42% on Povetacicept Reach KDIGO-Aligned UPCR Target in RAINIER

For adults with IgA nephropathy (IgAN), current Kidney Disease: Improving Global Outcomes (KDIGO) guidance recommends reducing proteinuria below 0.5 g/day, a target that can be difficult to achieve with supportive care alone. I

nterim phase 3 RAINIER data presented at the American Society of Nephrology (ASN) Kidney Week 2026 in Denver, Colorado, suggest the dual APRIL/BAFF inhibitor povetacicept could help substantially more patients reach a corresponding urine protein-to-creatinine ratio (UPCR) threshold of <0.5 g/g.¹

“For clinicians prior to this, there was sort of a nebulous recommendation of keeping the protein less than 1000. We now know that getting below 500 makes a tremendous difference in this decline in GFR over time,” James Tumlin, MD, president of NephroNet, director of research at Georgia Nephrology, and professor of medicine at Emory University School of Medicine, said in an interview with HCPLive.

RAINIER Interim Analysis Shows More Patients Reaching Lower Proteinuria

RAINIER is an ongoing randomized, double-blind, placebo-controlled trial in adults with biopsy-proven IgAN receiving optimized standard of care. The main cohort randomized 557 participants to povetacicept 80 mg (n = 371) or placebo (n = 186), administered subcutaneously every 4 weeks.¹

The prespecified interim efficacy analysis included 199 participants, including 131 receiving povetacicept and 68 receiving placebo. The primary endpoint was change from baseline in 24-hour UPCR at week 36.¹

Povetacicept reduced 24-hour UPCR by 52.0% compared with 4.3% for placebo, yielding a placebo-adjusted treatment effect of 49.8% (95% CI, 39.2%–58.6%; P < .0001). The effect was consistent across all evaluated subgroups.¹

Notably, 42.2% of patients receiving povetacicept achieved a 24-hour UPCR <0.5 g/g at week 36 compared with 6.2% receiving placebo.¹ The finding is particularly relevant as clinicians increasingly focus on achieving lower proteinuria levels associated with better long-term kidney outcomes.

Povetacicept also met both secondary endpoints. Galactose-deficient IgA1 (Gd-IgA1) decreased by 77.4% with povetacicept compared with a 9.1% increase with placebo. Among participants with hematuria at baseline, 85.1% experienced resolution compared with 23.4% receiving placebo.¹

HCPLive's full RAINIER results coverage provides a detailed breakdown of the trial's efficacy and safety endpoints.

Why Dual APRIL and BAFF Inhibition Targets Gd-IgA1 Production

Tumlin described povetacicept as part of a newer class of B-cell-modifying agents targeting pathways involved in IgAN pathogenesis.

APRIL and BAFF are cytokines with overlapping but distinct roles in B-cell activation, differentiation, and survival. In IgAN, increased signaling through these pathways contributes to the production of Gd-IgA1 and antibodies against it, which can form pathogenic immune complexes that deposit in the kidneys.¹

Some therapies in development or clinical use target APRIL alone, whereas povetacicept inhibits both APRIL and BAFF.

“There are previous basic science data that suggest that combination inhibition of both APRIL and BAFF is required to block the progression of a developing B cell to a plasma cell,” Tumlin said. “There is speculation, completely unknown but thought about, that the potency of povetacicept and being an APRIL/BAFF antagonist may be able to induce longer-term remissions.”

Whether dual inhibition produces more durable clinical remissions than APRIL inhibition alone remains unknown. RAINIER's interim findings demonstrate reductions in proteinuria and Gd-IgA1 but do not establish comparative superiority over other agents or long-term remission durability.

Tumlin raised a similar possibility in an interview with HCPLive following the presentation of phase 1/2 RUBY-3 data at Kidney Week 2025.

Povetacicept Safety Profile and Every-4-Week Subcutaneous Dosing

Povetacicept was generally well tolerated in the interim analysis, with adverse events occurring at similar rates in the povetacicept and placebo groups (75.0% vs 78.4%). Serious adverse events were reported in 3.0% and 4.3% of participants, respectively.¹

Tumlin noted injection-site reactions and some gastrointestinal adverse effects but did not identify major infections as a concern in his discussion of the findings.

He also highlighted the potential practical benefit of povetacicept's dosing schedule. The therapy is administered subcutaneously every 4 weeks, which Tumlin suggested could support treatment adherence as injectable therapies become increasingly common in IgAN management.

eGFR Slope Data and the FDA Decision Timeline for Povetacicept

Although the interim RAINIER findings demonstrate substantial reductions in proteinuria, longer-term kidney function outcomes remain pending. The trial continues in a blinded manner until the last enrolled participant completes 104 weeks, with estimated glomerular filtration rate (eGFR) slope through week 104 serving as the final primary endpoint.²,³

These findings will help determine whether the proteinuria reductions observed at week 36 translate into slower kidney function decline over time.

The US Food and Drug Administration (FDA) has accepted Vertex Pharmaceuticals' application for potential accelerated approval of povetacicept in IgAN, with a target action date of November 30, 2026.³

“It’s an exciting time to be a physician that treats this because we finally have some arrows in our quiver that really seem to make a difference,” Tumlin said.

Editor's Note: Disclosures for Tumlin include Vera Therapeutics, Calliditas Therapeutics, Alexion Pharmaceuticals, and Vertex Pharmaceuticals.

References

1. Lafayette RA, Azzi JR, Nester CM, et al. Povetacicept for treatment of IgA nephropathy: RAINIER phase 3 interim efficacy and safety analysis (IA). Abstract SA-OR076. Presented at: ASN Kidney Week 2026; October 24, 2026; Denver, CO. doi:10.1681/ASN.20263qa5c40z

2. Barratt J, Zhang H, Han SH, et al; RAINIER AIS-D08 Trial Group. Interim analysis of a phase 3 trial of povetacicept in IgA nephropathy. N Engl J Med. Published online October 23, 2026. doi:10.1056/NEJMoa2608682

3. Phase 3 RAINIER results supporting best-in-class potential of povetacicept in IgA nephropathy published in the New England Journal of Medicine and presented at the American Society of Nephrology Kidney Week 2026. News release. Vertex Pharmaceuticals. October 23, 2026. Accessed October 25, 2026. https://www.stocktitan.net/news/VRTX/phase-3-rainier-results-supporting-best-in-class-potential-of-i8qdc4svlmdr.html