Povetacicept Reduces Proteinuria in IgA Nephropathy, suggests trial

Povetacicept, a dual BAFF/APRIL inhibitor, significantly lowered proteinuria in patients with immunoglobulin A nephropathy (IgAN), as demonstrated in the RAINIER trial.

The trial met its primary objective. In the interim analysis population, patients treated with povetacicept achieved a 52.0% reduction from baseline in urine protein to creatinine ratio (UPCR) at Week 36, with a statistically significant and clinically meaningful 49.8% UPCR reduction compared to placebo (P<0.0001). The reduction in proteinuria was consistent across all pre-specified subgroups.

The trial also met its secondary objective. For the first secondary endpoint, patients treated with povetacicept demonstrated a 77.4% reduction from baseline in serum galactose deficient IgA1 (Gd-IgA1) compared to an increase of +9.1% in the placebo group, yielding a reduction of 79.3% compared to placebo (P<0.0001). For the second secondary endpoint, in patients with baseline hematuria, 85.1% achieved hematuria resolution in the povetacicept treatment group compared to 23.4% in the placebo group, resulting in hematuria resolution of 61.7% compared to placebo (P<0.0001).

Povetacicept was generally safe and well tolerated. The majority of adverse events (AEs) were mild to moderate. There were no serious adverse events (SAEs) related to povetacicept and no deaths in the trial. There were no opportunistic infections, and no discontinuations due to infections. As expected, anti-drug antibodies (ADAs) were observed; these ADAs had no impact on efficacy or the risk profile.

Treatment discontinuations (for any reason) were 8.8% in the placebo group and 3.8% in the povetacicept group, and trial discontinuations (for any reason) were 1.5% in the placebo group and 0.8% in the povetacicept group in this interim analysis population.

“The Phase 3 RAINIER 36-week interim analysis results in IgAN are remarkable. With its clinical profile, dosing and administration advantage, and breadth of potential indications, povetacicept demonstrates best-in-class potential and establishes renal medicine as Vertex’s fourth franchise alongside cystic fibrosis, hematology and acute pain,” said Reshma Kewalramani, M.D., FASN, Chief Executive Officer and President of Vertex. “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. These results are important for patients with IgAN and also bring us one step closer to realizing povetacicept’s pipeline-in-a-product promise. We thank the patients and trial investigators for their trust and for making RAINIER the largest and fastest enrolling of any contemporary IgAN trial.”

Trial Design, Population Characteristics and Efficacy Results

RAINIER is a global Phase 3 randomized, double-blind, placebo-controlled pivotal trial of povetacicept 80 mg administered subcutaneously every four weeks versus placebo on top of standard of care.

A total of 605 patients were randomized in the trial, N=557 are in the main cohort, of which N=199 are in the interim analysis population, and N=48 patients are in an exploratory cohort. These patients are representative of real world IgAN patients at risk of kidney disease progression. The median time from diagnosis of IgAN to randomization in the main cohort was approximately 3.8 years and the trial patients had high rates of background supportive care, with 97.8% of patients on angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARBs), and 67.7% of patients on sodium-glucose co-transporter 2 (SGLT2) inhibitors, the latter representing the highest percentage in recently completed IgAN trials.

For the interim analysis, the trial’s primary endpoint is percent change from baseline in 24-hour UPCR, and the two alpha-controlled secondary endpoints are percent change from baseline in serum Gd-IgA1 and the proportion of patients to achieve hematuria resolution, all at Week 36. Exploratory endpoints for this interim analysis included the proportion of patients with 24-hour UPCR <0.5 g/g, in line with the most recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines.

Figure 1: Pre-specified Subgroup Analysis in Percent Change from Baseline in 24-Hour UPCR at Week 36

Safety Results

Povetacicept was generally safe and well tolerated. The data below reflect 557 patients in the main cohort with a mean duration of treatment of 33.7 weeks for the povetacicept cohort and 33.4 weeks for placebo.

Next Steps

The U.S. Food and Drug Administration (FDA) has granted rolling review of the Biologics License Application (BLA) for povetacicept in IgAN. As such, Vertex has already submitted several modules and will complete the full BLA submission by the end of March for potential accelerated approval. As announced previously, Vertex is using a priority review voucher to expedite the review of the povetacicept BLA from ten months to six months.

If povetacicept is approved by the FDA, Vertex plans to launch povetacicept in a low volume (<0.5 mL) subcutaneous auto-injector delivered once every four weeks via at-home administration.

The RAINIER Phase 3 trial continues in a blinded manner, and final analysis will occur at two years of treatment, with a primary endpoint of total estimated glomerular filtration rate (eGFR) slope through Week 104. Full enrollment for the RAINIER trial was announced in November 2025.