On December 19, 2017, the U.S. Food and Drug Administration approved a new gene therapy, voretigene neparvovec-rzyl (Luxturna), manufactured by Spark Therapeutics in Philadelphia. Luxturna is the first gene therapy approved in the United States that’s directly administered into the eye, targeting diseases caused by mutations in the gene RPE65. Mutations in this gene can produce Leber’s congenital amaurosis or retinitis pigmentosa, both rare but potentially blinding diseases.

The RPE65 gene provides genetic instructions for making an enzyme that converts light to an electrical signal in the retina; mutations in the gene cause reduced or no enzyme activity, resulting in impaired vision. Luxturna uses a naturally occurring adeno-associated virus, modified using recombinant DNA techniques, to deliver a healthy RPE65 gene to the retinal cells via a subretinal injection to restore vision. Treatment is followed by a short course of oral prednisolone to limit any potential immune reaction. (Each eye must be treated on separate days, at least six days apart.) In the pivotal study, the most common adverse reactions to treatment included conjunctival hyperemia, cataract, increased intraocular pressure and retinal tear.

The safety and efficacy of Luxturna were established in a clinical development program involving 41 patients with confirmed RPE65 mutations between the ages of 4 and 44 years. A Phase III study with 31 participants measured the change in a subject’s ability to navigate an obstacle course at various light levels, from baseline to one year. Patients that received Luxturna demonstrated significant improvements in their ability to complete the obstacle course at low light levels, compared to the control group.

Jean Bennett, MD, PhD, is a professor of ophthalmology and director of the Center for Advanced Retinal and Ocular Therapeutics at the University of Pennsylvania in Philadelphia. She’s also scientific co-founder of Spark, and was the scientific director for the RPE65 deficiency clinical trials. “This is the second gene therapy approved by the FDA,” she notes, “but it’s the first one to target a genetic disease, and the first in which the gene is delivered directly into the person, rather than first being delivered into a cell in a dish. It’s also the first gene therapy approved worldwide for a retinal disease. Seventeen years ago, our team demonstrated that we could reverse blindness in a dog born with the same mutation that causes blindness in children, Leber’s congenital amaurosis. Since then we’ve been moving this through clinical trials. The approval comes upon finishing a Phase III study, which was the first controlled, randomized gene therapy clinical trial for a genetic disease.”

As for availability of the treatment, Dr. Bennett says Spark Therapeutics is establishing centers of excellence that will be set up to deliver the drug to qualified candidates. “This involves surgical delivery and a training plan for retinal surgeons at these centers,” she explains. “The estimate I’ve been given for availability
is six months from now. We’ll be setting up a center here at the University of Pennsylvania, and that matches our time estimate.”

Current estimates of the cost of the procedure are very high, ranging up to $500,000 per eye. Dr. Bennett says pricing issues are outside of her purview. “I’ve been assured by Spark Therapeutics that they’ll do their best to accommodate people who could benefit from the procedure,” she says. “Part of the challenge of pricing this is that it’s unusual for a drug company to be selling a one-shot drug treatment, rather than something that requires repeated dosing over time, and it’s a procedure that will have ramifications for the person’s life and career and reduce the need for family and caregivers to help the person. We certainly hope it will get less expensive over time.”

Dr. Bennett notes that one benefit of this FDA approval is that there was previously no FDA pathway for the development of a gene therapy. “I hope that having that pathway will expedite the development of other drugs for diseases for which we don’t have good treatments now,” she says. In that vein, the FDA plans to begin issuing guidance documents to help with the development of specific gene therapy products for high-priority diseases next year. Meanwhile, the manufacturer plans to conduct a post-marketing observational study of patients treated with Luxturna to further evaluate its long-term safety.

Clinical Alert Issued On Intracameral Epinephrine
The American Society of Cataract and Refractive Surgery recently issued a clinical alert to warn surgeons that PAR Pharmaceutical (Chestnut Ridge, N.Y.) has updated its epinephrine formula, rendering it inappropriate for intraocular use: ASCRS recommends that surgeons make sure their centers are not ordering the new epinephrine for ophthalmic use, and offers advice on how to safely use epinephrine from alternative sources.

Last January, PAR started making and shipping epinephrine containing 0.457 mg/ml of sodium metabisulfite (bisulfites can damage the corneal epithelium at concentrations of 0.1%) and 2.25 mg/ml of tartaric acid (no published data or reports exist regarding intracameral tartaric acid). Although PAR has disseminated new prescriber information and its 30-ml bottles of the new epinephrine are labeled “Not for Ophthalmic Use,” its single-dose, 1-ml vials don’t have this warning. ASCRS would like to avoid inducing TASS as a result of using the product.

ASCRS adds that even “preservative-free” epinephrine from alternative sources is likely to contain bisulfite as a stabilizer, but that studies have demonstrated that corneas exposed to sodium bisulfite 0.05% show no endothelial changes. Therefore, diluting preservative-free epinephrine containing bisulfite 0.1% 1:4 with BSS should be safe for intracameral use, as should mixing epi-Shugarcaine (9 cc BSS Plus; 4 cc 1:1000 epinephrine; and 3 cc nonpreserved lidocaine 4%). ASCRS also says that diluting bisulfite-containing epinephrine in the irrigating bottle is safe, but recommends avoiding epinephrine with tartaric acid, regardless of concentration, until more data becomes available.

The full ASCRS clinical alert can be found at: http://www.ascrs.org/about-ascrs/news-about/clinical-alert-intraocular-use-epinephrine-maintain-mydriasis-during-cataract-surgery