FDA Claims ‘Manipulated’ Data Led to Drug’s Approval, Proposes Withdrawal

The FDA said that “manipulated” data supported the approval of avacopan (Tavneos) for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, and the agency is proposing to withdraw the drug’s marketing approval.

In a Monday letter to Amgen, which now holds avacopan’s rights, the agency’s top drug regulator said that new information came to light showing avacopan lacks “substantial evidence of effectiveness,” and that developer ChemoCentryx’s new drug application (NDA) contained “untrue statements of material facts” — both legal bases for pulling a drug.

Unblinded study personnel “manipulated” primary endpoint results for the pivotal ADVOCATE study, said Tracy Beth Høeg, MD, PhD, acting director of the Center for Drug Evaluation and Research.

“That manipulation was designed to change results that were not statistically significant and make the product look effective when the original analysis did not support that conclusion,” she wrote in the letter. “If the data as originally analyzed according to the prespecified statistical analysis plan had been submitted to the agency, the study would not have been viewed as establishing substantial evidence of effectiveness, which is a legal requirement for approval of an NDA.”

In an email to MedPage Today, Amgen said it remains “confident in Tavneos as a safe and effective medicine, supported by years of clinical data and real-world evidence. Our perspective on the benefit-risk profile of Tavneos differs from the agency’s.” The company said it would evaluate next steps and respond to the FDA.

The move marks the latest in an ongoing saga between FDA and Amgen over avacopan.

The oral complement 5a receptor inhibitor was first approved in 2021 as an adjunctive treatment for adults with severe ANCA-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis).

But in January of this year, the agency requested the drug be voluntarily withdrawn from the market, raising concerns about cases of liver injury, as well as the trial data underpinning the initial approval. Amgen rebuffed the agency’s request.

Then in March, the FDA warned that postmarketing data had turned up dozens of serious cases of drug-induced liver injury (DILI) associated with avacopan, including eight fatal cases.

Avacopan was approved on the basis of the ADVOCATE trial, which randomized patients to either avacopan or prednisone tapering with standard therapy in each arm (cyclophosphamide or rituximab). In the phase III study, the primary endpoint of sustained remission at week 52 was observed in 65.7% of the avacopan group and in 54.9% of the prednisone group, which was significant for both noninferiority and superiority.

But the FDA said an initial analysis of the primary endpoint failed to achieve significance, and that unblinded ChemoCentryx personnel selected participants for readjudication and ultimately changed five patients treated with avacopan from “not in sustained remission” to “sustained remission.” That resulted in a statistically significant superiority benefit over the control arm, all of which was not disclosed to the FDA in the NDA.

That information came from the so-called Walton Report, an expert report from Marc Walton, MD, PhD, as part of a securities fraud litigation case.

Høeg’s letter also cited concerns about avacopan over liver safety.

In its March safety alert, the FDA said that three of the fatal DILI cases involved patients who developed vanishing bile duct syndrome (VBDS), a condition that can lead to permanent liver damage where the bile ducts are progressively destroyed before disappearing altogether.

Hepatotoxicity was listed as a potential serious adverse event in the product labeling based on premarket trial data. For example, serious adverse events related to liver-function testing occurred in 5.4% of patients in the avacopan group and in 3.7% of those in the prednisone group. But FDA said the VBDS and DILI cases with fatal outcomes represented new, more serious safety concerns.