Systemic Pharmacodynamic Efficacy of a Complement Factor B Antisense Oligonucleotide in Preclinical and Phase 1 Clinical Studies

Abstract

Purpose : Over-activation of the alternative pathway (AP) of complement system may have a role in the development of geographic atrophy (GA) secondary to AMD. Complement factor B (FB), a pivotal fluid-phase component of AP, is produced predominately in the liver and circulates at high levels throughout the vascular system. To diminish AP activity in the choriocapillaris, we have identified a highly specific and efficacious antisense oligonucleotide (ASO) targeting the human CFB gene to reduce circulating levels of FB protein.

Methods : HepG2 cells were used to screen second generation MOE gapmer ASO for reduction of FB mRNA levels. In vivo efficacy of ASO was demonstrated in humanized FB transgenic mice (hTg). Clinical safety, pharmacokinetic (PK) and pharmacodynamic (PD) activity were evaluated in a Phase 1, masked, placebo-controlled single and multiple ascending dose studies (SAD and MAD) in healthy volunteers.

Results : The FB ASO had an in vitro IC50 of 0.18 uM in HepG2 cells and in vivo EC50 of 4.52 mg/kg/wk in FB hTg mice. In vivo targeting of the ASO to hepatocytes was dramatically augmented by conjugation to a GalNAc moiety, resulting in a lowering of the EC50 in FB hTg mice to 0.52 mg/kg/wk. In a Phase 1, SAD study, IONIS-FB-L_RX reduced plasma FB levels dose dependently by approximately 50%, 34% and 11% at 30 days after a single, subcutaneous, administration of 40 mg (~0.6 mg/kg), 20 and 10 mg, respectively. The 50% reduction of FB levels was accompanied by similar reductions of FB function and Bb, without meaningful changes of AH50, CH50, C3 or factor D (mean +/- SE % reductions of -49+/-3, -33+/-5, -55+/-6, - 6+/-9, 15+/-9, -11+/-15 and -6+/-5%, respectively). No drug-related adverse events were reported during the Ph 1 SAD study. In addition, PKPD modeling indicates response durability suitable for weekly or monthly dosing. Multiple dose administration of IONIS-FB-L_RX during a six week period provided greater reductions in circulating FB levels.

Conclusions : In summary, a novel antisense oligonucleotide targeting complement factor B, IONIS-FB-L_RX, effectively reduces circulating levels of FB, with a potential to diminish over-activity of the alternative complement pathway in the choriocapillaris of patients having GA associated with AMD. The safety profile of IONIS-FB-L_RX supports further development.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.