Spark Therapeutics announced that the FDA has accepted for filing the biologics license application (BLA) and granted priority review for voretigene neparvovec, an investigational, potential one-time gene therapy candidate for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease (IRD). The investigational gene therapy, which has the proposed trade name Luxturna (voretigene neparvovec), has the potential to be both the first pharmacologic treatment for IRD and the first gene therapy for a genetic disease in the United States.
Priority Review is granted to therapeutics that would offer major advances over existing therapies or would provide a treatment where no adequate therapy exists. FDA’s goal for taking an action on priority review applications is 6 months. For the review of Luxturna, FDA has assigned a PDUFA date of Jan. 12, 2018.
“FDA acceptance for filing of our BLA for Luxturna is an important development for people living with RPE65-mediated IRD, a significant milestone for the gene therapy field, and a strong testament to the dedication of our collaborators and employees,” Jeffrey D. Marrazzo, chief executive officer of Spark Therapeutics, said in a company news release. “As we work closely with FDA in the months ahead, we will remain steadfast in our commitment to bring this important investigational therapy to people living with RPE65-mediated IRD who currently have no pharmacologic treatment options.”
Investigational Luxturna is intended to be administered one time per eye in patients with vision loss due to biallelic RPE65-mediated IRD. A natural history study has shown that people with this IRD eventually progress to complete blindness.
“Today’s announcement is an important and exciting step forward in the effort to treat blindness caused by inherited retinal diseases,” Gordon Gund, co-founder and chairman emeritus, Foundation Fighting Blindness (FFB), a nonprofit organization focused on research for preventing and treating blindness caused by IRDs, said in the news release. “While we await the FDA review process, it is fitting to note that FFB is proud to have been a part of the early support of the research that led to the development of this potential therapy.”
Luxturna Clinical Trial Overview
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 1-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 4 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 1-year time point, were published in The Lancet.
Results 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=0.001). 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 (P<0.001) and the mobility test change score for the first injected eye (P=0.001). 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 2 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 1 year, similarly, was maintained through at least 2 years.
In continuation of the trial to include crossover of the control group to receive Luxturna, 93 percent (27 of 29) of all treated phase 3 trial participants saw a gain of functional vision as assessed by bilateral MLMT over the follow-up period of at least 1 year from administration of Luxturna to each eye. Additionally, 72% (21 of 29) of all phase 3 trial participants receiving Luxturna successfully completed MLMT at the lowest light level evaluated (1 lux) at 1 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 3 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 deposit (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.