Rare Daily Staff
Shares of ChemoCentryx plunged more than 45 percent after the U.S. Food and Drug Administration released a document ahead of an advisory committee meeting on May 6 that questioned the company’s rationale for the benefit of avacopan as a treatment for anti-neutrophil cytoplasmic antibody-associated vasculitis.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA-associated vasculitis or ANCA vasculitis) refers to a group of rare systemic diseases in which over-activation of the complement pathway over-activates neutrophils, leading to inflammation and destruction of small blood vessels. This results in organ damage and failure, with the kidney as the major target, and is fatal if not treated. Current treatment for ANCA vasculitis consists of courses of non-specific immuno-suppressants (cyclophosphamide or rituximab), combined with high-dose long-term corticosteroid therapy that can be associated with significant clinical risk including death from infection.
“Complexities of the study design, as detailed in the briefing document, raise questions about the interpretability of the data to define a clinically meaningful benefit of avacopan and its role in the management of AAV,” the FDA wrote.
ChemoCentryx’ pivotal global study that it used to support its marketing application, enrolled 331 patients with acute ANCA vasculitis who were randomized to receive avacopan plus non-specific immune-suppressants, or immune-suppressants plus high-dose corticosteroids.
The FDA conceded that the study met its primary endpoints by demonstrating non-inferiority of avacopan to prednisone in disease remission at week 26 and sustained remission at week 52, and superiority to prednisone for sustained remission at week 52 but not at week 26. But the agency voiced concern over non-inferiority being sufficient to show that avacopan can replace glucocorticoids, especially because both treatment arms received non-study supplied glucocorticoids at the investigator’s discretion.
“Although primary efficacy comparisons were statistically significant, the review team has identified several areas of concern, raising uncertainties about the interpretability of these data and the clinical meaningfulness of these results,” the FDA wrote.
The concerns included non-inferiority at week 26 as justification for approval, study participants being supplied with non-study glucocorticoids at investigator discretion, the clinical pharmacology of avacopan that has the potential to increase exposure systemic glucocorticoids with similar pharmacology, disparity in subgroups that received oral and IV induction treatment, and differences in assessments performed by the Investigator and the Adjudication Committee.