03888105).² The single-arm, multicenter, dose-escalation and -expansion ELM-1 trial enrolled patients aged at least 18 years with CD20-positive R/R B-cell malignancies.³

Investigators found that all efficacy-evaluable patients (n = 145) with non-Hodgkin lymphoma (NHL) achieved an overall response rate (ORR) of 51% (95% CI, 42%-59%) and a complete response (CR) rate of 37% (95% CI, 29%-45%). Among patients with R/R DLBCL who were not previously treated with chimeric antigen receptor (CAR) T-cell therapy (n = 49), ORR was 39% (95% CI, 25.2%-53.8%) and CR was 24% (95% CI, 13.3%-38.9%).

Among patients with R/R DLBCL who were previously administered CAR T-cell therapy (n = 33), ORR was 33% (95% CI, 18.0%-51.8%) and CR was 24% (95% CI, 11.1%-42.3%). Patients with R/R grade 1 to 3 FL (n = 40) achieved an ORR of 78% (95% CI, 61.5%-89.2%) and a CR rate of 63% (95% CI 45.8%-77.3%).

The open-label ELM-2 trial found that at a median follow-up of 21 months (range, 3-30), patients with relapsed/refractory DLBCL who were not previously treated with CAR T-cell therapy (n = 130) achieved an ORR of 49% and a CR of 31%, with an 18-month median duration of CR (95% CI, 10–not evaluable [NE]).^4,5 At a median follow-up of 22 months, evaluable patients with R/R FL (n = 121) achieved an ORR of 82% and a CR of 75%, with a 20.5 month median duration of CR (95% CI, 17-NE). Patients achieved median progression-free survival of 20 months (95% CI, 15-NE), whereas median overall survival had not yet been reached (95% CI, NE-NE).^4,5

“Regeneron has been actively enrolling patients in multiple phase 3 trials for odronextamab as part of the OLYMPIA program—one of the largest clinical programs in lymphoma. As the OLYMPIA program is intended to change the treatment paradigm of several B-cell non-Hodgkin lymphoma subtypes—including in earlier lines of therapy—in agreeing to the program, the FDA required that the trials include both dose-finding and confirmatory portions,” Regeneron stated in a press release. “Enrollment in the dose-finding portion has begun, but the CRLs indicate that the confirmatory portions of these trials should be underway and that the timelines to completion be agreed prior to resubmission.”¹

Regeneron added that it will work with the FDA and investigators to resolve the issues cited in the CRLs as quickly as possible, with plans on sharing updates on enrollment and regulatory timelines later this year.

References

1. Regeneron Provides Update On Biologics License Application For Odronextamab. Regeneron. News release. March 25, 2024. Accessed March 25, 2024. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application

2. Odronextamab BLA for treatment of relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) accepted for FDA priority review. News release. Regeneron Pharmaceuticals. September 29, 2023. Accessed March 25, 2024. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-bla-treatment-relapsedrefractory-follicular

3. Bannerji R, Arnason JE, Advani RH, et al. Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. Lancet Haematol. 2022;9(5):e327-e339. doi:10.1016/S2352-3026(22)00072-2

4. Pivotal odronextamab (CD20xCD3) phase 2 data in patients with relapsed/refractory diffuse large B-cell lymphoma debut at ASH. News release. Regeneron Pharmaceuticals. December 11, 2022. Accessed March 25, 2024. https://investor.regeneron.com/news-releases/news-release-details/pivotal-odronextamab-cd20xcd3-phase-2-data-patients

5. Odronextamab (CD20xCED3) demonstrates high and durable complete response rate among patients with relapsed/refractory follicular lymphoma in pivotal phase 2 trial. News release. Regeneron Pharmaceuticals. December 12, 2022. Accessed March 25, 2024. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-cd20xcd3-demonstrates-high-and-durable-complete