RAINIER: Povetacicept Cuts Proteinuria, Gd-IgA1 in IgA Nephropathy

Povetacicept, an investigational dual B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) inhibitor, reduced 24-hour urinary protein-to-creatinine ratio (UPCR) by 52.0% at week 36 in adults with IgA nephropathy, compared with 4.3% with placebo, according to a prespecified interim analysis of the phase 3 RAINIER trial.1

Vertex Pharmaceuticals first announced topline RAINIER results in March 2026.2 The US Food and Drug Administration has since accepted a Biologics License Application seeking accelerated approval of povetacicept in IgA nephropathy, with a Prescription Drug User Fee Act target action date of November 30, 2026.3 Povetacicept is an engineered variant transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI)–Fc fusion protein designed for greater binding affinity to BAFF and APRIL than wild-type TACI.1

How Much Did Povetacicept Reduce Proteinuria in the RAINIER Trial?

RAINIER randomized adults with biopsy-proven IgA nephropathy receiving stable background therapy in a 2:1 ratio to subcutaneous povetacicept 80 mg or placebo every 4 weeks through week 100. Eligible participants had 24-hour urinary protein excretion of ≥ 1 g/day or UPCR of ≥ 0.75 and an eGFR of ≥ 30 mL/min/1.73 m². The main cohort included 557 participants across 224 sites in 29 countries.1

The interim efficacy analysis included the first 199 participants, 131 receiving povetacicept and 68 receiving placebo.1 At baseline, mean UPCR was 1.5, mean eGFR was 72.3 mL/min/1.73 m², and 97% and 66% of participants were receiving an ACE inhibitor or ARB and an SGLT2 inhibitor, respectively.

The adjusted between-group difference in UPCR change at week 36 was −49.8 percentage points (95% CI, −58.6 to −39.2; P < .001). Spot UPCR separated from placebo by week 4, and the treatment effect was consistent across prespecified subgroups, including age, race, sex, baseline proteinuria, baseline eGFR, and region. At week 36, 42% (54/128) of povetacicept-treated participants reached a 24-hour UPCR below 0.5, compared with 6% (4/65) receiving placebo.1

How Did Povetacicept Affect Gd-IgA1, Hematuria, and Safety Outcomes?

Galactose-deficient IgA1 decreased by 77.4% with povetacicept and increased by 9.1% with placebo at week 36 (adjusted difference, −79.3 percentage points; 95% CI, −82.2 to −75.9; P < .001). Reductions in galactose-deficient IgA1 occurred earlier than reductions in proteinuria, with a 56.5% decrease already evident at week 4.1

Among participants with baseline hematuria, resolution occurred in 85% with povetacicept versus 23% with placebo (adjusted difference, 62 percentage points; 95% CI, 45–78; P < .001). The median time to first hematuria resolution was 13 weeks in the povetacicept group.1

In the safety population of 557 participants, adverse events occurred in 75% receiving povetacicept vs 78% receiving placebo, and serious adverse events in 3% vs 4%, respectively. Infections occurred in 46% versus 41%, with serious or severe infections in 1% of each group. Injection-site reactions occurred in 15% versus 2%, all mild except one moderate event, and no deaths were reported.1

References

1. Barratt J, Zhang H, Han SH, et al. 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. Hillenbrand A. RAINIER: povetacicept reduces proteinuria by 52.0%. HCPLive. Published March 9, 2026. Accessed October 23, 2026. https://www.hcplive.com/view/ranier-povetacicept-achieves-primary-and-all-secondary-endpoints-for-igan

3. Hillenbrand A. FDA accepts BLA for povetacicept in IgA nephropathy. HCPLive. Published June 1, 2026. Accessed October 23, 2026. https://www.hcplive.com/view/fda-accepts-bla-for-povetacicept-in-iga-nephropathy