Opus Genetics Inc., a private ocular gene therapy company based in Raleigh, North Carolina, has announced a first-patient-dosed 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 a 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, open-label, 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-LCA5-1001”. 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. Commenting on the first-patient-dosed milestone, Ben Yerxa, PhD, CEO of Opus, that, “dosing our first patient establishes Opus as a clinical-stage company and is a point of progress in our mission to advance first-in-class gene therapies for inherited retinal diseases. Despite the severe retinal dysfunction in patients with LCA5, preclinical data suggest an opportunity for therapeutic intervention, including retinal structural and functional restoration when OPGx-LCA5 was administered prior to peak disease severity. We look forward to progressing the trial of this potentially transformative therapy for patients affected by LCA5.”