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CHICAGO -- A mutation-agnostic gene therapy for retinitis pigmentosa (RP) showed promise for improving vision in severely vision-impaired and blind patients, a randomized clinical trial showed.

After 52 weeks of follow-up, half of patients treated with MCO-010 had vision improvement of about three lines of 15 , increasing to 60% at 76 weeks. Improvement continued out to 100 weeks.

The results satisfied not only the numerical improvement required by regulatory bodies but represented clinically meaningful vision improvement for patients, said Allen C. Ho, MD, of Wills Eye Hospital in Philadelphia, at the American Academy of Ophthalmology meeting.

"Patients want vision every single day over time," said Ho. "If you look at the area under the curve, vision in the treatment arms compared to the sham control arm, you can see visually that there's significantly more vision achieved in the treatment arms compared to the sham control effect. It's five times more vision at week 100 in the intervention arms."

"The study met its primary and key secondary endpoints, with clinically meaningful improvements and a favorable safety profile," he added. "The cumulative vision improvement was durable over a 2-year period, and we continue to follow these patients. The vision improvements have been consistent with what was seen in the uncontrolled, open-label phase I/II studies."

The therapy's developer, Nanoscope Therapeutics, expects to submit a biologics license application early next year, said Ho.

Patient Video

Following the presentation, Ho fielded questions related to the quality of vision improvement and the use of sham injections. To illustrate the magnitude and quality of vision improvement, he showed a video of an interview with what he acknowledged to be a patient who had among the best responses. The patient described seeing a "pin light" that was "throwing everything up." As a passenger in a motor vehicle, the patient said he could now see cars and houses, which had not happened in 15 to 20 years.

Despite severe vision impairment, the patient had developed rock-climbing skills. He described seeing different-colored holes that guide the climbing. Previously, the patient could feel the holes but not see them.

"I can see red, orange, yellow, green, blue," the unidentified patient said. "I can see the colors, and they're vibrant, like really, really vibrant colors that I haven't seen since I was a kid."

After the video ended, Ho said, "I don't put much weight into anecdotal stuff, but I do put some weight when you have a randomized, multicenter, sham-controlled clinical trial."

Assessing vision in ultra-low vision patients is difficult, he acknowledged. Currently, the "is the best we have today." Other tests have been developed, but measures of clinically meaningful vision improvement "are in evolution."

"What I showed you has been tested and is reproducible and is sham controlled," Ho added.

An unidentified member of the audience offered a cautionary note about use of sham injections as a control.

"There's old literature showing that injecting saline into an animal eye will cause temporary improvement in ERG [electroretinography] function in a variety of animal models," the speaker said. "I'm not saying this because I think every one of our patients should have a saline injection .... I am saying that it's really important to think about what the word 'sham' means, because it means different things in different trials.... Just keep in mind that sometimes saline can have an effect."

Co-moderator Jennifer Lim, MD, of the University of Illinois at Chicago, asked how patients' perception of color matched with true colors.

"This particular strategy targets bipolar cells, which are closer to the photoreceptors," said Ho. "It doesn't target all of the bipolar cells; the expression only gets activated in the 'on' bipolar cells because of a specific promoter. There are 'off' bipolar cells as well, so maybe because it's more proximal to rods and cones, maybe there's some frequency sensitivity."

Trial Background, Results

RP comprises a group of rare eye diseases that affect the retina. An estimated 1.5 million people worldwide have the condition. More than 270 different genetic mutations have been associated with inherited retinal diseases, Ho noted. The FDA approved the first gene therapy for RP (voretigene neparvovec, Luxturna) in 2017, but the treatment is limited to patients who have Leber's congenital amaurosis associated with the RPE65 mutation, which accounts for fewer than 1% of all RP cases.

MCO-010 represents a therapy based on optogenetics, a mutation-agnostic therapy that targets bipolar cells in the retina of patients who have lost rods and cones and sensitizes the cells to light. The therapy might also have applicability to other retinal diseases, such as macular degeneration and Stargardt disease.

Initiated in 2018, the phase IIb/III RESTORE trial evaluated a single intravitreal injection of two different dose levels of MCO-010 in nine patients each and compared outcomes to those of nine patients assigned to a sham injection. The primary endpoint was change in best-corrected visual acuity (BCVA) at 52 weeks. The key secondary endpoint was change in BCVA at 76 weeks.

The trial met the primary endpoint, as patients randomized to the lower dose of MCO-010 had an improvement of -0.382 LogMAR (P=0.0290) and -0.337 in the high-dose group (P=0.0209) versus -0.050 in the sham control group. Ho noted that a change of -0.3 is equivalent to three lines of 15 ETDRS letters. At 76 weeks, the change in LogMAR from baseline in the high-dose group averaged -0.539 (P=0.0014) and the difference in mean LogMAR in the lower-dose group was -0.374 (P=0.0652) as compared with -0.078 in the control group. The improvement in both MCO-010 groups remained durable through 100 weeks.

The most frequently reported ocular adverse events (AEs) reported with MCO-010 (both groups combined) were ocular hypertension (38.9%), conjunctival hemorrhage (38.9%), vitreous haze (27.8%), and keratic precipitates (22.2%). No patient treated with MCO-010 developed retinitis, choroiditis, vasculitis, ischemic neuropathy, hypopyon, or hypotony.

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