Investigation evaluates safety of single and multiple intravitreal injections.
Reviewed by Charles C. Wykoff, MD, PhD
The phase 1 study of NGM621 (NGM Biopharmaceuticals), a novel, humanized, monoclonal IgG1 antibody, showed promising results that support the continued clinical development of the drug to treat geographic atrophy (GA).
The drug was well tolerated without development of serious adverse effects, according to Charles C. Wykoff, MD, PhD, of Retina Consultants of Houston, Texas.
“Overactivation of the complement cascade has been implicated repeatedly in GA pathogenesis,” he explained. “C3 represents the central point of convergence for the 3 activation pathways in the eye: the classical, lectin, and alternative pathways.”
NGM621 works by inhibiting C3 cleavage, thereby preventing C3a and C3b subunit generation and inhibiting downstream propagation of the complement cascade. Because of its design, it has a high affinity for C3.
Phase 1 study
The trial evaluated the safety and tolerability of the single and multiple intravitreal injections of the treatment in patients with GA that was at least 2.5 mm2 and best-corrected visual acuities (BCVAs) ranging from 20/80 to 20/400.
The secondary outcomes were to determine the pharmacokinetic profile and the immunogenicity of the treatment.
The study included a total of 15 eyes in 4 cohorts. The patients in 3 cohorts of 3 patients each received 1 injection in ascending doses: 2 mg per eye, 7.5 mg per eye, and 15 mg prt eye; the 6 patients in cohort 4 received 2 doses of 15 mg/eye separated by 4 weeks, Wykoff recounted.
All patients were followed for 12 weeks.
Patients were a mean age of 78.6 years, with a mean VA of about 20/250. The mean area of GA was large at 14.9 mm.2 The patient demographics were well balanced across the 4 cohorts at baseline. All patients completed the study.
Wykoff noted that no vision-related safety signals or safety/tolerability signals were detected in any cohorts that were attributable to NGM621. No cases of endophthalmitis, intraocular inflammation, or choroidal neovascularization developed during the 12-week follow-up.
Any ocular adverse events were those normally associated with intravitreal injections.
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The maximal dose of 15 mg per eye administered twice was well tolerated with no safety signals associated with the study drug, no serious adverse events, and no deaths.
Both the BCVA and the GA lesion area remained stable over the 12-week course. The mean IOP 15 minutes after the treatment increased transiently by about 5 mm Hg and returned to the baseline level after 1 hour and remained there through the follow-up.
Wykoff noted that the mean serum pharmacokinetics of the study drug was linear and dose-proportional with low accumulation across the single-dose cohorts and in cohort 4 after every-4-week repeat intravitreal dosing.
The serum exposure of the study drug was below concentrations that produce systemic complement inhibition at the highest study dose.
Following the 15-mg dose, the drug was predicted to achieve more than 90% C3 target engagement in the eye for 7 weeks after 1 intravitreal dose based on the pharmacokinetics/pharmacodynamics model.
“The modeling supports investigating an every-8-week intravitreal dosing regimen,” he said.
Moreover, NGM621 serum exposure appeared dose-proportional, indicating linear pharmacokinetics in the studied range. The pharmacokinetics/pharmacodynamics model supports dosing intervals up to 8 weeks.
The trial also found that NGM621 was well tolerated up to 15 mg dosed twice, with no safety signals and no serious adverse drug-related events.
The drug is now in the phase 2 CATALINA study (NCT04465955) of 240 patients randomized to dosing every 4 or 8 weeks compared with sham treatment.
Charles C. Wykoff, MD
This article was adapted from Wykoff’s presentation at the Bascom Palmer Eye Institute Angiogenesis, Exudation and Degeneration 2021 virtual annual meeting. He is a consultant to and performs research for NGM Biopharmaceuticals.