Since the FDA approval of voretigene neparvovec (Luxturna, Spark Therapeutics) in December 2017 for RPE65-associated retinal degeneration, I have referred several patients for commercial treatment. Although my practice was not a site for the Phase 3 trial, I spoke at the FDA advisory committee in October 2017 on behalf of patients who were desperate to receive this therapy if approved. It was one of the most powerful moments of my career thus far as an inherited retinal disease (IRD) specialist and physician.

In December 2017, Luxturna was approved with an expedited review process by the FDA, becoming the first retinal gene therapy to receive approval. Luxturna is an adeno-viral associated vector carrying the RPE65 transgene that is delivered subretinally to the macula via a pars plana vitrectomy vitreoretinal surgery. It is approved for patients with biallelic RPE65-associated retinal degeneration. Patients must have viable remaining retinal cells as determined by the treating physician.

Since Luxturna’s approval, the retinal gene therapy field has exploded with multiple ongoing IRD clinical trials, though none have reached the FDA-approval finish line.

Here, I provide insights on the referral process and the impact this breakthrough therapy has had on my patients.

ABOUT RPE65-ASSOCIATED RETINAL DEGENERATION

Luxturna is intended for patients with RPE65-associated retinal degeneration, which can cause either Leber congenital amaurosis (LCA) or RP (retinitis pigmentosa). Patients with biallelic RPE65-associated retinal degeneration suffer progressive photoreceptor degeneration caused by mutations in the RPE65 gene, which affects the visual cycle and ability of photoreceptors to sense light. Patients are severely night-blind and become profoundly visually impaired by late adolescence. RPE65 disease primarily affects the rod photoreceptors, explaining this severe nyctalopia.

RPE65-associated retinal degeneration must be diagnosed and confirmed by genetic testing, which can be ordered by the physician.

THE REFERRAL PROCESS

This process is navigated by the Spark Therapeutics patient liaison team. Patients are referred by the physician seeing the patient to one of 10 academic centers of excellence that have trained vitreoretinal specialists adept in the very precise technique of a subretinal injection to the macula. Bascom Palmer in Florida is the treatment site where all of my patients have been treated.

Both eyes are treated, typically a couple of weeks apart, with a steroid regimen induced just prior to surgery and relatively quickly tapered and discontinued within weeks. The patients are followed by the surgical team at the treatment center in the acute postoperative period, but I have had the pleasure of seeing all of my patients postoperatively in my retina clinic as well.

There are risks associated with either the surgery or the gene therapy. The FDA label for Luxturna lists these safety risks, which should not be minimized or discounted. Per the FDA label, “the most common adverse reactions (incidence ≥5%) in the clinical trials were conjunctival hyperemia, cataract, increased IOP, retinal tear, dellen (thinning of the corneal stroma), macular hole, subretinal deposits, eye inflammation, eye irritation, eye pain, and maculopathy (wrinkling on the surface of the macula).” Patients and families should be carefully counseled and consented as to these risks prior to consideration of this therapy.

As a referring physician, I have played a role in diagnosing the patient, including genotyping, clinically characterizing their disease status, counseling them regarding consideration for gene therapy with Luxturna, postoperative monitoring and continued follow-up post-treatment. It has been rewarding being a part of their journey from diagnosis through surgery to life post-Luxturna.

COUNSELING ON LUXTURNA’S ROLE

Given that the rods (rather than the cones) were the primarily affected cells, visual acuity was not an appropriate outcome to follow for a therapeutic effect. A novel functional vision outcome measure was introduced (and accepted by the FDA) to evaluate the efficacy of gene therapy for this disease. This was called the multi-luminance mobility test, or MLMT. In short, this is a maze with obstacles that patients are asked to walk through at varying low light levels. This outcome measure showed a statistically significant improvement in treated patients’ ability to navigate this maze at low light levels.¹

This trial, and this therapy, paved the way for the concept of “functional vision” to become not only a respected and discussed concept in the retinal community but an FDA-approvable clinical trial outcome as well. Functional vision refers to a patient’s ability to function within their environment, given their vision. I try to explain to patients that the goal of the therapy is to allow them to function better visually in their environment. To most of my treated patients, post-therapy translates to subjectively improved night vision and the ability to function in low-light conditions.

PATIENT INSIGHTS

Since FDA approval, I have referred three of my patients with RPE65-associated Leber congenital amaurosis (LCA) for commercial treatment with Luxturna. Without treatment, these patients typically proceed to blindness in late adolescence and are desperate. Now, they have real hope with an FDA-approved treatment.

All of my patients who had surgery had bilateral vitrectomies spaced a couple of weeks apart, remaining at the treatment center until both surgeries were done before returning home and seeing me in the first few months postoperatively.

I have had the pleasure of becoming good friends with the mother of one of the children I referred for treatment. Without details that would betray confidentiality, since being treated with Luxturna, this patient has been able to see a rainbow and stars in the sky for the first time and ride his bike late into the evening hours without difficulty.

Another patient was a young girl who had a somewhat surprising improvement in her visual acuity (again, not technically expected with a rod-based gene therapy). Her father told me that he was able to take her to a father-daughter dance at school for the first-time post-treatment, because she was no longer hesitant about dancing in the dark.

Additionally, another patient was an adolescent boy who had such a surprising improvement in his visual field that he now meets visual field criteria in his state required for driving. It still gives me chills recalling a day in one of my satellite clinics when his whole family (mom, dad and a handful of little sisters and brothers) accompanied him on his visit 1 year post-Luxturna treatment. It felt a little like the twilight zone getting to compare visual fields pre- and post-treatment with the family. The current visual fields were vastly larger than the baseline fields, which was the first time I have ever seen this in a patient with LCA. Tears were shed in the exam room, but for perhaps the first time in a room with an RPE65 patient, they were tears of joy.

What a welcome change as an IRD specialist to finally get to see one of our retinal degeneration patients get better! The field has been waiting for this day for a long time.

These stories are anecdotal, but the Phase 3 trial data and the FDA approval and label speak to the safety and efficacy of the therapy, and the real-world PERCEIVE study is underway, which will provide 5-year stability data on durability of efficacy. The therapy has been a life-changer for the patients I have referred, and it has been such a fulfilling experience having the opportunity to be a part of their journey.

THE FUTURE OF GENE THERAPY

While only a minority of patients will qualify for an ongoing gene therapy trial (and an even smaller number of patients will qualify for the one FDA approved therapy, Luxturna), I am still a huge proponent of genetic testing. In fact, I order this in 100% of my IRD patient population.

I strongly believe we are living in an era with a new and elevated standard of care for patients with IRDs. Given one FDA-approved product and dozens of ongoing gene therapy clinical trials, I believe we are ethically bound to offer patients genetic testing and be prepared to offer them genetic counseling for these results (or set this up through one of the many genetic counseling services including telecounseling options) since results may have family planning implications or relevance for other living family members. I think it is also part of the standard of care of management of IRD patients to be prepared to counsel them as to any potentially relevant clinical trials for which they may be a candidate, or refer them to an IRD center that can do this, as well as necessary clinical characterization and testing that can allow appropriate clinical counseling as to disease status and progression.

Endpoints such as improving night vision or low luminance visual acuity, improving color vision, improving macular structure and slowing photoreceptor loss or improving navigation may be life changing for patients with IRDs. Hopefully, Luxturna will be the beginning to an explosion of approvable gene-based therapies, or drug therapies, that we can finally offer to these patients with rare IRDs. OM

REFERENCES

1. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial [published correction appears in Lancet. 2017 Aug 26;390(10097):848]. Lancet. 2017;390(10097):849-860.
2. ClinicalTrials.gov . ADVM-022 Intravitreal Gene Therapy for DME (INFINITY). https://www.clinicaltrials.gov/ct2/show/NCT04418427 . Accessed May 23, 2022.
3. ClinicalTrials.gov . A Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS). https://clinicaltrials.gov/ct2/show/NCT03116113 . Accessed May 23, 2022.
4. ClinicalTrials.gov . Efficacy and Safety of BIIB111 for the Treatment of Choroideremia (STAR). https://clinicaltrials.gov/ct2/show/NCT03496012 . Accessed May 23, 2022.
5. ClinicalTrials.gov . Safety and Efficacy of rAAV-hRS1 in Patients With X-linked Retinoschisis (XLRS). https://clinicaltrials.gov/ct2/show/NCT02416622 . Accessed May 23, 2022.
6. ProQR Therapeutics. ProQR Announces Top-Line Results from Phase 2/3 Illuminate Trial of Sepofarsen in CEP290-mediated LCA10. https://bit.ly/3zcWgDw . Accessed May 23, 2022.
7. ProQR Therapeutics. ProQR Announces Additional Sepofarsen Illuminate Trial Analyses and Provides Update on Company Strategy. https://bit.ly/396ewUI . Accessed May 31, 2022.

Christine Kay, MD, is a vitreoretinal surgeon and inherited retinal disease specialist at Vitreoretinal Associates in Gainesville, Fla. She is involved in multiple inherited retinal disease trials.

Financial disclosure: Dr. Kay is a consultant for Spark Therapeutics.