Rachel Huckfeldt, MD, PhD
Inherited Retinal Diseases Service
Mass Eye and Ear / Harvard Medical School
Earlier this week on Tuesday December 19th, the FDA announced its approval of Luxturna gene replacement therapy for the treatment of biallelic RPE65-associated retinal dystrophy in children and adults. This decision followed a unanimous but non-binding recommendation for approval made by a 16-member FDA advisory committee in October. Luxturna (voretigene neparvovec; Spark Therapeutics), which is delivered subretinally and uses an adeno-associated virus (AAV) as a vector, is the first in vivo gene therapy to receive FDA approval.
This landmark decision was preceded by a decade of clinical investigation. Initial reports on the safety of AAV gene replacement therapy for RPE65-associated Leber congenital amaurosis were published in 2008, and earlier this year, the results of the Phase 3 RPE65 gene therapy trial sponsored by Spark Therapeutics were published in The Lancet. Participants in Spark’s Phase 3 trial were randomized to either treatment with Luxturna or observation at a 2:1 ratio with patients in the treatment group undergoing surgery in the second eye within 18 days of surgery in the first eye. One year after treatment, subjects met the primary efficacy endpoint by demonstrating an ability to navigate a mobility maze at significantly lower light levels than pre-treatment. No drug-related serious adverse events occurred.
Even prior to FDA approval, these results suggested the potential of gene therapy for previously untreatable retinal diseases. I discussed the impact of this therapy’s success with Dr. Jacque Duncan, an expert in inherited retinal degenerations from UC-San Francisco.
Rachel Huckfeldt (RH): Do you think that the approval of Luxturna by the FDA will expedite the clinical trial and approval pathway for subsequent gene replacement therapies?
Jacque Duncan (JD): I certainly hope that will be the case. I do think that Spark has done important groundwork to understand what would be necessary to get through the FDA approval process. Once one therapy like this gets approved, then it probably does make it easier for the FDA to review and approve other gene replacement therapies. There are certainly lots of clinical trials of gene replacement therapy underway right now, so I’m hopeful that others will have an easier time clearing the regulatory process due to Spark’s efforts.
I do think that every vector and promoter will independently have to demonstrate safety and then efficacy, but the lessons learned from this experience should make it easier for other investigators to pursue similar paths with their own treatments. The success of retinal gene replacement thus far has also led to retinal degenerations being considered a field that is worthy of investigation and investment, and hopefully there will be additional clinical trials leading to FDA submissions and approvals as a consequence.
RH: One of the really wonderful aspects of RPE65 gene replacement therapy has been the potential for improved visual function. But, many of our patients with retinal degenerations maintain good central vision until late in disease such that our goal would be preventing vision loss. That goal becomes challenging with regard to clinical trial endpoints and trial duration. How can we design endpoints to identify this type of efficacy?
JD: The RPE65-related retinal degenerations are a very special case, in part because the gene is expressed specifically in the RPE cells rather than in the photoreceptors. There are not very many retinal degenerations for which that is the case, and with a few exceptions, I think it is naïve to expect that other gene replacement therapies are likely to restore function in the same way. But, it’s wonderful that it was the first therapy that made it this far because it has probably made it easier to pursue the development of other treatments.
The vast majority of inherited retinal degenerations are caused by mutations that are expressed primarily by photoreceptors. The goal would be to identify patients at an early stage of disease and then slow down the rate of degeneration and preserve as much vision and photoreceptor structure as possible. Since these tend to be slowly degenerating conditions, we need to find measures of photoreceptor function, and ideally also structure, that can be monitored over reasonably short periods of time. This is where natural history studies become really important. The Foundation Fighting Blindness has supported research into the natural history of ABCA4-related retinal degenerations, and a study of USH2A-related degenerations is underway as well. The goal of these studies is to identify the most sensitive, objective, and reliable measures, as well as what time frame is necessary, to detect a meaningful change.
Outcomes being developed include quantitative measures of visual field, which are recognized by the FDA to be a measure of visual function. A structural variable like the area of the ellipsoid zone band measured on OCT scans is a very sensitive and objective outcome measure, but it has limitations with regard to applicability to patients in the earliest or latest stages of disease. I think those are likely to be the main outcome measures for gene replacement therapies.
High-resolution structural imaging, such as adaptive optics imaging of photoreceptors, is promising but not a widely available technology at this point in time. I think it merits investigation as an exploratory or secondary outcome measure given that it may enable us to visualize photoreceptors during the course of degeneration.
RH: What can we do in our own clinics and in the ophthalmology community more generally to make sure that as many patients as possible have the opportunity to benefit from gene therapies?
JD: If you’re thinking about gene-specific therapies as a potential treatment, then the most important thing is to facilitate genetic testing. There are a number of commercial and academic options for testing. With FDA approval of the RPE65 treatment, then my hope is that insurance companies will be more likely to pay and reimburse for genetic testing and genetic counseling. Patients who know their mutations can then follow the research that is most relevant to them, participate in clinical trials, and hopefully benefit from gene-specific therapies that also get approved by the FDA in the future.
RH: I’ve noticed a greater sense of optimism in many of my retinal degenerations patients over the past few months as a result of the attention that RPE65 gene replacement has received. Several patients have returned after not being seen in years solely because of these reports. Have you noticed something similar?
JD: The success of this treatment has really raised awareness of this field and made patients feel like it is worth seeking care from an ophthalmologist that has expertise about retinal degenerations. Patients as well as their family and friends are inquiring about the results and have been interested in learning more about what this therapy means for them and the field. The results of this trial have raised awareness of the opportunity to develop groundbreaking therapies that may really change the future. Even if this particular gene replacement therapy is not relevant for individual patients, its success is giving people a lot of optimism and hope.