Panel splits slightly in favor of FDA approving ChemoCentryx’s rare disease drug

 The FDA’s Arthritis Advisory Committee on Thursday voted 10 for and 8 against the approval of ChemoCentryx’s investigational drug avacopan as a treatment for adults with a rare and serious disease known as anti-neutrophil cytoplasmic autoantibody (ANCA)-vasculitis.

The tie vote on whether the FDA should approve the drug was preceded by a vote of 9 to 9 on whether the efficacy data support approval, and 10 to 8 that the safety profile of avacopan is adequate enough to support approval.

Contentious debate over whether the one, relatively small Phase III trial comparing avacopan with prednisone was robust enough for a full approval. FDA raised concerns about the statistical analyses of the data in the trial and what effect the use of glucocorticoids on top of cyclophosphamide or rituximab in both treatment arms had on the avacopan efficacy. ChemoCentryx defended its trial design and explained how it met its primary endpoint and showed a reduction in the use of steroids with avacopan.

Those voting against approval raised concerns about relying on the single trial as evidence, the insufficient amount of safety data, and questions on whether the trial was statistically robust enough. Some panelists called for ChemoCentryx to run another trial.

AAC panelist John Sperati, associate professor of medicine at Johns Hopkins University School of Medicine, voted no on whether the FDA should approve the drug and said he had concerns with the study design and persuasiveness of the data. He explained how if avacopan is approved by the FDA, one would have to use it in a similar fashion as in the trial, but where its true efficacy lies remains unclear from that trial data.

Another panelist Julia Lewis, professor of medicine at Vanderbilt University Medical Center, also voted against approval and said the indication is too broad and far exceeds the data presented.

Those voting in favor of approval noted that the trial just cleared the bar to meet its primary endpoint and that trials in this population are difficult to conduct.

AAC panelist Walter Kraft, professor of medicine and surgery at Sidney Kimmel Medical College of Thomas Jefferson University, voted for avacopan to be approved, saying regulatory decisions are not made in a vacuum, but with existing therapeutics in mind, and that the trial met its goal. He also raised concerns about delays in access to avacopan if the FDA requires an additional trial.

Fellow panelist Margrit Wiesendanger, associate professor at Icahn School of Medicine at Mount Sinai, also voted in favor of approving the drug, but said judicious use of it will be warranted and additional guidance will be necessary to explain who exactly should receive it.

Those voting in favor of approval followed a series of concerns raised by FDA statistical reviewer Yura Kim on the company’s assessments of the data, noting, “Statistical analyses of the primary endpoint using the Investigator assessment of BVAS [a clinical scoring system of disease activity to identify active vasculitis in nine organ systems] remission resulted in smaller magnitude of treatment effect and would not support superiority of avacopan.”

The agency also questioned if the other drugs used in the study may have contributed to the efficacy seen for avacopan.

“In this case, both treatment arms received background therapy in the form of cyclophosphamide or rituximab. The benefit of glucocorticoids on top of cyclophosphamide or rituximab is not well understood,” Kim said. “As a result, it is difficult to determine if similar remission rates observed on both arms can support a conclusion that avacopan is effective or if similarities can be primarily attributed to both arms receiving rituximab or cyclophosphamide.”

The company defended its study design, noting that when rituximab won approval in this indication, it was primarily based on results from a single trial of about 200 patients, and was designed as a non-inferiority, comparator trial over 26 weeks.

Following that lead, ChemoCentryx in July 2016 initially proposed a 26-week randomized, double-blind trial comparing avacopan to prednisone in 232 patients receiving either rituximab or cyclophosphamide, Pirow Bekker, the clinical lead for the avacopan clinical development program, explained.

The European Medicines Agency agreed to the non-inferiority study, according to Bekker, with the demonstration of superiority in a secondary endpoint, such as glucocorticoid toxicity.

But in the US, FDA said a 26-week non-inferiority study was not sufficient, he noted. In order to address both FDA and EMA’s feedback, ChemoCentryx revised the study to be a 52-week study in about 300 patients, with the superiority assessment built in as well.

FDA’s Rachel Glaser confirmed that there was an expectation agreed to in the pre-submission discussions that superiority would need to be confirmed for avacopan and that non-inferiority would not be enough.

The FDA is not required to follow the advice of its advisory committee on ChemoCentryx’s avacopan, but in general, the agency usually does.

https://endpts.com/adcomm-splits-slightly-in-favor-of-fda-approving-chemocentryxs-rare-disease-drug/