Spark Therapeutics is on track to win FDA approval later this year to market the first gene therapy ever authorized to treat an inherited disease in the U.S., following an advisory committee’s unanimous recommendation yesterday in favor of the company’s Luxturna™ (voretigene neparvovec).

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 16 to 0 to recommend approval of Spark’s lead candidate Luxturna, after concluding that the gene therapy’s benefits outweighed its risks. Luxturna is indicated as a potential one-time gene therapy for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal dystrophies, a group of rare blinding conditions caused by one of more than 220 different genes.

The FDA usually, but not always, follows the recommendations of its advisory committees. Luxturna is under Priority Review with the agency, which has assigned a Prescription Drug User Fee Act (PDUFA) target decision date of January 12, 2018.

“(Yesterday’s) unanimous advisory committee vote recommending the approval of Luxturna moves us closer to bringing this investigational adeno-associated viral (AAV) vector gene therapy to patients with vision loss due to confirmed biallelic ,RPE65-mediated inherited retinal disease,” Katherine A. High, M.D., Spark’s president and head of R&D, said in a statement. “We look forward to continuing to work with the FDA as it completes its review of Luxturna.”

Spark has based its Biologics License Application (BLA) for Luxturna on positive safety and efficacy results from an open-label, randomized, controlled Phase III trial assessing the gene therapy in inherited retinal dystrophy patients with a confirmed genetic diagnosis of biallelic RPE65 gene mutations and two open-label Phase I trials—a natural history study and a multiluminance mobility testing (MLMT) validation study—that continue to follow participants who received Luxturna between 2007 and 2012.

According to results published in July in The Lancet, the Spark-funded Phase III study showed statistically significant and clinically meaningful improvement following one year of treatment in the 21 patients receiving Luxturna—compared with 10 control patients—in the trial’s primary endpoint of mean bilateral MLMT change score.

The mean bilateral MLMT change score was 1.8 light levels for Luxturna-treated patients, compared with 0.2 for the control group, researchers reported in Efficacy and Safety of Voretigene Neparvovec (AAV2-hRPE65v2) in Patients with RPE65-Mediated Inherited Retinal Dystrophy: A Randomised, Controlled, Open-Label, Phase 3 Trial.”  Eleven of the 21 Luxturna-treated patients using both-treated eyes and 15 of the 21 using their first treated eye showed MLMT improvement of two light levels or more—a statistically significant improvement over control patients.

MLMT is designed to evaluate functional vision by documenting patients’ ability to navigate a mobility course under a variety of specified light levels ranging from one light level or “lux” (a moonless summer night) to 400 lux (an office environment).

Questions from FDA Staffers

Yet a review by FDA staffers questioned whether enough data existed to justify the novel outcome measure, how the MLMT score related to daily living activities, and whether the improvement seen in the study could be sustained or decline beyond one year, in the absence of long-term data.

Following the one-year control period of the Phase III study, all control participants elected to cross over and received Luxturna.

According to Spark, two secondary endpoints showed statistically significant improvement—full-field light sensitivity threshold (FST) testing averaged over both eyes and the mobility test score change for the first injected eye.

However, a third secondary endpoint, the change in visual acuity (VA) averaged over both eyes, did not demonstrate statistical significance between intervention and control participants. At one year, VA improvement of LogMAR 0.3 occurred in 11 (55%) of the first-treated eyes and 4 (20%) of the second-treated eyes, while no control patient had VA improvement in either eye. Yet mean VA changes were not significantly different for either first- or the second-treated eyes over the duration of the study.

The FDA raised concerns about the third secondary endpoint in a staff report to the advisory committee.

“The MLMT score when both eyes are used in testing is almost always a representation of the better-seeing eye. Consequently, with an endpoint using both eyes, a subject could have improvement in one treated eye, lose all sight in the other treated eye, and still be considered to have successfully improved following treatment,” the FDA staff report asserted. “This concern led FDA to recommend co-primary efficacy endpoints, i.e., MLMT score change using both eyes and MLMT score change using the first eye.”

Spark has also cited statistical significance on another endpoint specified by protocol, using the Goldmann III4e test stimulus to measure the visual field area of the original intervention group. That measure nearly doubled in Luxturna patients a year following treatment, while the control group showed a slight decrease over the same time period. 

Luxturna’s clinical program includes up to four years of efficacy data from a single dose, Spark added.

Luxturna has received the FDA’s orphan drug, breakthrough therapy, and rare pediatric disease designations—as well as orphan designations in the EU, where the European Medicines Agency is reviewing Spark’s Marketing Authorization Application for the gene therapy, an application validated in August.

Spark Therapeutics halted trading in its stock yesterday pending the advisory committee decision, the second time in three months that an FDA panel has moved toward approval of a pace-setting gene therapy. On July 12, another advisory committee unanimously recommended in favor of Novartis’ chimeric antigen receptor T-cell (CAR-T) treatment Kymriah™ (tisagenlecleucel), setting the stage for full agency approval on August 30.

“Congrats $ONCE,” tweeted Brad Loncar, CEO of Loncar Investments, yesterday at 3:39 p.m. “We've been watching history unfold in medicine this year. Pretty sweet.”

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