At the American Society of Retina Specialists (ASRS) meeting in Montreal, Arshad M. Khanani, MD, presented 1-year results from the phase 2 ArMaDa study of OCU410 (Ocugen), an investigational subretinal modifier gene therapy for geographic atrophy (GA). Unlike gene therapies designed primarily as drug-delivery platforms, OCU410 is intended to modulate multiple pathways implicated in GA, including complement activation, inflammation, and lipid metabolism.
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In this month’s Retina Minute, Michael A. Singer, MD, speaks with Dr. Khanani about the study’s safety and efficacy findings, an unexpected difference between the medium-dose and high-dose groups, and what investigators hope to learn as the program advances into phase 3 trials.
Michael A. Singer, MD: Arshad, you recently presented some really intriguing data about OCU410. Can you explain it to our readership?
Arshad M. Khanani, MD: Absolutely, Mike. At ASRS, I presented for the first time the 1-year results from the phase 2 ArMaDa study, which is looking at a subretinal novel modifier gene therapy, OCU410, for GA.
When you look at the mechanism of action, OCU410 is a modifier gene therapy that is modulating chronic inflammation and complement overactivation in GA. Overexpression of RORA increases CD59, which inhibits terminal complement membrane attack complex activity. Because of that, you have reduced complement activation, less inflammation, and less injury to the RPE and photoreceptors.
Preclinically, this mechanism of action has also shown reduced drusen and lipid deposits and improved retinal preservation. So it’s a very different gene therapy than what we are used to in retina, where we’re using gene therapy as a drug-delivery platform. This is more about modulation of inflammation and complement overactivation.
Dr. Singer: Tell us about the trial design.
Dr. Khanani: The phase 2 study is looking at the safety and efficacy of a single subretinal injection of OCU410 in patients with GA. Patients were aged 50 years or older, and the GA lesion area could range from 2 mm2 to 20.5 mm2, so we were allowing larger lesions than in traditional trials. GA could be foveal or nonfoveal, and choroidal neovascularization (CNV) in the fellow eye was allowed. If subjects had a history of complement inhibitor treatment, there was a 3-month washout period.
There were 3 groups: the medium dose, 1x1010 vector genomes (vg) delivered per eye; the high dose, 3×1010 vg/eye; and a control group with no treatment. Patients were randomized 1:1:1, with 17 patients in each cohort.
Safety was the primary focus, including serious adverse events, treatment-emergent adverse events, adverse events of special interest, and systemic and ocular safety. For efficacy, we looked at change in GA lesion size by fundus autofluorescence at month 12 and change in ellipsoid zone area loss by spectral-domain optical coherence tomography (OCT).
Dr. Singer: What did the patient population look like?
Dr. Khanani: The average age was about 75 to 78 years, and the majority were women. Most patients had bilateral disease, and the average GA lesion area was around 8.5 mm2 to 9 mm2. The majority, as expected, had foveal-involving GA.
The study also included both phakic and pseudophakic patients. A lot of gene therapy trials only include pseudophakic patients. Average visual acuity in the control group was a little lower, at around 48 ETDRS letters, compared with about 58 letters in the treated groups.
Dr. Singer: What did you see from a safety standpoint?
Dr. Khanani: OCU410 was well tolerated. There were no cases of endophthalmitis or retinal detachment, no cases of vasculitis or retinal vascular occlusion, and no cases of ischemic optic neuropathy.
There was 1 case of intraocular inflammation. It was deemed procedure-related and was rated as a grade 1 adverse event by the investigator, with 2+ vitreous cells. The patient received no treatment, and it resolved within 1 week.
We also saw CNV in 1 patient in the control group, 2 patients in the medium-dose group, and 1 patient in the high-dose group.
Dr. Singer: Let’s talk about efficacy. What happened with GA lesion growth?
Dr. Khanani: I think the most important thing is to look at lesion growth over time. In the overall population, we saw that the medium dose showed slower GA progression at month 12 compared with control.
There was a 34% reduction in GA lesion growth over the 12-month period with the medium dose of OCU410 compared with control. But we did not see a treatment effect in the high-dose group. In the evaluable subjects, there was actually 18% higher growth in the high-dose group.
We then did a post hoc analysis looking at lesion sizes more commonly used in GA trials—2.5 mm2 to 17.5 mm2—to see whether we needed to adjust that criterion for a phase 3 trial. The effect was pretty similar, with a 31% reduction.
Dr. Singer: Why do you think there was an effect with the medium dose but not with the high dose?
Dr. Khanani: Some of the preclinical data suggest there is a bell-shaped efficacy curve for RORA expression. I think when you go to the high dose, you may be outside that therapeutic benefit, which can lead to overactivation and decreasing the treatment effect.
Dr. Singer: One concern with subretinal gene therapy is the development of areas of hyperpigmentation. What did you see in this trial?
Dr. Khanani: There was really no hyperpigmentation reported. One reason may be that the doses we are using here are very low. Hyperpigmentation with subretinal blebs can be dose-related, and placement of the bleb also matters. We try to place the bleb away from the center so that we can measure GA lesion growth and it is not confluent with the GA. We have not seen hyperpigmentation so far, potentially because of the lower doses, but it is something that will need to continue to be followed over time.
Dr. Singer: We should also talk about function. Did you see any functional improvement in vision in phase 2?
Dr. Khanani: There was no functional benefit. Jay Chhablani, MD, presented the ellipsoid zone data, so there is a structural benefit, but there was no functional benefit seen.
Dr. Singer: What’s the plan going forward?
Dr. Khanani: Based on these data and the treatment effect from the medium dose, the program is moving forward. The global phase 3 ArMaDa3 trial has been designed and will include around 240 patients with GA.
The lesion size will be 2.5 mm2 to 17.5 mm2, similar to other registrational trials, and we will still allow patients with CNV in the fellow eye. This will be a global program with 1:1 randomization to treatment vs control. Patients will be followed for 5 years, as with other gene therapy studies, with an analysis at 12 months. The primary endpoint will evaluate the rate of change, or slope, of the square root-transformed GA lesion area through month 12 compared with control, using multiple time points. There will also be secondary endpoints looking at function, including low-luminance visual acuity.
Dr. Singer: If this medicine is ultimately approved, who do you think might be the right patient for this type of approach?
Dr. Khanani: We are lucky to have 2 approved treatments, but we know the treatment burden is high, and it’s not feasible for many patients to continue for a long time on complement inhibitors. I start my patients on them, but there is a dropout rate, and there is progression of disease.
My hope is that with gene therapy, we are able to eliminate the treatment burden for patients. Of course, if we get a functional benefit or any benefit beyond what we see with injections, that would be even better.
In a world of equal efficacy to intravitreal injections, I think a one-time treatment could be attractive for patients who tend to be elderly and for whom coming in frequently is difficult. On the flip side, taking a patient to the operating room means we have to look at comorbidities and whether that patient is a good candidate for surgery.
There are multiple programs looking at gene therapy for GA. At the end of the day, the program that is going to be successful is the one that has good efficacy, maybe a functional signal, and good safety.
I’m excited that, as a field, we’re looking at multiple different shots on goal with gene therapy for GA. We need to see the data from larger trials, and then we can determine how these approaches may fit into the world of other treatments that are available.
Dr. Singer: Because OCU410 works through CD59 and also appears to affect pathways beyond the complement system, could there eventually be a role for combination treatment?
Dr. Khanani: GA is such a heterogeneous disease, with so many risk factors, that it’s very difficult to know. But the point is that this is a multimechanistic gene therapy. It is working on the complement system, and it’s also working on lipid metabolism and inflammation outside the complement system.
The whole idea is that hopefully we can get better disease control, but we don’t know yet because we don’t have a large data set. Small trials have their own limitations. We have seen a trend of efficacy here, but I think it has to be validated in larger trials.
My hope would be that whatever gene therapy we have, we can help patients so they don’t have to get injections on top of gene therapy.
Dr. Singer: Arshad, I always learn so much from you. I really appreciate you taking the time to educate our readers. We’ll look forward to seeing the phase 3 results.
Dr. Khanani: Thank you, Mike. It’s always a pleasure. RP
