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Spark Therapeutics Announces U.S. Orphan Drug Designation Amendment and Study Updates for Lead Investigational Gene Therapy

FDA grants request to amend orphan drug designation for voretigene neparvovec to encompass all Inherited Retinal Disease (IRD) caused by biallelic RPE65 mutations, which is aligned with proposed indication

New longer-term, four-year Phase 1 clinical data show durability of effect of one-time administration of investigational voretigene neparvovec

Natural history study confirms degenerative course of IRD caused by biallelic RPE65 mutations and enhances understanding of the clinical significance of voretigene neparvovec clinical trial results

PHILADELPHIA, Jan. 09, 2017 (GLOBE NEWSWIRE) -- Spark Therapeutics (NASDAQ:ONCE), a fully integrated gene therapy company dedicated to challenging the inevitability of genetic disease, today announced new four-year data from a Phase 1 clinical trial and natural history study findings that enhance the understanding of investigational voretigene neparvovec, a one-time adeno-associated viral (AAV) gene therapy for Inherited Retinal Disease (IRD) caused by biallelic RPE65 mutations.

The company also announced that the U.S. Food and Drug Administration (FDA) has granted a request to amend the orphan drug designation for voretigene neparvovec to "the treatment of inherited retinal dystrophy due to biallelic RPE65 mutations." This expanded designation aligns with the proposed indication for voretigene neparvovec. As reported previously, voretigene neparvovec has received breakthrough therapy and orphan product designations from the FDA, as well as orphan product designation from the European Medicines Agency (EMA). Spark Therapeutics has initiated a rolling submission of the Biologics License Application (BLA), which is expected to be completed in early 2017.

Updated Longer-Term Efficacy and Safety Data from Phase 1 Clinical Trial of Voretigene Neparvovec
Mean improvements in functional vision and visual function were maintained through four years as measured by both the multi-luminance mobility test (MLMT) and full field light sensitivity threshold (FST) testing in a Phase 1 clinical trial in which investigational voretigene neparvovec was administered to the contralateral, or second previously uninjected, eye. This cohort of participants (n = 8) received the same dose of voretigene neparvovec that was administered in the Phase 3 trial and would have met the Phase 3 eligibility criteria.

MLMT evaluates functional vision by documenting the participants' ability to navigate a mobility course under a variety of specified light levels ranging from one lux (equivalent to a moonless summer night) to 400 lux (equivalent to an office environment). Results after four years showed a sustained average durability of effect across the Phase 1 clinical trial cohort, with a mean lux score change of 2.4 ± 0.46 at year four, compared to 2.6 ± 0.56 at year one.

Average improvement in FST testing, which reflects underlying physiological function by measuring light sensitivity of the entire visual field, were similarly maintained. Results after four years continued to show a more than 100-fold average improvement in the Phase 1 clinical trial cohort, with light sensitivity measures of -3.82 ± 0.98 log10(candela.m/sec2) at year four, compared to -4.27 ± 1.21 log10(candela.m/sec2) at year one.

"Beyond an initial gain of functional vision seen in 93 percent of all Phase 3 trial participants at year one, these four-year data from the Phase 1 cohort further add to the clinical evidence relating to the potential long-term effect of one administration of investigational voretigene neparvovec on IRD caused by biallelic RPE65 mutations," said Jeffrey D. Marrazzo, chief executive officer of Spark Therapeutics.

Safety results in the clinical program have been consistent to date. No serious adverse events (SAEs) associated with voretigene neparvovec or deleterious immune responses have been observed. There was one SAE in one eye of a Phase 3 participant related to the surgical procedure, rather than to the product candidate. The participant exhibited foveal thinning and a sustained reduction in visual acuity (VA) over the first year of follow-up, but did show an improvement on the MLMT and a gain in FST testing. An additional SAE occurred in one eye of a Phase 1 participant; in this case, the treatment for bacterial endophthalmitis led to elevated intraocular pressure and subsequent optic atrophy.

Natural History Study Shows Early, Profound Vision Loss with Continuous Decline in Patients with IRD Caused by RPE65 Gene Mutations
To bolster knowledge of the natural disease course of IRD due to RPE65 gene mutations and enhance understanding of the clinical significance of the voretigene neparvovec clinical trial results in this disease, Spark Therapeutics conducted a retrospective natural history study (n = 70). The data showed that biallelic RPE65 mutations are characterized by a continuous decline in visual function beginning in early childhood. The study was a retrospective chart review of longitudinal ocular history and visual function testing data (primarily VA and visual field (VF)), designed to describe the natural course of degeneration in individuals with confirmed biallelic mutations in the RPE65 gene. Participants in the study, enrolled from seven centers worldwide, all had confirmed biallelic RPE65 mutations and were followed at the centers for up to 33 years (mean duration of observation time was 7.3 years).

In the natural history study cohort, a statistically significant effect of age on VA (p < 0.001) was observed. While there was individual variability, the rate of decline in VA appeared to accelerate later in the course of disease, presumably corresponding to continued irreparable damage to retinal pigment epithelium and photoreceptor cells. The majority of participants in the natural history cohort were legally blind (VA of 20/200 or worse in the better-seeing eye) by the time they were 18 years of age. There also was a correlation between advancing age and declining VF that was statistically significant (p < 0.0001 for both the III4e and V4e Goldmann test stimuli). As with VA, progressive VF loss adversely impacts functional vision, with the natural history study cohort experiencing a rapid decline in VF during the first and second decades of life.

"These retrospective findings expand our understanding of the progressive decline of visual function, which contributes to decline in functional vision, caused by IRD due to biallelic RPE65 gene mutations over time in this population. Given that genotyping in IRDs has only recently been added to the diagnostic armamentarium, comprehensive natural history studies in patients with autosomal recessive mutations in RPE65 had been lacking," said Katherine A. High, M.D., president and chief scientific officer of Spark Therapeutics. "The natural history data we have generated provide a clear baseline for comparison of the results in the Phase 3 clinical trial, where for example, the participants in the intervention group showed significant improvements in visual field, nearly doubling at year one, while a slight decrease was observed in the control group over the same time period, consistent with the natural history data. Importantly, these data findings help us better understand investigational voretigene neparvovec's demonstrated effect on a progressive disease."

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. Our validated platform successfully has delivered proof-of-concept data with investigational gene therapies in the retina and liver. Our most advanced investigational candidate, voretigene neparvovec, in development for the treatment of biallelic RPE65-mediated IRD, has received orphan designations in the U.S. and European Union, and breakthrough therapy designation in the U.S. The pipeline also includes SPK-7001, in a Phase 1/2 trial for choroideremia, and two hemophilia development programs: SPK-9001 (which also has received both breakthrough therapy and orphan product designations) in a Phase 1/2 trial for hemophilia B being developed in collaboration with Pfizer, and SPK-8011, in a Phase 1/2 trial for hemophilia A to which Spark Therapeutics retains global commercialization rights. To learn more about us and our growing 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 voretigene neparvovec program. 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) the improvements in functional vision and retinal function demonstrated by voretigene neparvovec in our clinical trials may not continue to be sustained over extended periods of time; (ii) the data from our Phase 3 clinical trial of voretigene neparvovec may not support a label for the treatment of RPE65-mediated IRD other than Leber congenital amaurosis (LCA); and (iii) we could experience delays in submitting our regulatory filings of voretigene neparvovec, including our Biologics Licensing Application with FDA and, once submitted, such regulatory filings may not be approved. 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.

Spark Therapeutics Corporate Contacts
Stephen W. Webster, Chief Financial Officer
Daniel Faga, Chief Business Officer
 (855) SPARKTX (1-855-772-7589)

Media Contact Dan Quinn
 Ten Bridge Communications
 (781) 475-7974
dan@tenbridgecommunications.com

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