The FDA has issued a second complete response letter (CRL) to Regeneron's biologics license application for odronextamab (Ordspono), a CD20 x CD3 bispecific antibody for treating adult patients with relapsed or refractory follicular lymphoma who have received at least 2 prior lines of systemic therapy. According to Regeneron's announcement, this latest CRL was related to observations from an FDA general site inspection at Catalent Indiana, LLC, a manufacturing facility.
This regulatory setback follows an initial CRL issued in March 2024, which was related to confirmatory trial enrollment status rather than safety, efficacy, or manufacturing concerns. In February 2025, the FDA had accepted a resubmission of the biologics license application, with a new Prescription Drug User Fee Act goal date set for July 30, 2025.
Long-Term Efficacy Data Support Continued Development
Despite the regulatory delay, updated long-term data from the ELM-2 trial continue to demonstrate the therapeutic potential of odronextamab in heavily pretreated follicular lymphoma patients. At a median follow-up of 28.3 months (95% CI, 25.5-32.8), 128 evaluable patients achieved an overall response rate of 80.5% (95% CI, 72.5%-86.9%), including a complete response rate of 74.2% (95% CI, 65.7%-81.5%).
The median duration of response was 26.0 months (95% CI, 18.8-42.5), and the median duration of complete response was 32.2 months (95% CI, 20.8-42.6). These results represent an improvement over earlier data readouts, with the median progression-free survival extending from 20.7 months to 23.0 months.
"With the longer follow-up, the efficacy data are confirmed, with the suggestion of an additional slight improvement," said Stefano Luminari, MD, associate professor of oncology at the University of Modena and Reggio Emilia in Italy, who presented the updated ELM-2 data at the 2025 EHA Congress.
High-Risk Patient Population Demonstrates Durable Responses
The ELM-2 study enrolled a particularly challenging patient population, with 57.8% having high-risk Follicular Lymphoma International Prognostic Index scores. Patients had received a median of 3 prior lines of therapy, with some having received up to 13 previous treatments. Additionally, 71.9% of patients were refractory to their last line of therapy, and 49.2% were classified as POD24, meaning they had relapsed within the first 2 years of their initial treatment.
The study utilized a step-up dosing strategy to mitigate cytokine release syndrome risk, with patients receiving intravenous odronextamab over an improved 3-week step-up period, followed by weekly dosing for up to 12 weeks, then every other week for up to 9 months, and finally monthly administrations thereafter.
Safety Profile Remains Manageable with Infection Prevention Focus
The safety profile of odronextamab remained consistent with previous reports, with no new safety signals identified in the updated analysis. Cytokine release syndrome occurred in 56.3% of patients but was mostly grade 1 and 2, primarily during cycle 1. Other frequent adverse events included neutropenia, fever, and notably, COVID-19 was reported in 32.8% of patients, reflecting enrollment during the pandemic period.
Treatment-related adverse events leading to death occurred in 5 patients, primarily due to infections including progressive multifocal leukoencephalopathy, pneumonia, pseudomonal pneumonia, sepsis, and COVID-19. Treatment discontinuation was mostly attributed to infection, particularly COVID-19.
"Since most of the AEs that were considered clinically relevant were related to infections, the only rule we have to follow when a patient is considered for a treatment with a bispecific antibody in general—or odronextamab in particular—is to carefully assess the patient, consider the profile of the patient's infections risk, and adopt all possible preventive measure," Luminari advised.
European Approval Provides Treatment Option
While awaiting FDA approval, odronextamab received European Commission approval in August 2024 for treating adult patients with relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma who have received 2 or more prior lines of systemic therapy. This approval was supported by data from both the ELM-2 and phase 1 ELM-1 trials.
The confirmatory phase 3 OLYMPIA-1 trial is currently ongoing to provide additional evidence supporting the bispecific antibody's efficacy and safety profile in this patient population.
Odronextamab represents an off-the-shelf, CD20×CD3-directed bispecific antibody designed to redirect T cells to kill malignant B cells, addressing an important unmet need in multiple-relapsed follicular lymphoma where treatment options have historically provided unsatisfactory results.
