PHASE II RESULTS OF AN INVESTIGATIONAL RNA THERAPEUTIC TO COMPLEMENT FACTOR B, IONIS-FB-LRX, FOR TREATMENT

Promising Results for Antisense Therapy Targeting Complement Factor B in IgA Nephropathy

A phase II open-label trial of IONIS-FB-LRx (ISIS 696844, RO7434656) has shown significant reductions in proteinuria for patients with biopsy-confirmed IgA nephropathy (IgAN). The antisense oligonucleotide therapy targets complement factor B (FB) mRNA in the liver, reducing activation of the alternative pathway (AP) of the complement system, a mechanism implicated in IgAN pathogenesis.

Study Design and Objectives

The trial enrolled 23 patients with renal C3 deposits, hematuria, and 24-hour proteinuria >1.5 g/day, with an eGFR >40 mL/min/1.73m² despite receiving maximum tolerated RAAS blockade. Six patients were also on stable doses of SGLT2 inhibitors. Patients received monthly subcutaneous doses of IONIS-FB-LRx for 24 weeks with an optional treatment extension period. The primary endpoint was a change in 24-hour proteinuria at week 29 compared to baseline.

Key Findings

The results demonstrated a robust effect on proteinuria:

• Proteinuria Reduction:A 43% (95% CI: 23%, 58%) reduction in geometric mean 24-hour proteinuria was observed at week 29.
• Secondary Markers:Additional reductions in urinary protein-to-creatinine ratio (UPCR) and urinary albumin-to-creatinine ratio (UACR) were also noted.
• Renal Function Stability:Mean eGFR remained stable, showing no significant decline (Baseline: 70.4±21.6; Week 29: 73.2±19.9 mL/min/1.73m²).
• Extended Treatment Benefits:Sustained reductions in proteinuria were observed in all seven patients who opted for treatment extension including four treated for over 12 months.

Mechanistic Insights

The therapy selectively reduced markers of AP activity including plasma complement FB, Factor Bb, urinary Factor Ba and urinary sC5b-9 without affecting serum CH50 levels.

Clinical Implications

The study met its primary endpoint, providing compelling evidence for the efficacy and safety of IONIS-FB-LRx in IgAN. These findings support the continued development of this therapy in the ongoing phase III trial (NCT05797610) to further evaluate its potential in reducing IgAN progression.

This novel approach targeting complement factor B could mark a significant advancement in the management of IgAN, offering hope for improved outcomes in patients with this chronic kidney disease.