Potential for first gene therapy for a genetic disease to be approved in both the U.S. and EU
Spark Therapeutics, a fully integrated gene therapy company dedicated to challenging the inevitability of genetic disease, announced today that it has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for LUXTURNA™, the proposed trade name for voretigene neparvovec, an investigational, one-time gene therapy for the treatment of patients with vision loss due to Leber congenital amaurosis or retinitis pigmentosa caused by confirmed biallelic RPE65 mutations. The MAA includes data from three clinical trials that enrolled 41 participants with RPE65-mediated inherited retinal dystrophy (IRD), including the first randomized, controlled Phase 3 trial for a gene therapy for a genetic disease.
Once EMA has validated the application, the review period will begin. Spark Therapeutics has previously received orphan product designations for LUXTURNA from EMA for the treatment of both Leber congenital amaurosis and retinitis pigmentosa.
“Today’s announcement represents an important moment in the effort to treat blindness caused by inherited retinal degenerative diseases," said Christina Fasser, president of Retina International, an umbrella organization of more than 43 patient organizations world-wide promoting research in view to find a cure to inherited retinal degenerative diseases. "We are excited about the potential of this application to bring the first gene therapy to patients with this form of IRD.”
The investigational therapy is under Priority Review with the U.S. Food and Drug Administration, with an assigned Prescription Drug User Fee Act (PDUFA) date of Jan. 12, 2018.
“With LUXTURNA now in regulatory review on both sides of the Atlantic, we are building out our medical and commercial infrastructure to prepare to bring investigational LUXTURNA to patients in the U.S. and Europe,” said John Furey, chief operating officer of Spark Therapeutics. “For the first time, these individuals, who eventually will progress to complete blindness, have hope for a potential treatment option that may restore their vision. We remain steadfast in our commitment to bring this important investigational therapy to patients in the EU with vision loss due to Leber congenital amaurosis or retinitis pigmentosa caused by confirmed biallelic RPE65 mutations.”
Clinical Trial Overview of LUXTURNA™ (voretigene neparvovec)
The safety and efficacy of LUXTURNA were assessed in two open-label Phase 1 trials, which continue to follow participants who received LUXTURNA between 2007 and 2012, and one open-label, randomized, controlled Phase 3 trial. Following the one-year control period of the Phase 3 study, all control participants elected to cross over and received LUXTURNA; long-term safety and efficacy continue to be assessed in the Phase 3 participants who received LUXTURNA between 2013 and 2015. The clinical trial program included 41 participants with vision loss aged four to 44 at the time of first administration. Confirmed biallelic RPE65 mutations and the presence of sufficient viable retinal cells were established in all participants.
LUXTURNA Phase 3 clinical trial data, including data from the intent-to-treat population of all randomized participants through the one-year time point, were published in The Lancet. Results reported in The Lancet showed a statistically significant and clinically meaningful difference between intervention (n=21) and control participants (n=10) at one year, per the clinical trial’s primary endpoint, mean bilateral multi-luminance mobility testing (MLMT) change score (difference of 1.6; 95% CI, 0.72, 2.41; p=0.0013). In addition, participants who received LUXTURNA showed a marked difference compared to control participants across the first two secondary endpoints: full-field light sensitivity threshold (FST) testing averaged over both eyes (p=0.0004) and the mobility test change score for the first injected eye (p=0.0005). A third secondary endpoint, the change in visual acuity (VA) averaged over both eyes, was not statistically significant between intervention and control participants (p=0.17).
On average, participants in the original Phase 3 intervention group maintained functional gains observed by the day-30 visit through at least two years, as measured by MLMT and FST. The more than 100-fold (or greater than two log units) average improvement in FST testing observed in the original intervention group at one year, similarly, was maintained through at least two years.
In continuation of the trial to include crossover of the control group to receive LUXTURNA, 93 percent (27 of 29) of all Phase 3 trial participants injected with LUXTURNA saw a gain of functional vision as assessed by bilateral MLMT over the follow-up period of at least one year from administration of LUXTURNA to each eye. Additionally, 72 percent (21 of 29) of all Phase 3 trial participants receiving LUXTURNA successfully completed MLMT at the lowest light level evaluated (1 lux) at one year.
Data from a cohort of the Phase 1 clinical trial, in which investigational LUXTURNA was administered to the contralateral, or second previously uninjected eye, showed mean improvements in functional vision and visual function. These improvements were maintained through at least three years, as measured by both MLMT and FST testing. This cohort of participants (n=8) received the same dose of LUXTURNA that was administered in the Phase 3 trial and would have met the Phase 3 eligibility criteria.
No serious adverse events (SAEs) associated with LUXTURNA or deleterious immune responses have been observed. Two ocular SAEs were reported in the clinical program. There was one SAE related to the surgical procedure in one eye of a Phase 3 participant, in which there was foveal thinning and a sustained reduction in VA. One additional ocular SAE was reported in one eye of a Phase 1 participant in which the treatment for bacterial endophthalmitis led to elevated intraocular pressure and subsequent optic atrophy. There were three non-serious AEs of retinal deposits (subretinal precipitate) in three participants (three eyes) that were considered to be related to LUXTURNA. All three of these events were mild in intensity, transient in nature and resolved without consequences. The most common adverse reactions related to LUXTURNA reported in 10 percent or greater of the combined Phase 1 and Phase 3 trial participants included conjunctival hyperemia, cataract, intraocular pressure increased, and retinal tear.