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WASHINGTON -- A candidate biosimilar to rituximab (Rituxan) won unanimous support today from an FDA advisory committee.

By a 16-0 vote, the Oncologic Drugs Advisory Committee (ODAC) agreed that Celltrion/Teva's CT-P10 met or exceeded standards for demonstrating similarity to Rituxan. The companies requested FDA approval of the drug for three indications in non-Hodgkin's lymphoma -- two in follicular lymphoma and one in non-progressing B-cell lymphoma.

Echoing comments of multiple ODAC members, committee chair Brian Rini, MD, of the Cleveland Clinic, said that "the preclinical analytics were fairly consistent. I think the clinical data support efficacy, at least in terms of response rate. There were some safety concerns, and I think that's probably just what you get when you have a lower number of patients treated in this type of clinical development program. You get some imbalances in baseline characteristics that, to me, explain some of the differences observed."

The fact that the sponsor provided consistent data from two clinical trials -- one demonstrating noninferiority to Rituxan and the other equivalence -- "really sealed the deal and will give higher confidence in this product," said Jerry M. Collins, PhD, of the National Cancer Institute Division of Cancer Treatment and Diagnosis.

Paul Smith, PhD, of the University of Maryland in College Park, said minor discrepancies identified in early analyses "were completely overwhelmed by the good clinical results."

The ODAC decision and recommendations will go to the FDA for consideration and a final decision on approval. Although not bound by recommendations of its advisory committees, the agency acts in accordance with the recommendations more often than not.

Much of the discussion that preceded the vote revolved around the composition, pharmacokinetics, and pharmacodynamics of CT-P10. After reviewing all the data, authors of an FDA staff report to ODAC concluded that "the totality of safety and efficacy from the clinical studies support the assertion that there are no clinically meaningful differences between [CT-P10 and U.S.-branded rituximab]. Results from the sensitivity analyses and subgroup analyses were consistent and agree with the primary analysis results."

The data submitted in support of the application showed that "CT-P10 is highly similar to U.S.-licensed Rituxan, notwithstanding minor differences in clinically inactive compounds, and support a demonstration that there are no clinically meaningful differences between CT-P10 and U.S.-licensed Rituxan in terms of safety, purity, and potency of the product."

In support of the application for approval, Celltrion and Teva submitted results from two randomized clinical trials comparing CT-P10 and Rituxan. One study (CT-P10 3.3) involved 140 patients with advanced follicular lymphoma, and patients received the randomized therapy plus cyclophosphamide, vincristine, and prednisolone (CVP) chemotherapy. The second study (3.4) compared the two drugs as single agents in 258 patients with low tumor-burden follicular lymphoma. Both trials had objective response rate as the primary endpoint.

Results of the 3.3 trial showed a response rate of 95.7% with CT-P10 (38.6% CR, 57.1% PR) and 90.0% with rituximab (32.8% CR, 57.1% PR). The trial met prespecified statistical criteria for noninferiority of CT-P10, and the upper limit of the 95% confidence intervals did not rule out the possibility of superiority, according to the FDA staff report. The estimated progression-free survival (PFS) was 31 months in both groups.

In the 3.3 trial, the rituximab had a more favorable safety profile, as treatment-emergent adverse events (TEAEs, 90.0% versus 85.7%), serious adverse events (30.0% versus 18.6%), discontinuation because of TEAEs (10.0% versus 7.1%), and TEAEs resulting in death (4.3% versus 1.4%) all occurred more often in the CT-P10 group. As Rini and others pointed out, most of the differences could be explained by imbalances in baseline characteristics, such as a higher proportion of patients in the CT-P10 arm with bone marrow involvement.

In the 3.4 trial, centrally reviewed objective response rates were 83.1% in the CT-P10 arm and 81.3% in the rituximab arm. The CR rate (including unconfirmed) was 32.3% with CT-P10 and 35.2% with rituximab, and the PR rates were 50.8% and 46.1% with CT-P10 and rituximab, respectively.

The two treatment groups in the 3.4 trial had similar rates of TEAEs (72.3% with CT-P10 versus 70.3% with rituximab), serious adverse events (5.4% versus 2.3%), discontinuation because of TEAEs (3.1% versus 0%), and TEAEs resulting in death (1.5% versus 0%).

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