Systemic Antisense Oligonucleotide Inhibition of Complement Factor B for Treatment of Geographic Atrophy: Results of a Placebo-controlled Phase 1 Dose-Escalation Study

Abstract

Purpose : An over-active alternative complement pathway (ACP) is implicated in geographic atrophy (GA) pathophysiology and ACP end products are present in the choriocapillaris (CC), drusen and Bruch’s membrane of eyes with AMD. In monkeys, a systemic Factor B antisense oligonucleotide (ASO) reduced ocular factor B (FB) protein >99%. We determined clinical safety, pharmacokinetic (PK) and pharmacodynamic (PD) activity of IONIS-FB-L_Rx, an ASO specifically targeting human complement factor B gene (CFB) and subsequent factor B (FB) production in the liver, as a means to decrease ACP activity in the CC.

Methods : In a phase 1 masked, randomized placebo-controlled single and multiple ascending dose study, healthy volunteers (HV) were randomized to either placebo or IONIS-FB-L_Rx (ACTRN12616000335493). The drug was administered (8 administrations in 6 wk – twice wk for 2 wk then once wk for 4 wk) at doses of 10 mg or 20 mg in the multiple ascending dose study. Endpoints assessed throughout the study: ocular and systemic safety, pharmacokinetic (PK) and pharmacodynamic (FB and ACP activity (AH50).

Results : 54 HV (age range 27- 65 yrs) were enrolled and all subjects completed study (wk 19). There were no safety signals or clinically-relevant changes in ocular endpoints (BCVA, IOP, comprehensive examination), blood chemistries, hematology or vital signs following IONIS-FB-L_Rx dosing. The maximum tolerated dose (MTD)was not reached. The systemic PD markers of plasma FB levels reduced in a dose dependent manner by approximately 56% and 72% after multiple administrations of 10 mg and 20 mg, respectively. The mean (+/- SE) % reductions of FB, ACP activity (AH50) and classical complement pathway activity (CH50) levels for the 20 mg dose on Day 43 (7d post last administration) was -72 (+/-3), -62 (+/-5) and -12 (+/-5)%, respectively.

Conclusions : IONIS-FB-L_RX, is a novel antisense oligonucleotide drug, administered subcutaneously with a potential for monthly dosing. This first-in-human IONIS-FB-L_Rx study found the antisense drug to exhibit robust lowering of systemic FB and excellent safety profile. Based on these data, a Phase 2 double-masked, randomized placebo-controlled trial (N=330), the GOLDEN study, is currently underway to determine the potential of systemic IONIS-FB-L_Rx in reducing progression of GA (NCT03815825).

This is a 2021 ARVO Annual Meeting abstract.