Inhibiting the alternative pathway of complement by reducing systemic complement factor B: Randomized, double-blind,...

Area of Science:

• Pharmacology
• Immunology
• Genetics

Background:

• Overactive alternative complement pathway is linked to IgA nephropathy and geographic atrophy.
• Sefaxersen is an antisense oligonucleotide targeting complement factor B (FB) mRNA.

Purpose of the Study:

• To evaluate the safety and pharmacodynamics of sefaxersen in healthy volunteers.
• To assess the effect of sefaxersen on complement factor B (FB) levels and alternative complement pathway activity.

Main Methods:

• First-in-human, double-blind, placebo-controlled Phase 1 studies.
• Subcutaneous administration of sefaxersen or placebo (single or repeated for 6 weeks).
• Assessment of safety, plasma complement protein levels, and complement pathway activity.

Main Results:

• Sefaxersen was safe and well-tolerated with no significant safety signals.
• Mean FB levels decreased by up to 38% (single dose) and 69% (repeated dose).
• FB reduction correlated with decreased alternative complement pathway activity (AH50).

Conclusions:

• Sefaxersen demonstrates a favorable safety profile and potent reduction of complement factor B (FB).
• The long-lasting effect supports monthly dosing for future clinical trials.
• Results support further development for IgA nephropathy and geographic atrophy.