Abstract
Purpose :
Genetic studies have demonstrated a strong association of alternative pathway (AP) complement system variants with the incidence of geographic atrophy (GA) secondary to AMD. Furthermore, complement activation end products have been identified in the choriocapillaris and Bruch’s membrane. Herein, we determined whether a novel specific antisense oligonucleotide (ASO) targeting the human CFB gene could reduce circulating levels of complement factor B (FB), a pivotal fluid-phase component of AP, and thereby decrease AP activity in the choriocapillaris
Methods :
Since FB is produced predominately in the liver and circulates at high levels throughout the vascular system, including the choriocapillaris, a second generation MOE gapmer ASO was conjugated to GalNAc moiety to enhance targeting to hepatocytes. Clinical safety, pharmacokinetic (PK) and pharmacodynamic (PD) activity of the drug, IONIS-FB-LRx, was evaluated in a Phase 1, masked, placebo-controlled single and multiple ascending dose studies in 54 healthy volunteers (ACTRN12616000335493).
Results :
IONIS-FB-LRX reduced plasma FB levels in a dose dependent manner by approximately 56% and 72% after 36 days of multiple, subcutaneous administrations of 10 mg and 20 mg, respectively. A larger reduction of FB levels at the 20 mg dose was associated with greater reduction of Bb and AH50 without a change of CH50. On Day 43, mean (+/- SE) % reductions of FB, Bb, AH50 and CH50 levels at 20 mg dose were -72+/-3, -73+/-2, -62+/-5 and -12+/-5%, respectively. There were no safety signals or clinically-relevant changes in blood chemistry, hematology, urinalysis, ECGs or vital signs. Based on these data, an adapted design, masked, placebo-controlled Phase 2 trial in patients having GA associated with AMD was initiated (NCT03815825) to determine whether IONIS-FB-LRx can reduce the GA area growth rate over 12 months, as assessed by multimodal imaging.
Conclusions :
A novel ASO targeting complement factor B, IONIS-FB-LRX, effectively reduces circulating levels of FB, with a potential to diminish the systemic over-activity of the alternative complement pathway of patients having ocular diseases. Based on these data, a Phase randomized prospective phase 2 trial has been initiated to assess the ability of IONIS-FB-LRX, to diminish growth of AMD-associated GA.
This is a 2020 ARVO Annual Meeting abstract.