Two-year results of RESTORE study highlight a mutation-agnostic gene therapy for retinitis pigmentosa

Allen Ho, MD, Director of Retina Research at Wills Eye Hospital in Philadelphia, talks about an exciting gene therapy option for retinitis pigmentosa.

Question:

You are presenting a paper at the AAO Annual Meeting titled, “Efficacy and Safety of MCO-010 Optogenetic Therapy for Vision Restoration in Patients with Severe Vision Loss Due to RP: Two-Year TOPLINE Results from a Phase 2b and 3 Randomized Sham-Controlled Clinical Trial (RESTORE).” Can you discuss the design of the study and its findings?

Allen Ho, MD, FACS, FASRS:

Here in Chicago at the American Academy of Ophthalmology, I’ll be presenting the 2-year results of the RESTORE study, the Nanoscope RESTORE study safety and efficacy, which is an optogenetic study for patients with severe vision loss from retinitis pigmentosa. We’re talking about patients that are hand motions, worse than hand motions, light perception, bare light perception vision due to the array of diseases that the array of gene mutations that cause retinitis pigmentosa.

Question:

MCO-010 is a mutation agnostic gene therapy. Can you talk more about this therapeutic and why it is unique?

Allen Ho, MD, FACS, FASRS:

Optogenetics, first of all, in the particular molecule in this program, MCO-010, optogenetics refers to gene therapy techniques to create a light-sensitive molecule that then will be activated in remaining retinal cells. In this particular program, MCO-010 is placed in an AAV2 viral vector. It’s injected once intravitreally, and then aims to take that transgene encoding for this synthetic bioengineered, visible light-responsive, fast kinetics, fast on and off, you need to have that in order to create reasonable vision, is injected intravitreally, and then specifically targets the bipolar cells.

In the layers of the retina, the rods and cones are gone or almost all gone in retinitis pigmentosa. This particular optogenetic therapy is then going to go to the bipolar cells. These opsins are light-sensitive molecules. They’re a family of light-sensitive molecules. Rhodopsin is what we natively have in rods and cones that is signaled by light that creates an electrical signal in the photoreceptors that then goes to bipolar cells, to ganglion cells, to the optic nerve, back to the visual cortex in the brain, the occipital cortex.

Opsins are not only light-sensitive for vision, there are other opsins in the body. For example, neuropsin, melanopsin, these are light-sensitive molecules, for example, in hair follicles, and other vision cells that drive other functions aside from vision. For example, light-dark cycles, circadian rhythms, may be responsible for seasonal affective disorder, hormonal secretion. Opsins are a family natively, rhodopsin, melanopsin, neuropsin. This MCO-010 is a synthetic bioengineered specifically for the bipolar cells that we’re using.

In the phase 1/2 trial, we saw that literally this program was making patients with severe loss of vision see again. That stimulated this randomized, controlled, multicenter trial where patients got a high dose of MCO-010, a lower dose MCO-010, or a sham injection.

From a safety standpoint, which is always important in these intravitreal gene therapies, the safety profile was excellent. Specifically no significant vasculitis, choroiditis, occlusive vasculitis, and no hypotony. That’s the first issue that’s important.

The second issue regards to efficacy. We saw significant improvements meeting primary and secondary endpoints in this study. Specifically at 52 weeks, there were 40% of the subjects going from hand motions or worse, going from basically off-chart vision into near on-chart or on-chart vision. Both high and low dose were significant at 52 weeks. At 76 weeks, the higher dose was significantly different than sham. At 2 years, the mean visual improvement was 0.3-log more or essentially 3 lines of vision on a vision chart, which has been the standard for approval for other retinal products.

What does this mean for patients? For me, it’s exciting from a scientific standpoint and a clinical trial standpoint, that we might have a gene therapy strategy for a group of the most needy patients that I’ve taken care of over the past 3 decades. These patients with advanced RP who come in and who we tell them we’re working on it. We don’t want to create false hope because we have nothing. There is no current treatment. Now we’re seeing positive safety and efficacy.

I think it’s fantastic clinical science. I think it provides real hope. Next steps include filing a biologic license application with the FDA. It’s an orphan designation; it’s a fast-track designation because there’s no current treatment available. We look forward to progress for this particular group of patients. It may be there from the science, optogenetic science.