Investigational LUXTURNA™ (voretigene neparvovec) has been recommended for approval for Patients with Biallelic RPE65-mediated Inherited Retinal Disease. Investigational LUXTURNA has the potential to be both the first pharmacologic treatment for an inherited retinal disease (IRD) and the first gene therapy for a genetic disease in the United States. It is the first adeno-associated viral (AAV) vector investigational candidate to reach this stage of FDA review its clinical program includes up to four years of efficacy data, with observation ongoing.
The U.S. Food and Drug Administration’s (FDA) Cellular, Tissue and Gene Therapies Advisory Committee has unanimously recommended (16-0) approval of LUXTURNA™ (voretigene neparvovec), an investigational, potential one-time gene therapy, for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease (IRD).
“Today’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 IRD,” said Katherine A. High, M.D., president and head of Research and Development, Spark Therapeutics. “The clinical program for LUXTURNA includes patient data that show efficacy for up to four years on endpoints including bilateral multi-luminance mobility test (MLMT) score change and full-field light sensitivity threshold (FST) testing, with observation ongoing. We look forward to continuing to work with FDA as it completes its review of LUXTURNA.”
The advisory committee’s recommendation is based on LUXTURNA’s clinical development program, which includes the first completed randomized, controlled Phase 3 gene therapy clinical trial ever conducted for a genetic disease. In the original Phase 3 intervention group, participants aged four to 44 years on average maintained the functional vision and visual function improvements demonstrated 30 days after LUXTURNA administration through their last annual follow-up visit, as measured by bilateral multi-luminance mobility test (MLMT) score change and full-field light sensitivity threshold (FST) testing.
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 similarly maintained mean improvements. As part of the Biologics License Application (BLA) to FDA, Spark also submitted the results of two Phase 1 clinical trials, a natural history study and a MLMT validation study. Today’s advisory committee vote is non-binding, but FDA will take its recommendation into consideration when reviewing the BLA for LUXTURNA.
“There currently are no pharmacologic treatment options for people living with RPE65-mediated IRD, who in most cases progress to complete blindness,” said Principal Investigator Albert M. Maguire, M.D., professor of ophthalmology at the Scheie Eye Institute at the University of Pennsylvania’s Perelman School of Medicine and attending physician in the Division of Pediatric Ophthalmology at Children's Hospital of Philadelphia. “As a practicing physician who often speaks with patients and families living with IRDs, these conversations have been, up to now, frustrating in that there has been nothing to offer. Today’s advisory committee vote is an important step closer to the day that discussion can include potentially treating the blindness caused by their IRD.”
No serious adverse events (SAEs) associated with LUXTURNA or deleterious immune responses have been observed. Two ocular SAEs were reported in the clinical program, one in Phase 1 and one in Phase 3. The SAE in Phase 3 was related to the surgical procedure, and resulted in foveal thinning and a sustained reduction in visual acuity (VA) in one participant. 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, increased intraocular pressure and retinal tear.
LUXTURNA is under Priority Review with FDA, with an assigned Prescription Drug User Fee Act (PDUFA) date of Jan. 12, 2018. LUXTURNA has received orphan drug, breakthrough therapy and rare pediatric disease designations from FDA. In August 2017, Spark Therapeutics’ Marketing Authorization Application (MAA) for LUXTURNA was validated by European Medicines Agency (EMA). LUXTURNA also has received orphan product designations from EMA.
Christina Fasser, president of Retina International a global umbrella group of 43 patient led organisations concerned with IRDs said ‘The decision of the FDA advisory group to unanimously recommend Luxturna for Patients with Biallelic RPE65-mediated Inherited Retinal Disease represents a significant day for our patient community. This marks the first gene therapy for an IRD and we are extremely hopeful that it will soon become available to those patients who will benefit from it’.
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. The LUXTURNA clinical program overall includes up to four years of efficacy data from a single dose. The overall safety profile has not changed over the period of observation, and has been previously reported (The Lancet 2016; The Lancet 2017).
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 ranging from mild to advanced, and included individuals from age four to 44 years 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 included in the BLA submission 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) score change (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 averaged over both eyes (p=0.001) and the mobility test score change 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 their last annual follow-up visit, as measured by MLMT and FST, with observation ongoing. Average improvement in FST testing observed in the original intervention group at one year was more than 100-fold (or greater than two log units).
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 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. This cohort of participants (n=11) received the same dose of LUXTURNA that was administered in the Phase 3 trial and would have met the Phase 3 eligibility criteria. See the publication of the three-year Phase 1 data in The Lancet.
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. No deleterious immune responses have been observed. 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, increased intraocular pressure and retinal tear.
About RPE65-mediated Inherited Retinal Disease (IRD)
Inherited retinal diseases (also known as inherited retinal dystrophies) are a group of rare blinding conditions caused by one of more than 220 different genes. People living with IRD due to biallelic RPE65 gene mutations often experience night blindness (nyctalopia) due to decreased light sensitivity in childhood or early adulthood and involuntary back-and-forth eye movements (nystagmus). As the disease progresses, individuals may experience loss in their peripheral vision, developing tunnel vision, and eventually, they may lose their central vision as well, resulting in total blindness. Independent navigation becomes severely limited, and vision-dependent activities of daily living are impaired. There are currently no approved pharmacologic treatment options for IRD due to biallelic RPE65 gene mutations.