Gene therapy could revolutionize AMD treatment
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Gene therapy could have the potential to revolutionize the treatment of many conditions, including age-related macular degeneration.
AMD is the leading cause of vision loss in older patients, and the current treatment standard consists of monthly or bimonthly injections, which can be difficult for patients and pose a significant burden on their time and life.
Gene therapy has the ability to reduce the number of injections or possibly eliminate them entirely.
“The bottom line is that AMD is a lifetime disease, and patients need treatment. We know the majority of our patients don’t come in for their treatment in a timely fashion,” Arshad Khanani, MD, MA, managing partner, director of clinical research and director of fellowship at Sierra Eye Associates and clinical associate professor at the University of Nevada, Reno, told Healio. “This is why real-world visual acuity outcomes are worse than in clinical trials.”
Positive efficacy data
Two gene therapy programs in development for AMD are RGX-314 (Regenxbio), which is delivered subretinally or suprachoroidally, and ADVM-022 (Adverum Biotechnologies), which is delivered intravitreally.
RGX-314, which consists of a novel adeno-associated viral vector (AAV8), is in development for wet AMD, diabetic retinopathy and other retinal diseases.
“Basically, the goal is to transfect the cells in the retina with the AAV vectors, so they become like a biofactory to generate the protein,” Khanani said.
Interim data from the phase 2 multicenter, open-label, randomized, active-controlled, dose-escalation AAVIATE trial showed suprachoroidal delivery of RGX-314 to be safe and effective for AMD.
Six months after one-time treatment, patients in the study group were more likely to have stable visual acuity and retinal thickness and at least a 70% reduction in anti-VEGF treatment burden. In addition, 40% of those in the treatment group were free from anti-VEGF injections after 6 months.
These results are similar to data from a study evaluating the therapy in subretinal delivery, which currently has 2 years of data.
A phase 1/2a trial in which patients were given RGX-314 subretinally during vitrectomy found a reduction in anti-VEGF treatment burden and a potential for treatment effect out to 3 years.
“With gene therapy, we’ve learned that delivery matters,” Khanani said. “The immune responses are different depending on where you put it.”
ADVM-022 consists of the AAV vector AAV.7m8.
In the multicenter, open-label, dose-escalation OPTIC trial, patients were stratified into four dosing cohorts. Cohort 1 received a high dose of 6 × 10¹¹ vector genomes per eye (vg/eye) and a 13-day course of oral steroids, cohort 2 received a low dose of 2 × 10¹¹ vg/eye and a 13-day course of oral steroids, cohort 3 received a low dose and 6 weeks of topical steroids, and cohort 4 received a high dose and 6 weeks of topical steroids.
After a median of 86 weeks of follow-up, the six patients in cohort 1 did not need any supplemental injections. Of those in cohort 2 who had a median follow-up of 64 weeks, three of the six patients did not need supplemental injections. Seven of nine patients in cohort 3, which had a median follow-up of 48 weeks, did not need supplemental injections. And in cohort 4, with a follow-up of 12 to 24 weeks, eight of nine patients did not need further injections.
Importance of safety
As these potential therapies make their way through the pipeline toward approval, safety is as important as efficacy.
Retinal pigmentary changes were recorded in some patients in the RGX-314 subretinal trials, but there has been no immune-related inflammation.
“This program enrolled heavily pretreated patients who are high need, and gene therapy is new, so safety is crucial to look at,” Khanani said.
In the suprachoroidal trials, some mild inflammation has been recorded, which has been treated with topical steroids, but there has been no chronic inflammation. This option may potentially be a game changer due to the fact that it can be done in the clinic rather than in an operating room.
In the ADVM-022 trials, inflammation has been seen in all of the study cohorts, which has thus far been addressed with oral or topical steroids.
“Efficacy is great, but we are still learning what is the right dose,” Khanani said. “That’s my concern: How can we optimize patient outcomes while addressing some safety concerns? It’s a new field, and we are still learning about long-term safety and efficacy, but we will continue to see long-term data from these programs and see how it pans out. It is super exciting.”
Looking ahead
In addition to RGX-314 and ADVM-022, which have reached clinical trials, more gene therapies are on the horizon for AMD treatment.
RetinoStat (Oxford BioMedica), which uses a recombinant equine infectious anemia virus, and AAVCAGsCD59 (Hemera Biosciences), which blocks formation of the membrane attack complex, are both in phase 1 studies.
The burden of anti-VEGF treatments can mean frequent office visits, which are difficult for even the most dedicated patients. For those who lack financial or transportation resources, it can be even more difficult. One-time gene therapies could reduce this treatment burden, especially as the population continues to age and more patients will begin to need regular injections, meaning that most patients with AMD will eventually be eligible for gene therapy once it becomes available.
“I think gene therapy clearly has great potential to change the course of disease in our patients. It’s an exciting time to see how the data pans out, but it is a lot of positive news for our patients,” Khanani said.
References:
- Arepalli S, et al. Int J Retina Vitreous. 2021;doi:10.1186/s40942-021-00325-5.
- Hussain RM, et al. Drug Des Devel Ther. 2021;doi:10.2147/DDDT.S295223.
- Regenxbio announces additional positive interim phase I/IIA and long-term follow-up data of RGX-314 for the treatment of wet AMD. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-additional-positive-interim-phase-iiia-and. Published Feb. 16, 2021. Accessed Dec. 2, 2021.
- Regenxbio presents additional positive interim data from trials of RGX-314 in wet AMD and diabetic retinopathy using suprachoroidal delivery at AAO 2021. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-presents-additional-positive-interim-data-trials-rgx. Published Nov. 12, 2021. Accessed Dec. 2, 2021.
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