Opus Genetics Inc., a private ocular gene therapy company based in Raleigh, North Carolina, has announced the FDA clearance of its Investigational New Drug (IND) application for a Phase 1/2 clinical trial. This is the first-in-human clinical trial (NCT05616793) of OPGx-001 in patients with Leber congenital amaurosis (LCA) resulting from biallelic mutations in the LCA5 gene (LCA5). A researcher at the Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, commented that “in the spectrum of severe early-onset retinal degenerative conditions, LCA5-LCA ranks as a particularly severe disease with profound vision loss and central structural abnormalities detected from early childhood”. According to a new press release, the proposed Phase 1/2, open-label, dose-escalation trial will evaluate the subretinal delivery of OPGx-001 in nine adult patients with LCA5. 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.
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.
Opus Genetics Inc., stated that OPGx-001 utilizes an adeno-associated virus 8 (AAV8) vector to precisely deliver a functional LCA5 gene to photoreceptors in the retina. Preclinical data, including animal and human iPSC models, have demonstrated preservation of retinal structure and visual function when OPGx-001 was administered prior to peak disease severity. Studies in LCA5 patients have reported evidence for the dissociation of retinal architecture and visual function in this disease, suggesting an opportunity for therapeutic intervention through gene augmentation. Commenting on the milestone, Ben Yerxa, PhD, CEO of Opus, that “this FDA clearance of our IND application for OPGx-001 for LCA5 marks a significant milestone for Opus, as our first program to enter the clinic. Preclinical studies in in vitro and in vivo models of LCA5 have provided support for the safety and efficacy of OPGx-001. We look forward to initiating our first-in-human trial of OPGx-001 in early 2023 and to continuing to build and advance our pipeline of gene therapies for unaddressed inherited retinal diseases in parallel.”