IMAgINATION: Sefaxersen Meets Phase 3 Proteinuria Endpoint in IgA Nephropathy

Sefaxersen, an investigational liver-directed antisense oligonucleotide targeting complement factor B, reduced 24-hour urine protein-to-creatinine ratio (UPCR) by 43.1% versus placebo at week 37 in adults with IgA nephropathy, according to an interim analysis of the phase 3 IMAgINATION trial.^1,2

Roche and Genentech, a member of the Roche Group, announced the results, presented as a late-breaking oral presentation at ASN Kidney Week 2026 in Denver, Colorado.^2,3 Jonathan Barratt, MBChB, PhD, FRCP, of the University of Leicester, is the study’s first author.¹

Sefaxersen is the first mRNA-targeted therapy evaluated in IgA nephropathy and suppresses the complement alternative pathway by reducing hepatic production of factor B protein.¹ The agent enters a complement-focused treatment landscape, including the oral factor B inhibitor iptacopan (Fabhalta) and the C5 inhibitor ravulizumab (Ultomiris), which received US Food and Drug Administration accelerated approval on October 21, 2026.⁴ Roche licensed sefaxersen from Ionis Pharmaceuticals.²

How Much Did Sefaxersen Reduce Proteinuria in the IMAgINATION Trial?

IMAgINATION is an ongoing, multicenter, randomized, double-blind, placebo-controlled trial in adults with biopsy-proven primary IgA nephropathy at high risk of progression.¹ Eligible patients in the primary cohort had a UPCR of ≥ 1 g/g, or ≥ 0.8 g/g with total urine protein excretion of 1 g/day, and an eGFR of ≥ 30 mL/min/1.73 m².

All participants received standard of care, including an ACE inhibitor or ARB at the maximum tolerated approved dose, with or without SGLT2 inhibitors, endothelin receptor antagonists, or other agents for blood pressure management. The primary cohort included 438 patients randomized in a 1:1 ratio to subcutaneous sefaxersen or placebo on days 1, 15, and 29, followed by dosing every 4 weeks for 105 weeks.¹ Roche and Genentech reported total enrollment of 459 participants.^2,3

At week 37, the primary endpoint, sefaxersen reduced 24-hour UPCR by 43.1% relative to placebo (95% CI, 32.5–52.0; P < .0001). According to Roche, the treatment effect was consistent across all prespecified subgroups. Among patients with hematuria at baseline, a greater proportion receiving sefaxersen achieved hematuria resolution at week 37 compared with placebo.²

What Were the Safety Findings and Next Steps for Sefaxersen?

According to Roche and Genentech, sefaxersen was well tolerated, with a safety profile consistent with the phase 2 study and no new safety signals identified.^2,3

For context, ravulizumab reduced 24-hour UPCR by 43.4% vs placebo at week 34 in the phase 3 I CAN trial, the basis for its accelerated approval.⁴ Differences in trial design, timepoints, and populations limit direct comparison between the 2 complement-targeting agents.

“By inhibiting complement factor B in the liver, sefaxersen may offer a novel approach to slow disease progression in IgAN,” said Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche.² In the Genentech release, Garraway added, “These Phase III results demonstrate the potential for sefaxersen to meaningfully reduce protein in the urine.”³

IMAgINATION continues as a blinded study, with change in eGFR over 2 years measured at week 105. After week 105, or at the common close of the trial if earlier, participants may switch to open-label sefaxersen at the investigator’s discretion. Roche and Genentech plan to share the data with health authorities but did not provide a regulatory filing timeline.^2,3

References

1. Barratt J, Cheng J, Duggal V, et al. Sefaxersen, a novel mRNA-targeted therapy for IgA nephropathy: interim analysis of the phase 3 IMAgINATION trial. Presented at: ASN Kidney Week 2026; October 21-25, 2026; Denver, CO. Abstract FR-OR104. doi:10.1681/ASN.2026n6sbk0tt

2. Roche. Roche presents interim phase III data showing sefaxersen significantly reduced proteinuria in people with IgA nephropathy (IgAN). GlobeNewswire. Published October 23, 2026. Accessed October 23, 2026. https://www.globenewswire.com/news-release/2026/10/23/3387561/0/en/roche-presents-interim-phase-iii-data-showing-sefaxersen-significantly-reduced-proteinuria-in-people-with-iga-nephropathy-igan.html

3. Genentech. Genentech presents interim phase III data showing sefaxersen significantly reduced proteinuria in people with IgA nephropathy (IgAN). Business Wire. Published October 23, 2026. Accessed October 23, 2026. https://www.businesswire.com/news/home/20261023402425/en/Genentech-Presents-Interim-Phase-III-Data-Showing-Sefaxersen-Significantly-Reduced-Proteinuria-in-People-With-IgA-Nephropathy-IgAN

4. Campbell P. Ravulizumab receives FDA accelerated approval for IgA nephropathy. HCPLive. Published October 22, 2026. Accessed October 23, 2026. https://www.hcplive.com/view/ravulizumab-receives-fda-accelerated-approval-for-iga-nephropathy