Trio of IgA Nephropathy Drugs Proves Mettle in Interim Analyses

— Significant proteinuria reductions reported, but still awaiting eGFR data

DENVER -- Significant proteinuria reductions were reported in phase III interim analyses assessing two investigational IgA nephropathy agents and a third that was recently granted accelerated approval.

First, in the RAINIER trial, povetacicept -- a dual inhibitor of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) -- reduced geometric mean 24-hour urinary protein-to-creatinine ratio (UPCR) by 52.0% versus 4.3% with placebo by week 36 (adjusted difference -49.8 percentage points, 95% CI -58.6 to -39.2, P<0.001).

"A reduction in proteinuria is a commonly used, validated surrogate end point for assessing the efficacy of therapies in IgA nephropathy," wrote Richard Lafayette, MD, of Stanford University in California, and colleagues in the New England Journal of Medicineopens in a new tab or window (NEJM).

Second, in the I CAN trial, the terminal complement C5 inhibitor ravulizumab (Ultomiris) achieved a 46.6% reduction in geometric mean 24-hour UPCR compared with a 5.6% reduction with placebo by week 34. This resulted in an adjusted geometric mean UPCR that was 43.4% lower with ravulizumab than with placebo (99% CI 30.1 to 54.2, P<0.001), reported Jonathan Barratt, PhD, of the University of Leicester in England, and colleagues in NEJMopens in a new tab or window.

Finally, in the IMAgINATION trial, Barratt's group demonstrated a 46.9% reduction in 24-hour UPCR with sefaxersen compared with 6.6% with placebo at week 37, representing a 43.1% relative reduction versus placebo (95% CI 32.5-52.0, P<0.0001).

All of the studies were simultaneously presented at the American Society of Nephrology Kidney Weekopens in a new tab or window annual meeting.

RAINIER

The ongoing, double-blind trialopens in a new tab or window evaluated adults with biopsy-proven IgA nephropathy receiving stable background supportive care (97% on RAS inhibitors and 66% on SGLT2 inhibitors). In the main cohort of 557 patients with an eGFR ≥30 mL/min/1.73 m², participants were randomized 2:1 to subcutaneous povetacicept 80 mg or placebo every 4 weeks. Efficacy findings were evaluated from the prespecified interim analysis population of the first 199 randomized patients.

"Povetacicept is an investigational TACI fusion protein designed to inhibit both BAFF and APRIL, two cytokines involved in B-cell activation, differentiation, and survival," Lafayette told MedPage Today. "By targeting both BAFF and APRIL, povetacicept is intended to address upstream drivers of IgAN and reduce the production of pathogenic immune complexes that contribute to kidney injury and eventually kidney failure."

Lafayette emphasized the evolving IgAN treatment paradigm: "Some approaches primarily address downstream consequences of kidney injury or provide supportive care, while newer immune-mediated approaches target elements of the underlying disease biology. If approved, povetacicept will be differentiated by its simultaneous inhibition of BAFF and APRIL, as well as its strong safety profile and administration approach via a low-volume subcutaneous autoinjector administered at home once every 4 weeks."

Key secondary and exploratory endpoints from the interim cohort included:

• KDIGO target: 42% on povetacicept achieved a 24-hour UPCR below 0.5 g/g vs 6% on placebo
• Galactose-Deficient IgA1 (Gd-IgA1): Levels dropped 77.4% with povetacicept vs a 9.1% increase with placebo
• Hematuria resolution: 85% on povetacicept cleared hematuria vs 23% on placebo

In the overall safety population (n=557), adverse events (AEs; 75% vs 78%) and serious AEs (3% vs 4%) were similar between povetacicept and placebo. Injection-site reactions occurred in 15% of povetacicept patients versus 2% with placebo, nearly all mild. No deaths occurred.

Povetacicept is currently under FDA review for accelerated approval with a PDUFA target action date of November 30. The trial continues toward its primary week-104 endpoint of total eGFR slope.

I CAN

The phase III trialopens in a new tab or window randomized 485 adults with biopsy-confirmed IgAN and persistent proteinuria despite standard care to IV ravulizumab or placebo every 8 weeks. The primary efficacy analysis included 352 patients (176 in each group) who had reached or would have reached week 34.

Ravulizumab recently received accelerated approval from the FDA to reduce proteinuria in adults with primary IgAN at risk of rapid progression. First approved in 2018opens in a new tab or window for paroxysmal nocturnal hemoglobinuria, the drug is also indicated for atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder.

Trial results highlighted improvements in markers of reduced glomerular and tubulointerstitial damage:

• Hematuria control: 42.4% on ravulizumab achieved resolution vs 11.1% on placebo among patients with baseline hematuria; 4.8% vs 33.3% developed new-onset hematuria among those without baseline hematuria
• Urinary biomarkers: Soluble biomarker reductions favored ravulizumab, including terminal complement activation (sC5b-9; between-group difference of -95.5%), alternative pathway amplification (factor Ba; -54.0%), macrophage infiltration (uCD163; -29.2%), and proximal tubular injury (KIM-1; -30.1%)

Rates of AEs (69.5% vs 75.8%) and serious AEs (4.6% vs 9.0%) were balanced between ravulizumab and placebo. No meningococcal infections or treatment-related deaths were reported.

As with RAINIER, complete 2-year data will assess long-term annualized eGFR slope to confirm sustained clinical benefit. Continued approval may be contingent on proving slowed kidney function decline.

IMAgINATION

In the primary cohort of the trialopens in a new tab or window, 408 participants were randomized 1:1 to subcutaneous sefaxersen or placebo on background standard of care. Eligible participants had biopsy-confirmed IgAN with persistent proteinuria and a baseline eGFR of at least 20 mL/min/1.73 m².

Sefaxersen is an antisense oligonucleotide targeting complement factor B mRNA in hepatocytes. The therapy is designed to provide selective, sustained inhibition of alternative complement pathway activation by silencing factor B expression at the source.

"This trial is one of the largest ever trials conducted of an RNA interfering therapeutic in any form of disease," noted Barratt.

Interim findings demonstrated:

• Subgroup consistency: UPCR reduction was uniform across all prespecified subgroups, including baseline eGFR, proteinuria severity, and background SGLT2 inhibitor use
• Hematuria resolution: 56.3% on sefaxersen achieved resolution vs 11.9% on placebo

Sefaxersen was well tolerated, showing AE rates comparable to placebo and no drug-related serious safety concerns. No deaths occurred.

Developer Roche statedopens in a new tab or window the study remains blinded through week 105 to assess long-term kidney function by total eGFR slope.