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The FDA has issued a second complete response letter (CRL) to Regeneron’s odronextamab based on issues with a third-party manufacturing site, Catalent Indiana LLC, the company announced in its Q2 earnings report.¹

FDA Cites Third-Party Site Issues at Catalent Indiana in CRL and Regulatory Delay

Regeneron’s Biologics License Application (BLA) is seeking the approval of odronextamab for 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.

Regeneron also stated that it anticipates regulatory approvals to be delayed for a pending application for Eylea HD (aflibercept) injection 8 mg. The application, which was granted FDA Priority Review status, seeks to expand use of the treatment for patients with macular edema following retinal vein occlusion to permit monthly dosing across all currently approved indications.² The application was assigned PDUFA target action date of August 19, 2025.

Odronextamab’s Path to Approval Complicated by Evolving Phase III Trial Timelines

These delays are associated with issues raised during an FDA general site inspection at the Catalent Indiana LLC filler site, which was recently acquired by Novo Nordisk A/S. The inspection was completed in mid-July and was not specific to Eylea HD or odronextamab, according to Regeneron.

“Novo has been in communication with the FDA and expects to submit its response next week,” Regeneron stated in a press release. “Based on the Company's review of the observations and Novo's proposed response to the FDA, along with the progress the Company has made with alternate third-party fillers, the Company anticipates an expeditious resolution of the filling issues for Eylea HD.”¹

The first CRL issued to the BLA for odronextamab in March 2024 was based on the enrollment status of the confirmatory trials, but the FDA did not cite approvability issues related to the drug’s efficacy, safety, trial design, labeling, or manufacturing, according to Regeneron.³

The FDA 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).⁴

“Regeneron has been actively enrolling patients in multiple Phase III trials for odronextamab as part of the OLYMPIA program—one of the largest clinical programs in lymphoma,” the company stated in a March 2024 press release. “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. 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.”³

Regeneron Posts Strong Q2 Earnings with Growth from Dupixent and Eylea HD US Sales

Despite these regulatory delays, Regeneron noted positive momentum across its lines of business. The company’s Q2 revenue increased 4% to $3.68 billion compared to the same period last year. This was powered by an increase in global net sales for Dupixent (dupilumab), which increased 22% to $4.34 billion. US net sales for Eylea HDincreased 29% to $393 million; however, total Eylea HD and Eylea US net sales dropped 25% to $1.15 billion.

"Regeneron had a strong quarter, marked by significant growth in US sales of Eylea HD and global sales of Dupixent and Libtayo along with multiple regulatory approvals," Leonard S. Schleifer, MD, PhD, board co-chair, president and CEO of Regeneron, said in the release. "We have made significant progress in our oncology portfolio, including FDA approval for Lynozyfic for relapsed or refractory multiple myeloma, exciting emerging data from the lead-in cohorts of our pivotal programs in myeloma and lymphoma, as well as positive pivotal data supporting a potential upcoming FDA approval for Libtayo in adjuvant CSCC.

"Dupixent continues to be the world-leading treatment for diseases driven by type 2 inflammation, adding recent FDA approvals for bullous pemphigoid and chronic spontaneous urticaria, the seventh and eighth distinct indications for this important medicine. We are confident in the near- and long-term potential of our diverse pipeline and look forward to additional data and regulatory milestones later this year."¹

References

1. Regeneron Reports Second Quarter 2025 Financial and Operating Results. News release. Regeneron. August 1, 2025. Accessed August 1, 2025. https://www.globenewswire.com/news-release/2025/08/01/3125690/0/en/Regeneron-Reports-Second-Quarter-2025-Financial-and-Operating-Results.html

2. EYLEA HD® (aflibercept) Injection 8 mg sBLA Accepted for FDA Priority Review for Both the Treatment of Macular Edema Following Retinal Vein Occlusion (RVO) and for Monthly Dosing in Approved Indications. Regeneron. April 17, 2025. Accessed August 1, 2025. https://investor.regeneron.com/news-releases/news-release-details/eylea-hdr-aflibercept-injection-8-mg-sbla-accepted-fda-priority

3. Regeneron Provides Update On Biologics License Application For Odronextamab. Regeneron. News release. March 25, 2024. Accessed August 1, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application

4. 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 August 1, 2025. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-bla-treatment-relapsedrefractory-follicular