Opus Genetics Inc., a private ocular gene therapy company based in Raleigh, North Carolina, has announced the completion in the first cohort for a Phase 1/2 clinical trial. This is the first-in-human clinical trial (NCT05616793) of OPGx-LCA5 in patients with Leber congenital amaurosis (LCA), resulting from biallelic mutations in the LCA5 gene (LCA5). OPGx-LCA5 is an adeno-associated virus 8 (AAV8) vector designed to deliver a functional LCA5 gene to the outer retina in patients with an open-label dose-escalation trial to evaluate the subretinal delivery of the experimental treatment. The objective of the trial is to evaluate safety and potential benefit. Once safety in adults has been cleared, Opus plans to add a pediatric cohort in due course.
Previously defined as a juvenile form of RP (retinitis pigmentosa), LCA is a severe congenital or early infant-onset form of non-syndromic retinal disease, characterised by severe retinal dystrophy, vision loss, nystagmus, an absence of a normal pupil response and an almost non-recordable ERG. The clinical diagnosis does not have a well agreed-upon definition and therefore a more recent structure for nomenclature, aiming to define the basis as being on genotype, rather than phenotype. To date, there are now 25 genes causative for LCA, one of which, Lebercilin (LCA5), now accounts ~ 2% of LCA cases and results in a particularly severe form of the disease. The LCA5 gene located in chromosome 6q14.1 encodes an 80 kDa protein expressed in the connecting cilium of photoreceptors.
The interventional clinical trial is a non-randomized Phase 1/2 dose-escalation study evaluating two doses of for the treatment using a single, unilateral subretinal injection (Cohort 1) and proceed to an intermediate dose (Cohort 2) and subsequent high dose (Cohort 3). Escalation to each next cohort will proceed only after review of all data and upon recommendation by an independent data monitoring committee (IDMC), formally referred to “OPGx-LCA5”. The primary outcome will measure toxicity, adverse-events and a change of retinal thickness (by OCT) and several secondary outcomes full-field stimulus testing (FST), visual acuity (BCVA), oculomotor control and fixation, dark-adapted transient pupillary light reflexes (TPLR) and a visual functioning questionnaire.
On their recent announcement, the company said that based on positive safety and efficacy data from the first cohort of three adult patients, the study will advance OPGx-LCA5 into the next highest dose. Opus anticipates initiating the next cohort mid-2024. There are also future plans to expand the study population to include subjects 13 years or older. Commenting on the milestone,principal investigator Tomas S. Aleman, M.D., from the Center for Advanced Retinal and Ocular Therapeutics (CAROT), of the Scheie Eye Institute, Department of Ophthalmology of the Perelman School of Medicine, University of Pennsylvania, stated that, “[i]n the first cohort, OPGx-LCA5 has been well-tolerated and demonstrated clear signs of biological activity through 90 days, warranting continued evaluation in the next highest dose. Moreover, early anecdotal and VR challenge test feedback is encouraging and indicates that some of the patients, who have been nearly totally blind all their lives, are now able to see and identify objects for the first time.”
Figure 1. Opus Genetics Inc. Board of Directors has commented that, “Opus’ core team has an ideal mix of experience in science, company formation, patient advocacy, financing and gene therapy drug development” (https://opusgtx.com/about/board-of-directors/).
Opus Genetics is a clinical-stage gene therapy company for inherited retinal diseases with a unique model and purpose, backed by Foundation Fighting Blindness’ venture arm, the RD Fund. The Opus website declares that, “the company leverages knowledge of the best science and the expertise of pioneers in ocular gene therapy to transparently drive transformative treatments to patients.”