FDA Issues Complete Response Letter for Rituximab Biosimilar

The FDA has issued a complete response letter (CRL) to Sandoz (Novartis) regarding a biologics license application (BLA) for the rituximab (Rituxan) biosimilar GP2013.

The CRL indicates that the FDA has completed its review and the BLA is not ready for approval. Sandoz did not provide further details in its statement on the CRL.

“Sandoz stands behind the robust body of evidence included in the regulatory submission and is currently evaluating the content of the letter. While disappointed, Sandoz remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible,” the company announced.

Sandoz reported in September 2017 that the FDA had accepted a biologics license application (BLA) for GP2013. The biosimilar would have been indicated for the hematologic malignancies follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia, as well as for rheumatoid arthritis. In June 2017, the European Commission approved GP2013 (trade name, Rixathon) to be marketed for these indications in the European Union.

Sandoz supported the application submitted to the FDA with a series of data, including results from the ASSIST-RA study in rheumatoid arthritis and the phase III confirmatory ASSIST-FL study in follicular lymphoma.

ASSIST-FL compared the efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of Rixathon plus cyclophosphamide, vincristine, prednisone (GP2013-CVP) versus rituximab-CVP in patients with previously untreated, advanced stage follicular lymphoma (N = 629).

The treatment phase lasted 6 months, with a 2-year maintenance phase, and a 3-year follow-up. Patients were randomly assigned to 8 cycles of GP2013-CVP (n = 314) or rituximab-CVP (n = 315). Patients with complete or partial response then entered the double-blind maintenance phase, and received treatment with either GP2013 or rituximab.

Patients were separated into low-, intermediate-, or high-risk groups as determined by Follicular Lymphoma International Prognostic Index (FLIPI) score risk group, and by geographic region.

Overall response rate was 87.1% in the GP2013-CVP arm versus 87.5% in the rituximab-CVP arm. The rate of complete response was 14.8% and the partial response rate was the 72.3% in the GP2013-CVP arm. Complete response rate was 13.4% with a partial response rate of 74.1% in the rituximab-CVP group.

Median progression-free survival and overall survival had not been reached.

Investigators found that the PK and PD of Rixathon were similar to rituximab. The ratio of geometric mean for C_max at cycle 4, day 1 was 1.00 (90% CI, 0.925-1.09). Investigators also observed comparable results for AUC(0-21d), AUCall, and Ctrough between the 2 groups.

Investigators assessed peripheral CD19+ B-cell counts were assessed as PD outcome. Ratio of AUEC(0-21d) was 0.939 (90% CI, 0.845-1.04), confirming the similarity between both the 2 drugs.

Incidence of serious adverse events (AEs) was similar between GP2013-CVP (22.8%) and rituximab-CVP (20.0%) arms. The most common serious AE for both groups was febrile neutropenia, 4.8% in the GP2013-CVP arm and 2.9% in the rituximab-CVP arm.

Four patients in the GP2013-CVP and 7 in the rituximab-CPV group died during the treatment phase. As of the July 10, 2015, data cutoff, 35 patients (18 in GP2013-CVP arm and 17 in the rituximab-CVP arm) died during the study. The most common cause was non-Hodgkin lymphoma, 2.6% in GP2013-CVP arm versus 1.9% in the rituximab-CVP arm.

Overall, 5 (1.9%) patients in the GP2013-CVP and 3 (1.1%) in the rituximab-CVP arm developed antidrug antibodies.