Advanced Retinitis Pigmentosa Optogenetic Therapy Demonstrates Vision Function Improvements

This article was previously published on our sister site, Ophthalmology Times.

Nanoscope Therapeutics' MCO-010, an ambient-light activatable Multi-Characteristic Opsin (MCO) optogenetic therapy intended to treat patients advanced retinitis pigmentosa (RP) irrespective of gene mutation, has demonstrated vision function improvements in data from the phase 2b multicenter, randomized, double-masked, sham-controlled RESTORE clinical trial (NCT04945772). The findings were presented in a poster at the Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting, held April 23-27, in New Orleans, Louisiana.

In the RESTORE trial, 18 patients with severe vision impairment due to RP received a single intravitreal injection of MCO-010 and 9 received a sham intravitreal injection. Vision function improvements after treatment consistent with previous studies were reported, along with a favorable safety profile. The key efficacy measures utilized in the study included Multi-Luminance Y-Mobility Test (MLYMT, vision-guided mobility), Multi-Luminance Shape Discrimination Test (MLSDT, near-field object recognition), and Best-Corrected Visual Acuity (BCVA) scores. For the MLYMT and MLSDT, a 2 or more luminance level change is considered clinically meaningful and for BCVA, a 0.3 LogMAR change is considered clinically meaningful.

Current gene therapies are aimed at treating patients with specific gene mutations in outer retinal cells. On the other hand, ambient-light activatable MCO optogenetic monotherapy targeting abundant inner retinal neurons is intended to restore vision lost due to advanced RP, with degenerated outer retinal cells. MCO-010 (sonpiretigene isteparvovec, suspension for intravitreal injection) is the most-light sensitive opsin currently in clinical trials. The MCO-010 expression cassette, which features bipolar cell targeting via mGluR6 promoter-enhancer, is designed for restoring high quality vision in real-world environments. MCO-010's proprietary AAV2 vector is intended to allow robust transduction of MCO-010 in bipolar cells upon intravitreal injection. MCO-010 has received both orphan drug and fast track designations from the FDA.

A significant proportion of the patients in RESTORE showed improvements in functional vision as assessed by vision-guided mobility, shape discrimination, and visual acuity. Composite outcomes in key efficacy measures at 12-months included:

• 18 of 18 (100%) treated patients showed vision improvement in the MLYMT, MLSDT, or BCVA compared to 5 of 9 (55.6%) receiving placebo (P = 0.007);
• 17 of 18 (94.4%) treated patients showed vision improvement in the MLYMT or BCVA compared to 4 of 9 (44.4%) receiving placebo (P = 0.008);
• 16 of 18 (88.9%) treated patients demonstrated an improvement of 2 or more luminance levels in the MLYMT or MLSDT compared to 4 of 9 (44.4%) receiving placebo (P = 0.02); and
• 14 of 18 (77.8%) treated patients showed vision improvement in the MLSDT or BCVA compared to 3 of 9 (33.3%) receiving placebo (P = 0.04).

MCO-010 was well-tolerated with no serious or severe ocular or systemic adverse events reported. Across study arms, the incidence of treatment emergent adverse events (TEAEs) was comparable; the most common ocular TEAEs reported were anterior chamber cells, ocular hypertension, and conjunctival hemorrhage.

These results are consistent with those observed in an earlier phase 1/2 trial (NCT04919473) in which 9 of 11 (82%) of subjects demonstrated 2 luminance level improvements in vision-guided mobility or 0.3 logMAR in visual acuity. In this phase 1/2 study, a favorable safety profile was observed, with no serious or severe adverse events. People with severe vision loss due to RP currently have no available treatments that can improve their vision.

David Boyer, MD, Retina-Vitreous Associates Medical Group in Beverly Hills, California, and Nanoscope Clinical Advisory Board member, presented the RESTORE trial results at ARVO.

“I have had the privilege of treating severely blind patients, enrolled in MCO-010 clinical trials, and have observed some improvement in their visual function,” Boyer said. “The fact that we see any gains in vision after a single intravitreal injection is remarkable."

He explained that some participants who were living with severe vision impairment due to RP have noticed improvement in visual function.

“In addition, MCO-010 had a favorable safety profile,” he added. “It is an honor to have been a part of the first randomized controlled trial to show a visual improvement in a profoundly visually impaired population."

Samarendra Mohanty, co-founder, president and chief scientific officer of Nanoscope, noted RP patients with severe vision loss are a heterogeneous population with different genotypes and phenotypic manifestations of degeneration in their macula and peripheral retina.

“For this reason, we strongly believe that no single assessment can adequately capture clinically important changes in vision across this broad population,” Mohanty said. “Composite endpoints can be used to evaluate overall vision function changes in a single measurement when the individual tests assess different aspects of vision performance, such as vision-guided mobility, object recognition and visual acuity.”

Mohanty pointed outthat across composite endpoints in the RESTORE study, significantly more MCO-010 treated patients experienced clinically significant vision improvements.

“This randomized controlled trial provides compelling evidence that MCO-010 optogenetic therapy, as a mutation-agnostic treatment, can improve vision in patients with advanced RP," Mohanty said.

Sulagna Bhattacharya, co-founder and CEO of Nanoscope, explained the treatment landscape for severe vision loss due to RP is one of no approved therapies and lacking a pre-defined single endpoint for approval.

“The improvements we are seeing in MCO-010 treated patients across the key composite measures of efficacy make it a promising candidate for the treatment of patients with severe vision loss due to RP," Bhattacharya noted. "We look forward to our upcoming conversations with the FDA on the totality of this data regarding an expeditious path to market for this exciting therapy. It truly brings us joy to see the impact and difference MCO-010 is making in the lives of patients, and we are grateful to all participants and investigators for being a part of the success of the RESTORE trial."