Abstract
Purpose :
Foselutoclax is a novel small-molecule BCL-xL inhibitor capable of promoting apoptosis of senescent cells and has shown benefit in a Phase II diabetic macular edema trial. Multifocal electroretinography (mfERG) is a potent diagnostic tool that simultaneously assesses the activity of multiple retinal areas. This study sought to determine if foselutoclax treatment improved mfERG responses in eyes with neovascular age-related macular degeneration (nAMD).
Methods :
In this Phase 2 ENVISION study, 51 nAMD subjects were enrolled in a 48-week, multi-center, double-masked, active-controlled study. All subjects met the following criteria: ≥2 anti-VEGF injections in the preceding 6 months, BCVA of 70-20 ETDRS letters, and presence of intraretinal or subretinal fluid.
Subjects were randomized into 2 cohorts. The control cohort received 2mg aflibercept every 8 weeks in the first 6 months and continued this dosage schedule in the last 6 months with the addition of 10ug foselutoclax at weeks 24 and 28. The experimental cohort received 10ug foselutoclax at weeks 0, 4, 24, and 28.
Along with assessments on safety and change in BCVA and CST, 7 subjects at one site underwent mfERG testing at all study intervals. mfERG measurements included amplitude and implicit time of N1, individual hexagon responses, standardized ring responses, and topographic 3D density plots.
Results :
Of foselutoclax-treated subjects who completed mfERG testing (N=5), there was no statistically significant change in BCVA with a mean of +0.4 letters. mfERG waveform analysis revealed stable overall responses confirming intertest stability in a majority of subjects. There was improvement of response at weeks 4 and 8 after foselutoclax injections in most subjects, and additional qualitative analysis of mfERG topographic 3D response plots overall displayed notable improvements in focal retinal regions, particularly in perifoveal zones by week 24. These improved responses often regressed to baseline by week 48.
Conclusions :
The results of this study support foselutoclax’s capacity to maintain retinal physiological functioning with potential for focal areas of improvement as noted in mfERG responses. This study also presents mfERG as a potential endpoint in retinal clinical trials. As well as excellent consistency in data, total responses in waveforms for each subject remained relatively stable, indicative of standardized testing conditions and reliability.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.