ANCA-Associated Vasculitis: Novel Biologic Shows Promise for Replacing Steroids

PHILADELPHIA -- An investigational monoclonal antibody targeting C5a complement, when partially or fully substituted for corticosteroids, appeared to help patients with ANCA-associated vasculitis (AAV) avoid some of the side effects that come with chronic steroid treatment, a researcher said.

Data from a small, 16-week phase II trial indicated that efficacy outcomes were essentially the same for AAV patients taking the biologic agent, vilobelimab, with or without steroids, according to Peter Merkel, MD, MPH, of the University of Pennsylvania in Philadelphia.

But adverse events (AEs) typical of steroids were much less common among patients receiving only vilobelimab, he said in a presentation at the American College of Rheumatology annual meeting. Glucocorticoid Toxicity Index (GTI) scores averaged exactly zero in the vilobelimab-alone group at week 16, versus 20 in participants receiving the biologic plus reduced steroid doses and about 35 in a group taking only steroids at standard doses.

Merkel said vilobelimab could find a place as an adjunct to cyclophosphamide or rituximab in AAV treatment that reduces the need for steroids.

AAV is actually a cluster of inflammatory conditions affecting the blood vessels, all stemming from antineutrophil cytoplasmic antibody (ANCA) production. As these antibodies destroy neutrophils, the resulting breakdown products activate the C5 complement pathway. C5 is then cleaved into C5a and C5b -- the latter is important for proper immune function while the former is less so. Vilobelimab potently blocks C5a activity while leaving C5b alone, Merkel said.

The current study, called IXchange, was conducted in two parts. For the first, 30 AAV patients were randomized in equal numbers to vilobelimab plus a reduced dose of corticosteroids or placebo plus steroids at regular doses. In the second and most important part, nine of this second group continued on (to serve as controls) while an additional 18 patients were assigned to receive vilobelimab plus placebo. Part 2 continued for 16 weeks. The primary endpoint was clinical response, defined as reduction of at least 50% in Birmingham Vasculitis Activity Score (BVAS). Steroid doses over the 4 weeks prior to randomization averaged 1,870 mg in prednisone equivalents.

Among the three arms in parts 1 and 2, BVAS scores did not differ substantially at week 16, with 75%-95% of patients achieving the primary endpoint. Rates of clinical remission were also very similar, at about 80% in all three groups. Merkel said this confirmed that vilobelimab is at least as effective as steroids.

But the main goal was to demonstrate a reduction in steroid-related toxicity with the substitution of vilobelimab for steroids, for which the GTI score stood as strong evidence, Merkel said. Overall rates of AEs were highest in the standard steroid-dose group; serious AEs were relatively uncommon (a t0tal of 14 in the study) and not markedly more frequent in any group. Most AEs appeared to stem from patients' underlying illness, Merkel said.

Despite these findings, it's unclear whether vilobelimab's sponsor, Germany-based InflaRx, plans to move on with phase III testing. Clinicaltrials.gov has no listings for additional studies in AAV, and the company has not included the condition in its prospective indications for the agent. InflaRx recently announced that it was beginning clinical tests with an oral C5a receptor inhibitor; it appears this agent may become its flagship product going forward.