Povetacicept Cuts Proteinuria by 52% in IgA Nephropathy at Week 36

Adults with immunoglobulin A nephropathy (IgAN) who received povetacicept, an investigational dual inhibitor of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), had a 52% reduction in proteinuria at week 36 compared with a 4.3% reduction with placebo, according to a prespecified interim analysis of the phase 3 RAINIER trial (NCT06564142) published in the New England Journal of Medicine.¹ The findings are also being presented at the American Society of Nephrology Kidney Week 2026 in Denver, Colorado.²

Povetacicept also met both secondary end points, lowering galactose-deficient IgA1 (Gd-IgA1) levels and resolving hematuria. Rates of adverse events (AEs) were similar to placebo.¹ Richard Lafayette, MD, of Stanford University Medical Center, the paper’s senior author, is presenting the data at Kidney Week.²

“What stands out from the RAINIER results is the important clinical validation of simultaneously targeting BAFF and APRIL to address upstream drivers and kidney injury in IgA nephropathy,” Lafayette said in a news release from Vertex Pharmaceuticals, the company developing povetacicept.² “Povetacicept was specifically designed as a high-potency, high-affinity TACI fusion protein with broad tissue distribution to deliver this dual inhibition in order to target upstream pathogenic immune complex production.”

Targeting BAFF and APRIL in IgA Nephropathy

IgAN is the most frequently diagnosed primary glomerular disease, and over a lifetime many patients progress to kidney failure even with supportive care such as sodium–glucose cotransporter 2 (SGLT2) inhibitors, the authors wrote.¹ In IgAN, Gd-IgA1–containing immune complexes lodge in the kidney’s filtering units, triggering inflammation that leads to proteinuria and hematuria. BAFF and APRIL, often elevated in people with IgAN, sustain the B cells that make IgA. Povetacicept’s modified transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI) domain bind both cytokines more tightly than the native receptor.

RAINIER is a double-blind, placebo-controlled, 2-year trial at 224 sites in 29 countries. Adults with biopsy-proven IgAN, 24-hour urinary protein excretion of at least 1 g/d or a 24-hour urinary protein-to-creatinine ratio (UPCR) of at least 0.75, and an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m² were randomly assigned 2:1 to povetacicept 80 mg or placebo subcutaneously every 4 weeks. Enrollment required at least 12 weeks of stable, maximally tolerated angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy; 97% were on one at baseline. Of 557 participants in the main cohort, the first 199 randomized (131 povetacicept, 68 placebo) formed the interim efficacy population, and 66% were receiving an SGLT2 inhibitor.

Povetacicept Lowers Proteinuria, Gd-IgA1, and Hematuria

The adjusted difference in UPCR change at week 36 was –49.8 percentage points (95% CI, –58.6 to –39.2; P < .001). The effect held across prespecified subgroups defined by age, sex, race, baseline UPCR, baseline eGFR, and region. In an exploratory analysis, spot UPCR curves separated by week 4. At week 36, 54 of 128 participants (42%) receiving povetacicept and 4 of 65 (6%) receiving placebo reached a UPCR below 0.5 g/g, the treatment target recommended in Kidney Disease: Improving Global Outcomes clinical practice guidelines.

“The results observed with povetacicept are among the most compelling I have seen in IgAN and highlight the potential of povetacicept to become an important new treatment option for patients living with this chronic progressive disease,” Lafayette said.²

Gd-IgA1 levels fell 77.4% with povetacicept and rose 9.1% with placebo (adjusted difference, –79.3 percentage points; 95% CI, –82.2 to –75.9; P < .001), with a 56.5% reduction evident by week 4.¹ Among participants with baseline hematuria, resolution occurred in 85% of the povetacicept group vs 23% of the placebo group (difference, 62 percentage points; 95% CI, 45-78; P < .001).

“The concordant reductions in 24-hour urinary protein-to-creatinine ratio and galactose-deficient IgA1 levels support the effect of povetacicept on the underlying biologic features of IgA nephropathy,” the authors wrote.

In the safety population, AEs occurred in 279 of 372 participants (75%) receiving povetacicept and 145 of 185 (78%) receiving placebo, and serious AEs in 3% and 4%, respectively; none of the serious AEs were judged related to povetacicept, and no deaths occurred. Injection-site reactions were more common with povetacicept (15% vs 2%), though only 1 was rated moderate, and none led to treatment interruption. Infections occurred in 46% vs 41% of participants, serious or severe infections in 1% of each group, and no opportunistic infections were reported. Serum IgG declined 38.0% by week 24, but no participant stopped treatment because of low IgG levels.

Study Limitations and Next Steps for Povetacicept

Because the readout came at week 36, the analysis could not yet show whether povetacicept slows eGFR decline or disease progression, or how it performs on safety over the longer term. The authors noted those questions will be answered at the trial’s 104-week final analysis.

The authors also pointed out that the FDA has already granted accelerated approval to several IgAN therapies on the strength of proteinuria reduction, a recognized surrogate for kidney outcomes. Efficacy data cover only the first 199 of 557 participants, and Vertex, which funded the trial, designed it with the steering committee and shared in data collection and analysis.¹

“This prespecified interim analysis of adults with IgA nephropathy showed a sustained reduction in the 24-hour urinary protein-to-creatinine ratio that was significantly greater with povetacicept than with placebo,” the authors concluded.

The FDA has accepted Vertex’s biologics license application for accelerated approval in adults with IgAN, with a target action date of November 30, 2026.²

References

1. 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

2. 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 24, 2026. https://news.vrtx.com/news-releases/news-release-details/phase-3-rainier-results-supporting-best-class-potential