| By Richard Mark Kirkner, Editor |
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| With Victor Gonzalez, MD |
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MCO-010 is an investigative transgene therapy that aims to improve vision in patients with Stargardt disease, a rare genetic retinal disease that causes vision loss in childhood and adulthood. No current treatment exists, but a host of investigative treatments along with MCO-010 are in the pipeline. The incidence has been reported at about 1:10,000.1
MCO stands for multi-characteristic opsins, a transgene for a high-performing opsin that sensitizes bipolar cells to light. MCO-010 is delivered by a proprietary adeno-associated virus (AAV2) in a single intravitreal injection. Topline 48-week data from the Phase II STARLIGHT trial, reported at the American Academy of Ophthalmology 2023 meeting, found no serious adverse events (SAEs) among the six treated patients.2
Secondary endpoints showed an average 5.5-letter improvement in best-corrected visual acuity, a 15-letter improvement with a wearable magnifier and a 2.6-decibel improvement in perimetry testing. An exploratory endpoint found improvements in reading along with color contrast vision and contrast sensitivity.
MCO-010 has received Food and Drug Administration Fast Track designation and orphan drug designations for Stargardt disease as well as retinitis pigmentosa. The latter indication is the focus of the Phase IIb RESTORE trial.
Here, Victor Gonzalez, MD, of Valley Retina Institute and Laredo Retina Associates in McAllen, Texas, answers questions about MCO-101 and the STARLIGHT trial. Dr. Gonzalez is a paid investigator and advisory board member for trial sponsor Nanoscope Therapeutics.
Q: In your own words, how would you describe the mechanism of action of MCO-010?
A: Optogenetics uses an AAV2 vector to target bipolar cells and introduce a genetic material that begins to produce three pigments that create an internal photosensitive material. In the case of Stargardt disease, and this is one of the differentiating factors of this therapy vs. others that are being produced, this particular combination of pigments activates ambient light. In the past these patients required goggles with high intensity light. With this therapy, ambient light activates it.
Q: Please briefly explain the design of the STARLIGHT trial.
A: This trial enrolled six patients who were genotyped positive for one of three known mutations—ABCA4, ELOVL4 or PROM1—to ensure enrollment of only patients who had Stargardt. They had visual acuity of 1.3 to 1.9 logMAR, or about 20/400 to 20/1,600, and the fellow eye was 20/200 or worse. By definition, these patients are legally blind.
Q: What are the key 12-month safety results from the STARLIGHT trial?
A: There were no significant red flags systemically. A few patients had vitreous cells. Two patients out of the six had self-limiting inflammation that was controlled with topical steroids.
We had none of the complications of interest, such as vasculitis or vaso-occlusive disease. One patient had a slight elevation of intraocular pressure that resolved on its own.
Q: What were the key findings from the secondary endpoints?
A: Four of the six patients had a very interesting improvement of their visual acuity. Two of three patients with the macular degeneration phenotype gained more than 7 letters and all three of them gained more than 30 letters with use of a wearable magnifier. Across all six patients, the BCVA gain with the magnifier was around 15 letters on average at week 48.
Q: Inflammation is an overriding concern with gene vectors in the eye. How did STARLIGHT account for that?
A: Three days before the injection we pretreated the patients with oral steroids 1 mg/kg for one week with a taper to 17 days because an inflammatory response to the vector is normal. They were then treated with topical steroids tapering from twice daily from week 2 to 12 to every other day from week 24 to 48.
Q: What’s next for the development of MCO-010 for this indication?
A: The next step is to gain a better understanding of which patients would benefit most in order to achieve the statistical significance. The Phase III trial is going to focus on patients with the macular degeneration phenotype of Stargardt disease because we think the treatment will show a statistically significant benefit.
Q: Would you have anything else to add?
A: STARLIGHT gives us a significant understanding of the proof of concept. First of all, can we safely give this drug to patients in the eighth spectrum of Stargardt? Yes. Can we do it without significant side effects from the inflammation or the need for systemic anti-inflammatory treatments? Yes.
This is one of the least intensive steroid regimens that we’ve seen for people being treated with gene therapy. RS
Dr. Gonzalez is with Valley Retina Institute and Laredo Retina Associates in McAllen, Texas. Dr. Gonzalez is an investigator and advisory board member for Nanoscope Therapeutics.
REFERENCES
1. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: Clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2017;101:25-30.
2. Tsang S. MCO-010 optogenetic therapy for vision loss in Stargardt disease: Topline data from the Phase 2 STARLIGHT trial. Paper presented at American Academy of Ophthalmology 2023; San Francisco, CA; November 4, 2023.
