A Liver-Targeted Drug Cuts Proteinuria in IgA Nephropathy

Phase III IMAgINATION Meets Primary Endpoint

Roche's investigational sefaxersen met the primary endpoint in the Phase III IMAgINATION study, showing a statistically significant and clinically meaningful reduction in proteinuria versus placebo at 37 weeks in adults with primary IgA nephropathy (IgAN).

In the phase III IMAgINATION study, sefaxersen demonstrated statistically significant and clinically meaningful reductions in proteinuria versus placebo at 37 weeks, showing best-in-class potential, Roche announced on September 23, 2026.

What Sefaxersen Is and Why Liver Targeting Matters

Sefaxersen, an investigational highly specific liver-directed antisense oligonucleotide that inhibits factor B production, is the first mRNA-targeted therapy for IgA nephropathy. Serum complement factor B levels are elevated in people with IgAN.

Sefaxersen inhibits complement factor B production at its primary source in the liver, thus blocking a key driver of IgAN-related kidney damage. When we reduce these levels, it in turn reduces the level of protein in urine, which is a key indicator of improved kidney function.

The Mechanism: Blocking Complement Factor B

IgA nephropathy is driven by galactose-deficient IgA1 immune complexes depositing in the glomerular mesangium, activating the alternative complement pathway. Factor B is the critical protease that amplifies that pathway. By silencing factor B mRNA in hepatocytes where most circulating factor B is made, sefaxersen stops amplification upstream, unlike terminal complement inhibitors.

The liver-directed antisense approach uses GalNAc conjugation to deliver the oligonucleotide specifically to liver, reducing systemic complement suppression and preserving host defense.

Trial Design and Results Context

The IMAgINATION study is a global Phase III randomized, double-blind, placebo-controlled trial in adults with biopsy-proven primary IgAN with persistent proteinuria despite optimized supportive care. Proteinuria reduction at 37 weeks is the FDA-accelerated approval endpoint accepted as reasonably likely to predict preservation of eGFR.

Positive interim data shows Roche's sefaxersen significantly reduces proteinuria, with Roche describing best-in-class potential versus existing endothelin and complement competitors like iptacopan, atrasentan and sibeprenlimab.

Competitive Landscape in IgAN

Sefaxersen is described as the first mRNA-targeted therapy for IgA nephropathy. It enters a crowded but still high-need space. Current FDA accelerated approvals include Tarpeyo (budesonide), Filspari (sparsentan) and Fabhalta (iptacopan), which inhibits factor B protein, not its production. Sefaxersen's approach of inhibiting production at source could offer deeper, more durable factor B lowering with less frequent subcutaneous dosing.

Safety and Liver-Directed Considerations

As a liver-directed antisense oligonucleotide, key safety questions are liver enzymes, platelet counts and injection site reactions, known class effects. Roche has not disclosed detailed safety in the interim press release, but stated data support continued development. Complement inhibition carries infection risk, particularly for encapsulated bacteria, requiring vaccination strategies similar to other complement blockers.

What Comes Next for Patients

Positive interim data shows Genentech's sefaxersen significantly reduces proteinuria in people with IgA nephropathy. Full data from IMAgINATION including eGFR slope at two years will be needed for full approval and for guidelines to position sefaxersen versus endothelin antagonists and other complement inhibitors.

If confirmed, a liver-targeted drug cutting proteinuria via mRNA silencing would represent a new paradigm: treating a kidney disease by silencing a liver protein that drives kidney damage.

Working Source Links:

Roche's Sefaxersen Cuts Proteinuria in Phase III IgA Nephropathy Study - https://pharmacally.com/roche-sefaxersen-phase-3-igan-proteinuria/

Positive interim data shows Roche's sefaxersen significantly reduces proteinuria - GlobeNewswire - https://www.globenewswire.com/news-release/2026/09/23/3367081/0/en/positive-interim-data-shows-roche-s-sefaxersen-significantly-reduces-proteinuria-in-people-with-iga-nephropathy-igan.html

Positive interim data shows Roche's sefaxersen - Manila Times - https://www.manilatimes.net/2026/09/23/tmt-newswire/globenewswire/positive-interim-data-shows-roches-sefaxersen-significantly-reduces-proteinuria-in-people-with-iga-nephropathy-igan/2430978

Positive Interim Data Shows Genentech's Sefaxersen Significantly Reduces Proteinuria - BusinessWire - https://www.businesswire.com/news/home/20260922541505/en/Positive-Interim-Data-Shows-Genentechs-Sefaxersen-Significantly-Reduces-Proteinuria-in-People-With-IgA-Nephropathy-IgAN

Roche's Sefaxersen Significantly Reduces Proteinuria: Interim Data - https://healthxploreindia.com/news/roches-sefaxersen-significantly-reduces-proteinuria-in-iga-nephropathy-interim-data/