A single-arm phase 2 trial of an investigational RNA therapeutic to complement factor B sefaxersen for treatment of IgA nephropathy.

Abstract

Activation of the complement system and subsequent local inflammation in the kidney plays a key role in the pathogenesis of IgA nephropathy (IgAN). Here, we investigated the efficacy and safety of sefaxersen, an antisense oligonucleotide inhibitor of complement factor B (FB), for the treatment of IgAN in a global exploratory, single arm, open-label trial (NCT04014335). Patients were included with biopsy-confirmed IgAN with kidney C3 deposits, hematuria, 24-hour proteinuria above 1.5 g/day, and eGFR under 40mL/min/1.73m² despite maximum tolerated renin-angiotensin-aldosterone-system blockade. Patients received sefaxersen 70 mg (RO7434656) subcutaneously monthly for 24 weeks followed by voluntary treatment extension. The primary endpoint was a change in 24-hour urinary protein excretion (UPE) at week 29 compared to baseline. The trial enrolled 23 patients with baseline geometric mean proteinuria of 2.5 g/day. There were selective reductions of plasma complement FB and Bb, urinary factor Ba and serum complement alternative pathway activity, without changes in classical pathway activity. At week 29, UPE was reduced by 43% to a geometric mean of 1.4 g/day, with similar reductions in UPCR and UACR. Estimated GFR at baseline was mean 70.4 ml/min/1.73m², remained stable through week 29 (mean 73.2 ml/min/1.73m²). Proteinuria reduction was sustained in all seven participants who opted to participate in the treatment extension, including four patients treated for over 12 months. There was one treatment emergent serious adverse event not related to study drug. Transient and reversible alanine amino transferase elevations (3-5X fold upper limit normal) without a change in bilirubin were observed in three individuals, who remained on study and completed treatment. Sefaxersen inhibited complement alternative pathway activity in patients with IgAN and reduced proteinuria with stable eGFR. Our findings support further evaluation of sefaxersen as a new therapy for IgAN in the Phase 3 IMAGINATION trial. Registered at ClinicalTrials.gov with study number NCT04014335.