Spark Therapeutics Inc.'s experimental gene therapy Luxturna improves vision in patients with a genetic disease that causes blindness, but uncertainties remain on the drug's lasting effect and in what age group it should be used, scientists at the U.S. Food and Drug Administration said.
The FDA also raised safety concerns about the product, which the agency said may have long-term consequences for patients.
Spark is seeking to market Luxturna, also known as voretigene neparvovec, as a treatment for patients with vision loss related to biallelic RPE65 mutation-associated retinal dystrophy, a rare progressive genetic eye disease that eventually results in near total blindness.
The hallmark of the disease is nyctalopia, the inability to see or perceive in dim light. Nyctalopia is accompanied by impairment in visual field and visual acuity, according to Spark.
Even though patients with biallelic mutations in the RPE65 gene have compromised vision, the retinal anatomy is preserved for a comparatively long period. Luxturna supplies a functional copy of RPE65 within the retinal pigment epithelium cells, allowing for restoration of the visual cycle, the company explained.
"Therefore, supplying the missing enzyme can result in restoration of the visual cycle and improvement in vision," Spark said in documents posted on the FDA's website.
If approved, Luxturna would be the first drug available in the U.S. to treat the eye disease.
It also could be the second gene therapy to make it to the U.S. market — following Novartis AG's Kymriah, a chimeric antigen receptor T-cell therapy approved Aug. 30 to treat pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia.
Novartis has been criticized for its $475,000 list price for a single course of treatment of Kymriah.
Spark has not yet disclosed what it will ask patients to pay for Luxturna, if approved.
In an Oct. 10 research note, RBC Capital Markets analyst Matthew Eckler estimated Spark would bank $550 million in worldwide sales at its peak.
Seeking expert advice
Before the FDA makes its decision on Luxturna, which is expected by Jan. 12, 2018, the agency wants a panel of outside experts to weigh in at an Oct. 12 meeting to help regulators untangle questions they have about the product.
Spark's gene therapy demonstrated improvement in vision in patients who received a one-time subretinal injection in the clinical trial on which Luxturna's application was based and the benefit was maintained throughout the one-year follow-up period. However, "it is unclear if the effect decays over time, as longer-term follow-up data is not available," FDA drug reviewers said in documents posted on the agency's website.
Individuals with more advanced disease did not demonstrate any improvement in functional vision over the course of the study, "suggesting that perhaps patients with advanced disease may be less likely to benefit" from Luxturna, they said.
Regulators noted the limitations of the outcomes measure Spark used in the trial — multi-luminance mobility testing, which was designed to assess the ability of a patient to navigate the course accurately and at a reasonable pace at different light levels.
Multi-luminance mobility testing has not been used as an efficacy endpoint in any other clinical studies, the FDA pointed out.
In Spark's study, which tested Luxturna in patients ages 4 to 44 years, a two-light level or more improvement in multi-luminance mobility testing occurred at one year in 11 of the 21 patients, or 52%, using both-treated eyes and 15 of the 21 participants, or 71%, using the first-treated eye, regulators said.
But 30 patients also reported ocular adverse events involving 51 injected eyes, or 63%, following the subretinal injection of Luxturna.
The most serious side effects included endophthalmitis, macular holes, foveal dehiscence, retinal hemorrhage, retinal tears, elevated intraocular pressure and cataract development — events that may have long-term consequences, especially if they were left untreated, the FDA's reviewers said.
What's on FDA's mind
At the Oct. 12 meeting, the FDA wants to hear the opinions from its Cellular, Tissue and Gene Therapies Advisory Committee about the clinical meaningfulness of a two-light level improvement in the multi-luminance mobility testing.
The FDA also is seeking the panel's advice about what may be the optimal disease stage to treat patients in which the benefits of the therapy may outweigh its risks.
In addition, regulators want the panelists to discuss what concerns they have about treating pediatric patients with Spark's gene therapy, given its adverse events, and a reasonable minimal age they would recommend for using the drug.
The agency also wants the committee to weigh in on how the FDA should handle the lack of data on any benefit and the risks of repeat administrations of Luxturna and if the agency should require Spark to provide another study before approving the gene therapy.
Finally, the panel is expected to be asked to vote on whether Luxturna's data provides an overall favorable profile supporting approval.