Are Concerns Over Avacopan Efficacy Overblown?

Avacopan (Tavneos), the complement pathway inhibitor for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), appeared strongly effective in an Italian registry study — a step, maybe, toward setting to rest questions about its efficacy, if not its safety.

Among 32 patients treated in 18 centers across Italy for at least 1 year, all but one patient achieved clinical remission on avacopan, with 55% able to stop corticosteroids entirely, according to Luca Quartuccio, MD, PhD, of the University of Udine, Italy, and colleagues.

Renal function also improved markedly, while mean steroid doses across the cohort fell nearly 80% through week 12, from 23 mg/day in prednisone equivalents at baseline to 5 mg/day, the researchers reported in ACR Open Rheumatology.

Albeit small and uncontrolled, the study is noteworthy in light of concerns that arose earlier this year when it was revealed that findings from the drug’s main registration trial were “re-adjudicated” after data were unblinded. The re-adjudicated analysis converted a missed endpoint into a success. That, in turn, led the New England Journal of Medicine to retract the paper reporting those findings.

The FDA had already asked avacopan’s current manufacturer, Amgen, to withdraw it from the market on account of new information on liver toxicity, as well as information it had on the re-adjudication. Amgen has thus far refused, and the FDA has not formally ordered a withdrawal. European regulators, meanwhile, revoked its authorization this past August.

With the drug’s trial data now under suspicion, “evidence from independent prospective real-world studies is particularly important to assess the effectiveness and safety” of avacopan and its mechanism of action, Quartuccio and colleagues argued. “Although randomized clinical trials provide the basis for regulatory approval, prospective real-world studies remain essential to describe clinical outcomes, safety, and patient-reported quality of life (QoL) in unselected patient populations.”

AAV is an antibody-mediated autoimmune disease in which blood vessels become inflamed, leading to organ damage, with the kidneys often the most important victim. Steroids have long formed the backbone of treatment. However, complement activation is also a critical part of the pathology, leading researchers to focus on it as a therapeutic target. Animal and human studies indicated that blocking complement receptor signalling could reduce the manifestations, including renal inflammation and dysfunction. Avacopan gained FDA approval in 2021.

For the new study, Quartuccio and colleagues pulled data on Italian AAV patients receiving avacopan, identifying 46 who started the drug from 2022 to 2024. The patients’ mean age was 59, and 63% were women. Eighteen were newly diagnosed while the rest had relapsing disease. In line with the norm for AAV, about one-third showed systemic manifestations, and a similar number had kidney involvement when starting avacopan; 20% demonstrated rapidly progressing glomerulonephritis. Pulmonary and ear-nose-throat symptoms were also common.

Clinical remission was defined as a Birmingham Vasculitis Activity Score of zero; any patients in remission who developed any new symptom, and thus a score greater than 0, were considered to have relapsed. Patients were followed for a mean of 61 weeks; for some, follow-up reached 130 weeks. One patient also received cyclophosphamide, while the rest were given rituximab (Rituxan), either alone or with cyclophosphamide.

Quartuccio and colleagues paid special attention to renal function. Median estimated glomerular filtration rate was 30.5 mL/min/1.73 m² at treatment baseline, rising to 53.5 mL/min/1.73 m² at week 52, certainly desirable though still short of normal (≥60 mL/min/1.73 m²). On the other hand, the researchers had little to say about hepatic outcomes, other than that two patients had shown grade 1 liver enzyme elevations that did not interrupt treatment. In avacopan’s phase III trial, 4.2% of patients on the drug had discontinued due to adverse liver effects, and 5.4% had “serious” hepatic reactions.

Another area of success was getting patients off steroids, which come with their own suite of serious adverse effects when taken for long periods. At week 52, steroid-free remission was achieved by 75% of patients with newly diagnosed disease, although those with relapsing disease did not do so well, with just 40% able to stop the agents altogether.

Among the 46 patients in the current study, nine discontinued at some point. Three were for worsened symptoms, four because of infections, and two for reasons other than AAV or drug reactions. The median time to discontinue for these nine patients was 26 weeks. Seven other patients had avacopan stopped temporarily because of infections or other reasons unrelated to treatment (e.g., scheduled surgery).

Three patients relapsed, all having a history of relapses prior to starting avacopan. One of these patients died from a fungal infection after getting rituximab in an attempt to bring her symptoms back under control.

At 104 weeks, attrition outcomes were known for 13 patients: eight were still taking the drug, and five had stopped after week 52 while in remission because they and their physicians believed they could safely halt treatment. All these latter patients remained in remission at last follow-up. Most patients with extended follow-up continued to receive rituximab, usually every 6 months.

Overall, Quartuccio and colleagues felt avacopan was a success for their patients, with improved symptoms and good tolerability. However, the study didn’t investigate hepatic effects in any detail, and the cohort was perhaps too small and follow-up too short to fully evaluate avacopan’s safety with long-term use.

“Further independent comparative studies will be important,” they wrote, “to better define the role of complement-targeted therapies in the management of AAV, particularly in light of the evolving therapeutic and regulatory landscape.”