FDA vs. Amgen: At Odds Over Avacopan Save

The FDA has requested that Amgen voluntarily withdraw avacopan (Tavneos), a treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, but the company said it has no plans to pull the drug from the market.

Originally developed by ChemoCentryx, the oral complement 5a inhibitor was approved in 2021 as an adjunctive treatment for adults with the two main types of ANCA-associated vasculitis -- granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The company was acquired by Amgen in 2022.

On Jan. 16 of this year, "the FDA raised concerns about the process followed by ChemoCentryx to re-adjudicate primary endpoint results for 9 of the 331 patients in the ADVOCATE trial," said Amgen Medical Affairs in a letter to healthcare providers.

The agency also raised concerns about hepatotoxicity "in the context of the benefit-risk profile" of avacopan, according to the letter, which noted that liver toxicity is a known risk that appears atop the warning section of the drug's prescribing information.

Avacopan was approved primarily off findings from ADVOCATE, which randomized patients to either avacopan or prednisone tapering with standard therapy in each arm (cyclophosphamide or rituximab).

In the phase III study, remission at week 26 was seen in 72.3% of the avacopan group and in 70.1% of the prednisone group, meeting criteria for noninferiority. 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.

In its letter, Amgen Medical Affairs said it was not aware of issues with the data, that the company had confidence in avacopan's effectiveness, and maintained that the complement 5a inhibitor had a favorable benefit-risk profile for patients with severe active GPA or MPA.

"Amgen is working with the FDA to determine a path forward, while keeping patient safety, needs, and support at the forefront," the company noted, adding that an FDA-required postmarketing study of avacopan is still ongoing. "Amgen remains confident that Tavneos represents an important treatment option for patients with severe, active ANCA-associated vasculitis (GPA and MPA), rare, serious autoimmune diseases with limited therapeutic alternatives."

GPA and MPA are characterized by excessive activation of the complement system and neutrophil upregulation, which can result in inflammation and destruction of small vessels. Organ damage, particularly to the kidney, can ensue, and if inadequately managed, the outcome can be fatal.

Labeling for avacopan recommends regular liver panel testing and monitoring. In ADVOCATE, 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.

Last week, similar action took plance when the  European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use inifiated a review of avacopan (Tavneos), an oral complement C5 inhibitor, based on serious questions about amendments to the data from the pivotal ADVOCATE study. The drug was approved in 2021 for use in GPA & MPA. https://buff.ly/Ir8mB0G