NEW YORK – Opus Genetics this week said it is planning a registrational trial of OPGx-LCA5, an investigational gene therapy for a rare form of inherited blindness, which could kick off as early as next year.
Durham, North Carolina-based Opus is designing the Phase III trial in the hopes that data from the study will support a biologics license application (BLA) to the US Food and Drug Administration as it pursues the gene therapy's market approval in one type of Leber congenital amaurosis (LCA), a group of rare genetic retinal diseases.
"The exact view of what the registrational trial looks like is still being talked about," said Opus CEO George Magrath, adding that as the company has continued discussions with the FDA, the agency has been receptive so far to Opus' ideas for a proposed Phase III trial design. Now, based on the FDA's feedback from a type D meeting last month, "we're going back to do our homework," he noted, and compile the full details of the study design protocol, the statistical analysis plan, and the validation data on proposed endpoints to bring back to the agency at a future meeting. Opus hopes to pursue accelerated approval, he added.
For OPGx-LCA5, which is one of the company's lead pipeline candidates, Opus has proposed a single-arm, pivotal trial evaluating the gene therapy in as few as 19 patients with LCA type 5 (LCA5). This rare and severe form of retinal degeneration is caused by biallelic mutations in the LCA5 gene and can lead to early-onset vision loss. The LCA5 gene encodes lebercilin, a protein that's essential for photoreceptor function.
Magrath noted that to establish efficacy in Spark Therapeutics' Luxturna (voretigene neparvovec), the only FDA-approved treatment available for any type of LCA, the FDA had considered a Phase III trial of only about 30 patients. Luxturna, a treatment for LCA caused by mutations in the RPE65 gene, was the first gene therapy approved in the US in 2017 for a genetic disease.
To the FDA, Opus has proposed using the multi-luminance orientation and mobility test to assess patients' functional vision and mobility after they receive an injection of OPGx-LCA5, and track differences in these measurements compared to a control group as the primary endpoint. The multi-luminance orientation and mobility test is a virtual-reality version of an existing test that's been used to support prior FDA approvals.
The company is also considering an internal control arm, in which patients are monitored during a six-month lead-in period. However, it hasn't ruled out a traditional randomized, controlled trial design with a cross-over component. That's still being discussed with the FDA, Magrath said.
OPGx-LCA5, a gene therapy that's administered subretinally and that uses an adeno-associated virus 8 vector to deliver a functional copy of the LCA5 gene to the outer retina, is the most advanced investigational gene therapy program at Opus, which has undergone significant changes in recent months.
In October, Ocuphire Pharma, another company developing treatments for eye disorders, purchased Opus Genetics in an all-stock acquisition but opted to retain the Opus Genetics name for the combined company as it advances a pipeline of gene therapies, eye drops, and oral medications for inherited retinal diseases and other ophthalmic disorders.
Ocuphire had an embattled pipeline. One of its assets, an oral drug for diabetic retinopathy known as APX3330, for which it's currently seeking a development partner, failed to meet the primary endpoint in a Phase II trial. Meanwhile, its lead asset Ryzumvi (phentolamine ophthalmic solution) had been approved, but was out-licensed to the pharmaceutical company Viatris.
Ocuphire had started evaluating other ophthalmology assets in the market to acquire, which led them to take a look at early data from Opus' ongoing Phase I/II trial of OPGx-LCA5. "They had a really good foundation and really good clinical data," Magrath, who joined Ocuphire as CEO in late 2023, said of Opus.
Ocuphire nabbed what seemed like a promising opportunity. "That's why we rebranded the company," he added, referencing the choice to keep the Opus Genetics name.
Opus continues to evaluate the safety and preliminary efficacy of a single subretinal injection of OPGx-LCA5 to just one eye within that first-in-human, open-label, dose-escalation Phase I/II trial, which launched in 2023. In the trial, investigators are enrolling adult and pediatric patients at least 13 years of age at the University of Pennsylvania Perelman School of Medicine.
The company recently dosed the first pediatric patient, a 16-year-old girl with LCA5 who couldn't see in either eye, Magrath said. Based on one month's worth of preliminary clinical data, the patient's visual function has improved in the treated eye. "Now she can see out of one eye," he said. "It really made a big difference in how she's able to navigate and go through life."
Tomas Aleman, an ophthalmologist at the Scheie Eye Institute at Penn Medicine and principal investigator for the clinical trial, described in a statement that objects are appearing significantly brighter for this patient, and only one month after treatment, she can "distinguish letters and navigate with an independence she had never had before." Additionally, investigators have not observed any dose-limiting toxicities or drug-related adverse events in the patient so far.
Those early results reaffirm previously reported data on adults in the Phase I/II study. The first three treated adult patients, who were legally blind at baseline, have experienced visual improvements through six months post-treatment. Opus will share new one-year clinical data from these patients at the Association for Research in Vision and Ophthalmology's annual meeting in May.
So far, adult and pediatric patients have only been treated with a low dose of OPGx-LCA5, though Opus had set up the Phase I/II trial to include three escalating doses. However, given the "compelling" efficacy and safety data that investigators have observed so far, Opus and the FDA are considering whether to advance the low dose to a pivotal trial.
The early pediatric data are particularly noteworthy, Magrath added, since, as a childhood-onset disease, treatment for LCA5 could be even more impactful when performed earlier.
Opus this week disclosed that it has treated a second pediatric patient in the Phase I/II study. The company said that it expects to complete enrollment in the three-person pediatric cohort before the end of the second quarter of 2025, with an initial data readout from those three patients in the third quarter.
"This is where we want to be treating patients, earlier in life," Magrath said, "in order to modify the disease to a greater extent."