Tavneos Withdrawal Sought Over Data Manipulation, Safety Risks

FDA is escalating efforts to prompt Amgen to voluntarily withdraw its autoimmune disease drug Tavneos (avacopan), concluding the therapy lacks reliable evidence of effectiveness and raising serious concerns about data integrity in the application submitted by its subsidiary ChemoCentryx.

In February, Amgen pushed back on an earlier FDA request to withdraw the 2021-approved drug, telling healthcare providers it does not plan to do so and is working with the agency on a path forward.

In a detailed 4/27 “proposal to withdrawal” notice, FDA says its original approval decision relied on what it now considers inaccurate and misleading representations of clinical trial data from the pivotal ADVOCATE study. It says the trial failed to demonstrate statistical significance on its prespecified primary endpoint — sustained remission at 52 weeks — in the original analysis, a fact it says was not understood by key officials at the time of approval. FDA alleges that subsequent, undisclosed analyses and data handling produced a nominally significant result that formed the basis of the approval decision.

“Absent manipulation, the study results were not statistically significant,” FDA writes, adding that the integrity of the trial was compromised by deviations from established protocols designed to minimize bias. The agency emphasizes that these undisclosed actions were material to its approval decision.

FDA’s review found that after the initial analysis failed, company-associated researchers used unblinded data to selectively identify patients for “readjudication” in a way that would shift the outcome toward statistical significance. This process, it says, violated core principles of clinical trial design, including the requirement to maintain blinding and adhere to prespecified statistical analysis plans.

The original analysis following an 11/2019 database lock yielded a p-value of 0.1025, missing the threshold for statistical significance. A later analysis reported a p-value of 0.0132, but FDA says that result was invalid because it was based on post hoc data modifications and did not control for multiplicity.

As a result, the agency concludes that the ADVOCATE study “cannot be considered adequate and well-controlled” and that its findings are “uninterpretable for regulatory decision making.” FDA further states that no subsequent reanalysis could salvage the study’s credibility due to the increased risk of false-positive findings from repeated, unplanned analyses.

In addition to methodological concerns, the agency accuses the applicant of making “untrue statements of material fact” in the NDA. Specifically, FDA says the company failed to disclose multiple database locks and analyses, instead presenting the trial as having undergone a single, statistically significant evaluation. These omissions, the agency contends, violated federal regulations requiring full transparency in drug applications.

In the notice, FDA also raises new safety concerns based on postmarketing data. A review identified 76 cases of drug-induced liver injury associated with avacopan, including several cases of a rare and serious condition known as vanishing bile duct syndrome. Most cases involved serious outcomes such as hospitalization, and eight resulted in death.

Given the lack of confirmed benefit and the presence of significant safety risks, the agency concludes that the drug’s benefit-risk profile is no longer favorable. “Without certain demonstration of benefit to balance the serious risks… the drug’s benefits cannot outweigh its known risks,” the FDA states

Additionally, the notice offers Amgen an opportunity for a hearing. The company has 30 days from publication of the notice in the Federal Register to request a hearing and 60 days to submit supporting evidence demonstrating a genuine issue of material fact.

Amgen says it remains confident in Tavneos as a safe and effective ​medicine, adding that it was supported by real-world evidence and years of clinical data. "Our perspective on the benefit-risk ‌profile of ⁠Tavneos differs from the agency’s. We will evaluate next steps and respond to the FDA," the company says in a statement provided to the media.