Gene therapy providing hope for patients diagnosed with inherited retinal diseases

(Image Credit: AdobeStock/ipopba)

A long-term review of voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) has demonstrated that the treatment has resulted in long-term improvements in vision with patients diagnosed with biallelic RPE65 mutation-associated retinal diseases.

In a conversation with Ophthalmology Times, Stephen R. Russell, MD, the Dina J. Schrage Professor of Macular Degeneration Research at the University of Iowa, detailed the 9-year data he presented at the American Society of Retina Specialists annual meeting. Russell served as one of the principal investigators on the phase 3 trial of voretigene neparvovec-rzyl.

The therapy was approved by both the European Medicines Agency (in 2018) and United States Food and Drug Administration (in 2017) after the supporting pivotal Phase III study revealed an improved ability to navigate a mobility course at different levels of environmental illumination (MLMT) as well as statistically significant functional vision improvement in patients in terms of increased light sensitivity (FST).

Russell said the Phase 3 trial met its primary endpoint early on, which was change in bilateral vision performance as assessed with a multi-luminance mobility test. Investigators have continued to track the patients to secure long-term data on the treatment.

“The original intervention group did quite well, improving approximately 2 light levels on the mobility test, the multi-luminance mobility test and other tests,” Russell said.

Kevin Yang Wu, MD, DMD, of the Division of Ophthalmology, Department of Surgery, University of Sherbrooke, Quebec, Canada, discussed the gene and cell therapies under development and the novel potential drug targets for RP. He presented that data earlier this year at the American Society of Cataract and Refractive Surgery Annual Meeting in Boston, Massachusetts. He noted the current conventional therapies, which only slow the progression of the disease, include retinoids, vitamin A supplements, protection from sunlight, visual aids and medical and surgical interventions to treat ophthalmic comorbidities.

Wu pointed out that only individuals with the RPE65 gene mutation, who comprise a small population of patients (0.3%-1% of all RP cases), are candidates for treatment with voretigene neparvovec-rzyl, the only available gene therapy.

The investigators have had to pivot, as the COVID-19 pandemic impacted the study, reducing the number of participants.

“The patients were randomized, again, because we were including pediatric patients, we had to treat both eyes with the treatment,” Wu explained. “In order to have a control group, we had to have some patients who didn't receive the intervention initially. They were randomized 2:1, with 2 patients randomized to early intervention to one patient who was left in the control group.”

The patients in the control group were given access to the medication. In 1 year, they were allowed to cross over and receive bilateral treatment, which all of them did. A total of 29 subjects were treated bilaterally in the trial.

Russell said the goal of investigators is to focus on the long-term outcomes of voretigene neparvovec-rzyl.To account for the pandemic, investigators decided to ensure they didn’t have a lot of variability in the trial for the 8- and 9-year data.

“So, we essentially synchronized the onset of intervention from the 2 groups so that we could follow all of them on the same time increments from the time of intervention until the time they were being measured,” he explained. “What we what we observed was, although there was increased variability as you go along, it didn't seem to be any drop off in terms of the effectiveness on the multi-luminance mobility test.”

With the test showing good results out to 9 years, investigators saw this as the highlight of the study.

“We also looked at some of the secondary endpoints, the full-field light sensitivity, or FST test, that also showed essentially flatline all the way out an improvement, a step improvement at the time of intervention, and then flatline the rest of the way out,” Russell said. “The visual field was a little bit more ambiguous, and we are not exactly sure how to interpret it. There does seem to be more variability, and there may actually be a little bit of a drop off at years 8 and 9.”

The trial hasn’t resulted in any new data regarding safety, though one area of concern has been the recognition of chorioretinal scarring, or chorioretinal atrophy, which was noted in the post-marketing study.

“We went back and looked at the Phase 3 patients to see if any of them have this,” Russell said. “There were 2 patients in the Phase 3 trial that demonstrated what would be classified now as chorioretinal atrophy.”

Investigators then went back to review the Phase 1 and Phase 2 patients, and Russell said there were a couple of patients in that study that had chorioretinal atrophy.

“It's a little difficult to know whether that's a new complication, or just sort of a natural history,” he said. “But it does seem to be accelerated in in terms of onset in the patients who have received Luxturna

Moreover, Russell noted that when investigators looked at potential adverse events linked to voretigene neparvovec-rzyl, and they have been dropping off. He noted that most of the issues were clustered in Year 1 and Year 2, right after or around the time of intervention, when the gene therapy was placed into the subretinal space.

“There are lots of lots of things that can happen around the time that you perform a vitrectomy, create a posterior vitreous detachment, and then inject subretinal fluid in the macula containing the gene therapy, especially in children” he explained. “As you get into the younger age category, the risk for having retinal tears retinal detachment macular holes, and other things.”

And with the vector now gone, Russell noted, so investigators are dealing with the DNA transgene itself.

“We are sort of in new territory here, because this is the only approved gene therapy for the eye so far,” he said. “It was the first one [gene therapy] that was approved for any inherited disease of any organ system.”

The investigators also are in uncharted territory when it comes to the length of the trial, which has passed the 9-year mark, and will continue for several more years to meet FDA requirements.

“Assuming that we're able to continue to follow these patients, and that they survive that long as some of them were, in their 40s at the time that they were treated, we should have some pretty good long-term data here over the next few years,” he said.

The data also suggest that the treatment is as close to “one-and-done” as is possible, and it is welcome news to retina specialists, and it gives hope to the patients they treat.

“The exciting thing is that we finally have a win on the board,” Russell said.

Russell pointed out that gene therapy has been around for about 50 years, and it has proven to be a challenge to find successful treatments.

“As is demonstrated by the study, if you can find the solution, and it is durable, it gives us some hope,” he said. “It gives us encouragement to continue to try to find these new therapies, especially for a lot of the patients who don't really have anything to look forward to or turn to, most of them would accept any kind of therapy that would simply stabilize the vision where it is.”

Despite the instances of chorioretinal scarring, Russell said patients have not been deterred.

“I haven't met a patient yet., and I have treated a number of patients since this was approved. Who would not want the therapy because of some low 10% to 25% chance of a complication,” he said. “They appreciate that they've had an improvement.”

And of the patients who have received the treatment, there is a 95% or better likelihood they will have some improvement.

“Who doesn’t want that?” Russell concluded.