Comment from Laure Larkin

Comment Regarding Proposed Avacopan Withdrawal I am submitting this comment regarding the proposed withdrawal of Avacopan because I am both an ANCA vasculitis patient who survived a nearly fatal flare in 2022 and a retired scientist who worked in the combination medical device and pharmaceutical field. At hospitalization, my eGFR was 5, and I suffered a lung collapse on the second day of my admission. I was successfully treated with Rituximab and Avacopan, which allowed me to recover and return to a largely normal life despite this chronic and often debilitating disease. I disagree with Section I of the proposed regulation, which concludes that there is insufficient evidence supporting the safety and effectiveness of Avacopan. Any assessment of safety or effectiveness must be evaluated in the context of ANCA-associated vasculitis (AAV) itself and the available alternatives. AAV is a rare disease that was usually fatal before the 1970s. Even today, many patients die or sustain permanent organ damage during their first flare because the disease is rarely encountered in clinical practice. Physicians are trained to first investigate more common illnesses, and while diagnosis is delayed, the immune system continues aggressively destroying blood vessels and vital organs. Once diagnosed, all available immunosuppressive treatments carry serious and potentially life-threatening risks. High-dose glucocorticoids remain the emergency standard used to stop vascular destruction and preserve organ function. They were initially necessary to save my life before I transitioned to Rituximab and Avacopan. I was tapered off glucocorticoids in less than four months, which reflects the current standard of care for AAV. During treatment, I underwent weekly comprehensive metabolic panel testing for the first three months to monitor liver function, followed by testing every two weeks for three additional months and then monthly. Three years later, I continue monitoring every two months. Because hepatotoxicity was already identified in the original label, these monitoring protocols appear sufficient to detect liver injury early and allow treatment adjustments when necessary. My kidney function improved substantially after transitioning from prolonged glucocorticoid exposure to Avacopan. My eGFR rose to 27 and continues to improve. I have avoided the devastating long-term complications commonly associated with steroid therapy. I am currently free of active AAV treatment and retain a fully functioning immune system, although residual kidney damage from my initial flare still requires blood pressure management and kidney-protective therapy. A complete market withdrawal of Avacopan would significantly harm patients with kidney-involved AAV, estimated to affect approximately 60 percent of patients. Without Avacopan, many patients will require prolonged glucocorticoid treatment, increasing rates of diabetes, hypertension, organ damage, dialysis, transplantation, and premature death. Because AAV is both rare and rapidly fatal, traditional clinical trial designs have important ethical and practical limitations. The original trials could not ethically require immediate discontinuation of adjunctive prednisone because the effectiveness of Avacopan had not yet been fully established. Since FDA approval in 2021, however, real-world clinical experience now provides meaningful evidence regarding both safety and effectiveness, particularly as rapid prednisone tapering has become standard practice. Rather than withdrawing Avacopan from the market, the labeling should more prominently emphasize hepatotoxicity risks and require rigorous liver monitoring protocols to ensure early detection and intervention. Hepatotoxicity is a serious concern and deserves strong surveillance, but that risk must be balanced against the severe and often irreversible consequences of uncontrolled AAV and prolonged steroid exposure.