Vertex's Povetacicept Cuts Proteinuria in Phase 3 RAINIER Interim Analysis for IgA Nephropathy

Vertex Pharmaceuticals said on March 9 that its investigational drug povetacicept met the primary endpoint and both secondary endpoints of a pre-specified Week 36 interim analysis of the Phase 3 RAINIER trial in immunoglobulin A nephropathy (IgAN), HCPLive reported. Ono Pharmaceutical, which holds rights to the drug in Japan and South Korea, republished Vertex's release on March 11.

Povetacicept is an engineered fusion protein that blocks two cytokines, BAFF and APRIL, which drive the activation and survival of B cells. IgAN is a progressive kidney disease in which immune complexes containing galactose-deficient IgA1 (Gd-IgA1) deposit in the kidney's filtering units. The FDA has granted povetacicept Breakthrough Therapy Designation in IgAN. The drug has not been approved by any health authority.

Interim results

RAINIER (NCT06564142) is a randomized, double-blind, placebo-controlled pivotal trial of povetacicept 80 mg injected under the skin every four weeks, on top of standard care. Of 605 patients randomized, 557 are in the main cohort, and the interim efficacy analysis covers 199 of them. Vertex said 97.8% of main-cohort patients were on ACE inhibitors or angiotensin receptor blockers and 67.7% on SGLT2 inhibitors.

At Week 36, patients on povetacicept had a 52.0% reduction from baseline in 24-hour urine protein to creatinine ratio (UPCR), a 49.8% reduction compared with placebo (P<0.0001), the primary endpoint. Vertex said the effect was consistent across all pre-specified subgroups.

Serum Gd-IgA1 fell 77.4% on povetacicept and rose 9.1% on placebo, a placebo-adjusted reduction of 79.3%. Among patients with blood in the urine at baseline, 85.1% on povetacicept and 23.4% on placebo saw it resolve (P<0.0001 for both secondary endpoints).

"As a nephrologist, I am struck by the rapid, deep and sustained response to povetacicept, as well as the consistency of benefit across all subgroups," said Reshma Kewalramani, Vertex's chief executive, in the release.

Safety and filing plans

In the 557-patient safety population, serious adverse events occurred in 3.0% of patients on povetacicept and 4.3% on placebo, with no serious adverse events judged related to the drug and no deaths, Vertex said. It reported no opportunistic infections and no discontinuations due to infections. Treatment discontinuations for any reason were 3.8% on povetacicept and 8.8% on placebo in the interim analysis population. Anti-drug antibodies were observed but had no effect on efficacy or risk, according to the company.

Vertex said it has already submitted several modules of a Biologics License Application under the FDA's rolling review and will complete the filing by the end of March for potential accelerated approval. It is using a priority review voucher to shorten the review from ten months to six. If approved, the company plans to sell the drug in a once-monthly at-home auto-injector.

RAINIER continues in a blinded manner. The final analysis, at two years of treatment, will use total estimated glomerular filtration rate slope through Week 104 as its primary endpoint.