Spark Therapeutics Announces Publication of Study

PHILADELPHIA, Sept. 06, 2017 (GLOBE NEWSWIRE) -- Spark Therapeutics (NASDAQ: ONCE ), a fully integrated gene therapy company dedicated to challenging the inevitability of genetic disease, today announced that Clinical and Experimental Ophthalmology , a peer-reviewed ophthalmology journal, has published a prospective, observational study that provides robust evidence for the construct and content validity of the multi-luminance mobility test (MLMT) to assess functional vision in people with inherited retinal diseases (IRDs). MLMT was used as the primary endpoint of the Phase 3 clinical 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 IRD.

MLMT measures functional vision, which refers to a person’s ability to perform, on his or her own, visually dependent activities of daily living. Visual function is measured by tests typically performed on each eye individually, such as light sensitivity as measured by full-field light sensitivity threshold (FST) testing, visual acuity and visual field. Measuring functional vision, rather than visual function, may be a more appropriate means to evaluate changes in vision loss in patients with IRDs.

In the study of the mobility test, which was conducted at Children’s Hospital of Philadelphia and sponsored by Spark Therapeutics, construct validity refers to the ability to differentiate participants with normal vision from those with impaired vision. Content validity references the test components of speed and accuracy score at defined levels of illumination during MLMT course navigation runs.

“Traditional mobility measures for people with IRDs lacked approaches to quantify mobility at varying light levels, which is important for people living with biallelic RPE65 -mediated IRD, who progressively lose their ability to perceive light,” said Katherine A. High, M.D., president and chief scientific officer at Spark Therapeutics and co-author of the paper. “MLMT introduced a robust approach to assess functional vision at varying light levels. The study results provide robust evidence for the construct and content validity of MLMT as a tool to assess functional vision in Spark Therapeutics’ clinical study of LUXTURNA.”

The study compared the ability of 29 participants with normal vision and 31 participants diagnosed with an IRD prior to enrollment, all between the ages of four and 40, to navigate a randomized mobility course at varying light levels over the course of one year. Each participant’s course navigation run was recorded on video and graded for both accuracy and time. More than 3,800 videos were recorded and assessed by independent graders across all course navigation runs, which included runs from all the sponsor’s studies using mobility as an endpoint. Twenty-six normal-sighted and 28 visually impaired participants completed four visits over one year.

MLMT demonstrated high overall reproducibility and clearly differentiated visually impaired participants from those with normal vision. All normal-sighted participants passed every MLMT attempt at all tested light levels, but visually impaired participants’ MLMT performances varied widely. Concordance of performance on two baseline visits was high; correlations for accuracy score were 94 percent and 98 percent for the lowest common and highest common lux levels, respectively. Lux is a unit of illumination that measures the amount of light falling onto (illuminating) and spreading over a given surface area. Please refer to the paper, “ Novel mobility test to assess functional vision in patients with inherited retinal dystrophies ,” for the full description of the design and results of this study.

Investigational LUXTURNA is currently under Priority Review with the U.S. Food and Drug Administration (FDA) for the treatment of patients with vision loss due to confirmed biallelic RPE65 mutation-associated retinal dystrophy.

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 test (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 MLMT 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 was similarly 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 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. 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, 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. 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 this disease.

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 Spark Therapeutics, a fully integrated company, strives to challenge the inevitability of genetic disease by discovering, developing and delivering gene therapies that address inherited retinal diseases (IRDs), neurodegenerative diseases, as well as diseases that can be addressed by targeting the liver, such as hemophilia. Spark Therapeutics has ongoing clinical trials investigating gene therapies in hemophilia A and B.  SPK-8011  is in an ongoing, dose-escalation Phase 1/2 clinical trial as a potential one-time therapy for hemophilia A. The company retains full global commercialization rights to the  SPK-FVIII  program for hemophilia A.  SPK-9001 , which has received both breakthrough therapy and orphan product designations by FDA, and access to the PRIority MEdicines (PRIME) Program by EMA, is in a Phase 1/2 clinical trial for hemophilia B and is being developed in collaboration with Pfizer. Our most advanced investigational candidate, with proposed trade name LUXTURNA™ (voretigene neparvovec), is currently under Priority Review with FDA for the treatment of biallelic  RPE65 -mediated IRD and has been designated as a drug for a rare pediatric disease. The MAA for LUXTURNA has been submitted to EMA for the treatment of vision loss due to Leber congenital amaurosis or retinitis pigmentosa caused by confirmed biallelic  RPE65  mutations. LUXTURNA has received breakthrough therapy and orphan product designations from FDA and orphan product designations from EMA. The pipeline also includes  SPK-7001  in an ongoing Phase 1/2 clinical trial for choroideremia. For more information on our pipeline, visit www.sparktx.com . 

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 candidates, including LUXTURNA™ (voretigene neparvovec),  SPK-7001 , SPK-9001  and  SPK-8011 . 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 for LUXTURNA may not be approved by the FDA or EMA, respectively; (ii) the data from our Phase 3 clinical trial of LUXTURNA may not support labeling for all biallelic  RPE65  mutations other than Leber congenital amaurosis (LCA); and (iii) the improvements in functional vision demonstrated by LUXTURNA in our clinical trials may not be sustained over extended periods of time. 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 Therapeutics undertakes no duty to update this information unless required by law.

Investor Contact: Ryan Asay Ryan.asay@sparktx.com (215) 239-6424 Media Contact: Monique da Silva Monique.dasilva@sparktx.com  (215) 282-7470