Regulatory Decision Summary for Tavneos

A single 52-week Phase 3, double-blind, randomized, controlled trial (ADVOCATE) with a total of 330 patients (166 patients in the avacopan arm and 164 patients in the prednisone tapering arm) was submitted to support the efficacy and safety of avacopan in the treatment of ANCA-associated vasculitis. This Phase 3 trial demonstrated the efficacy and safety profile for avacopan as an adjunctive therapy to standard-of-care at the time of the submission for the induction of remission of ANCA-associated vasculitis at Week 26 and the maintenance of remission at Week 52. The background immunosuppressive therapies used in this trial were cyclophosphamide or rituximab for the induction of remission. Patients who received cyclophosphamide in the induction phase, then mainly received azathioprine after 13 weeks for the maintenance phase. Patients who received rituximab in the induction phase did not receive any subsequent immunosuppressive therapy in the maintenance phase.

The co-primary endpoint of induction of remission at Week 26 was determined by the proportion of patients with a Birmingham Vascular Score (BVAS) of zero and no glucocorticoids in the 4 weeks prior to Week 26. The BVAS is a validated instrument for measuring the severity of ANCA-associated vasculitis, with a higher score on the BVAS demonstrating higher disease severity. Avacopan demonstrated statistically significant non-inferiority to a prednisone tapering comparator arm, with 72.3% of avacopan-treated patients achieving induction compared to 70.1% of patients in the prednisone tapering arm at Week 26. The co-primary endpoint of maintenance of remission at Week 52 was determined by the proportion of patients with no relapse since the induction of remission at Week 26, no glucocorticoids in the 4 weeks prior to Week 52 and a BVAS of zero at Week 52. Avacopan demonstrated statistically significant superiority at Week 52 for the maintenance of remission for patients with ANCA-associated vasculitis compared to patients in the prednisone tapering arm, with the percentage of responders as 65.7% and 54.9% of responders respectively.

The ADVOCATE trial did not demonstrate the elimination of glucocorticoid use. No prednisone was given in the induction phase in the avacopan arm or in the maintenance phase in either arm, however outside-of-study glucocorticoids was permitted throughout the entire study. More than 86% of patients in the ADVOCATE trial received outside-of-study glucocorticoids for a variety of reasons including persistent vasculitis, relapse vasculitis (prior to Week 26 only) and adrenal insufficiency. As such, this is specified in the indication. Further, the indication includes use of avacopan as an adjunctive therapy to current standard-of-care as is demonstrated by the trial design.

Safety concerns with the use of avacopan in patients with ANCA-associated vasculitis as an adjunctive therapy to standard-of-care at the time of the trial have all been addressed in the Product Monograph (PM). The use of avacopan in patients with cirrhosis or severe hepatic impairment is not recommended. Patients receiving avacopan need to be monitored for increased liver enzymes, reactivation of Hepatitis B, low white blood cells, hypersensitivity, infection and cardiovascular events. Initial assessment is also recommended in the PM prior to the initiation of avacopan. Special populations including pregnant and lactating patients have cautionary PM statements. Common adverse events include nausea, headache, hypertension, vomiting, diarrhea, nasopharyngitis, vomiting, upper respiratory infection, urinary tract infection, abdominal pain, pneumonia, sinusitis, rash, and fatigue. Common laboratory abnormalities include elevated liver function tests, elevated creatinine phosphokinase and leukopenia in patients receiving avacopan therapy.

Two Phase 2 studies and secondary endpoints of the Phase 3 ADVOCATE trial provided additional efficacy and safety information that were consistent with the findings of the primary endpoints of the ADVOCATE trial, although there were differences in the exact nature of the primary endpoints in the Phase 2 studies and the duration of the Phase 2 trials was much shorter.

Missing information includes long-term safety and efficacy data beyond 52 weeks, as well as use of avacopan in the pediatric population.

The Phase 3 pivotal clinical trial supports the proposed indication at the 30 mg BID dose and it has been determined that avacopan has a favorable benefit-risk-uncertainty profile when used at 30 mg BID.