Three-year Follow-up Phase 3 Data Provide Additional Information on Efficacy, Durability and Safety of Investigational LUXTURNA™ (voretigene neparvovec) in Patients with Biallelic RPE65-mediated Inherited Retinal Disease

PHILADELPHIA, Nov. 10, 2017 (GLOBE NEWSWIRE) -- Spark Therapeutics (NASDAQ:ONCE), a fully integrated gene therapy company dedicated to challenging the inevitability of genetic disease, today announced new three-year follow-up data from the continuing Phase 3 trial 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). These data were presented at the American Academy of Ophthalmology (AAO) Retina Subspecialty Day by Albert M. Maguire, M.D., a principal investigator of the Phase 3 clinical trial, 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.

“These data provide additional support information on the efficacy, durability and safety of investigational LUXTURNA, showing no statistically significant change in the primary endpoint from the initial gain in functional vision at the three-year time point for the original intervention group and at the two-year time point for the original control group after crossover,” said Katherine High, M.D., president and head of Research and Development at Spark Therapeutics. “We believe the data from these participants further support the positive benefit-risk profile of investigational LUXTURNA for patients with vision loss due to confirmed biallelic RPE65-mediated IRD.”

Functional vision is considered a key component in a person’s ability to perform daily living tasks and can be assessed through orientation and mobility testing and other measurements. 
           
Three years after the one-time administration of investigational LUXTURNA to both eyes, the cohort of 20 participants in the modified intent-to-treat (mITT) intervention group maintained the average improvement demonstrated at one year, as measured by multi-luminance mobility test (MLMT) score change, the primary endpoint, and full-field light sensitivity threshold (FST) testing, a secondary endpoint. The mean MLMT improvement measured 1.8 lux levels at three years, compared to 1.9 lux levels at one year. The more than 100-fold average improvement in FST testing observed in the intervention group at one year similarly was maintained through at least three years. Additionally, the increase in visual acuity (VA) averaged over both eyes, a secondary endpoint which was not statistically significant at one year, has been stable for at least three years for participants in the intervention cohort, at an eight-letter improvement using standardized AV testing.  

The mean change from baseline in Goldmann III4e test stimulus, a pre-specified exploratory measure of visual field (VF), was 282.2 sum total degrees averaged over both eyes for participants in the intervention group at the three-year time point, compared to a mean change of 302.1 sum total degrees at one year.

Likewise, all participants in the control group (n=9), who after one year of undergoing observation with the same retinal and visual function testing as the original intervention group elected to cross over and receive LUXTURNA in both eyes, maintained the same mean MLMT score change of 2.1 lux levels one year following the one-time injection through two years after administration. The more than 100-fold average improvement in FST testing observed in the crossover group at one year similarly was maintained through at least two years. Similarly, in the crossover group, the increase in VA averaged over both eyes, was not statistically significant at one year, but has remained improved compared to baseline for at least two years.

The mean change from baseline in Goldmann VF was 182.6 sum total degrees averaged over both eyes for participants in the crossover group at the two-year time point, compared to a mean change of 194.3 sum total degrees at one year.

No new serious adverse events (SAEs) associated with LUXTURNA or deleterious immune responses were observed. Most ocular adverse events (AEs) were mild in severity, with the most common being cataract, elevated intraocular pressure, retinal deposits and retinal tears. One participant in the crossover group experienced an SAE related to the surgical procedure in which there was foveal thinning and a sustained reduction in VA. Three participants in the intervention group had SAEs unrelated to study participation.

LUXTURNA is under Priority Review with the U.S. Food and Drug Administration (FDA), with an assigned Prescription Drug User Fee Act (PDUFA) date of Jan. 12, 2018. In October 2017, FDA’s Cellular, Tissue and Gene Therapies Advisory Committee unanimously recommended (16-0) approval of LUXTURNA. The advisory committee’s recommendation is non-binding, but FDA generally considers such recommendations when reviewing a Biologics License Application (BLA). 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.

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 (2016).

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, often disproportionally affecting children and young adults. 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.

About Gene Therapy
Gene therapy is an investigational approach to treat or prevent genetic disease by seeking to augment, replace or suppress one or more mutated genes with functional copies. It addresses the root cause of an inherited disease by enabling the body to produce a protein or proteins necessary to restore health or to stop making a harmful protein or proteins, with the potential of bringing back function in the diseased cells and slowing disease progression. To deliver the functional gene into the cell, a vector is used to transport the desired gene and is delivered either intravenously (IV) or injected into specific tissue. The goal is to enable, through the one-time administration of gene therapy, a lasting therapeutic effect.

About Spark Therapeutics
At Spark Therapeutics, a fully integrated company committed to discovering, developing and delivering gene therapies, we challenge the inevitability of genetic diseases, including blindness, hemophilia and neurodegenerative diseases. We have successfully applied our technology directed to the retina and liver, and currently have four programs in clinical trials or under regulatory review, including the first potential gene therapy for a genetic disease in the United States and product candidates that have shown promising early results in patients with hemophilia. At Spark, we see the path to a world where no life is limited by genetic disease. For more information, visit www.sparktx.com, and follow us on Twitter and LinkedIn.

Cautionary note on forward-looking statements
This release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the company's product candidate LUXTURNA™ (voretigene neparvovec). The words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘expect,’’ ‘‘intend,’’ ‘‘may,’’ ‘‘plan,’’ ‘‘predict,’’ ‘‘will,’’ ‘‘would,’’ ‘‘could,’’ ‘‘should,’’ ‘‘continue’’ and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Any forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that: (i) our BLA or MAA submitted for LUXTURNA may not be approved by FDA or EMA, respectively; (ii) the data from our Phase 3 clinical trial of LUXTURNA may not support US labeling for all biallelic RPE65 mutations other than Leber congenital amaurosis (LCA) or retinitis pigmentosa (RP); (iii) the improvements in functional vision demonstrated by LUXTURNA in our clinical trials may not be sustained over extended periods of time; and (iv) any one or more of our product candidates in preclinical or clinical development will not successfully be developed and commercialized. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the "Risk Factors" section, as well as discussions of potential risks, uncertainties and other important factors, in our Annual Report on Form 10-K, our Quarterly Reports on Form 10-Q and other filings we make with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Spark undertakes no duty to update this information unless required by law.