Spark Therapeutics Announces New Preclinical Data for Pompe Disease Gene Therapy Candidate
Data from IND-enabling studies in three species support moving SPK-3006 into the clinic in 2019

PHILADELPHIA, Oct. 08, 2018—Spark Therapeutics, a fully integrated, commercial gene therapy company dedicated to challenging the inevitability of genetic disease, today announced new data for SPK-3006, an investigational liver-directed adeno-associated viral (AAV) gene therapy for Pompe disease. The data from the Investigational New Drug (IND)-enabling studies were presented Saturday, Oct. 6, 2018, in an oral presentation, “Safety and efficacy evaluation of investigational liver gene transfer for secretable GAA in the treatment of Pompe disease,” during the Late Breaking Session at the 23rd International Congress of the World Muscle Society in Argentina.

Pompe disease is a rare, inherited lysosomal storage disease. It is a progressive, often life-limiting disease caused by the buildup of a complex sugar, glycogen, in the body’s cells. Mutations in the gene encoding acid alpha-glucosidase (GAA) result in deficiencies of the enzyme GAA and limit the breakdown of glycogen. The accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function. The skeletal muscle cells (including those used in respiration) and heart cells are most affected by Pompe disease.
Unlike the current standard of care, enzyme replacement therapy (ERT), where patients receive recombinant GAA infusions every two weeks, Spark’s one-time investigational gene therapy, SPK-3006, has been engineered to produce a modified GAA enzyme that is secreted from the liver with high efficiency. This is hypothesized to lower immunogenicity to GAA and, in preclinical models, has been shown to sustain plasma levels of GAA to provide increased uptake in muscle tissue throughout the body and more efficiently break down glycogen.
Spark Therapeutics licensed the intellectual property for the transgene in SPK-3006 from Genethon in 2017. Preclinical studies in a Pompe disease model demonstrated a greater therapeutic response and a lower immunogenicity profile of secretable GAA expressed by this transgene in liver cells following AAV gene transfer compared to both native GAA expressed by the liver as well as native GAA expressed directly in muscle tissue.

Preclinical studies evaluating activity of the secretable, modified GAA enzyme found in SPK-3006 in acid alpha-glucosidase knockout (Gaa-/-) mice showed decreased glycogen accumulation, increased survival and improved cardiac, respiratory and muscle function. In these studies, animals were followed up for up to 10 months after gene transfer and no vector-related toxicities were observed. Importantly, the induced liver expression of secretable GAA demonstrated greater ability in restoring muscle strength compared to the standard of care regimen of 20 mg/kg bi-weekly ERT. Secretable GAA was significantly better than ERT in breaking down glycogen in refractory muscle groups, including quadriceps and triceps.
Additionally, a single infusion of SPK-3006 at three ascending doses in a non-human primate (NHP) study conducted by Spark Therapeutics demonstrated dose-dependent expression of GAA in plasma. Long-term follow up of NHPs following infusion of SPK-3006 is ongoing, with a six-month follow up to date and no observed vector-related toxicities.

“We are capitalizing on our proven and proprietary AAV gene therapy platform to target and use liver cells to consistently express GAA in the plasma of animals. Early preclinical data suggest sustained plasma levels of GAA facilitate greater uptake into muscle tissue throughout the body, efficient clearance of glycogen, as well as improved restoration of GAA muscle strength when compared to standard of care,” said Federico Mingozzi, Ph.D., chief scientific officer at Spark Therapeutics. “In these studies, expression of GAA from hepatocytes was considerably less immunogenic because of an induction of immunological tolerance mediated by the liver rather than the muscle. To date, IND-enabling preclinical studies support our approach, leading us to plan for the initiation of a Phase 1/2 clinical trial to assess the safety of this investigational gene therapy in 2019.”

Spark Therapeutics has conducted a pre-IND meeting regarding SPK-3006 with FDA. After completing an ongoing Good Laboratory Practice (GLP) toxicology and biodistribution study, Spark Therapeutics will submit an IND application and Clinical Trial Application (CTA) to regulatory agencies and initiate a U.S. and EU Phase 1/2 clinical trial of SPK-3006 in adult patients in 2019.

About SPK-3006 for Pompe disease
SPK-3006 is an investigational liver-directed AAV gene therapy for Pompe disease. SPK-3006 has been engineered to produce a modified enzyme that is secreted from the liver, which may sustain GAA plasma levels and lower immunogenicity to GAA to potentially provide greater uptake in muscle tissue. The transgene was in-licensed in 2017 from Genethon, a non-profit research and development organization dedicated to the development of gene therapies for orphan genetic diseases from research to clinical validation. Spark Therapeutics retains global commercialization rights to SPK-3006.

About Spark Therapeutics
At Spark Therapeutics, a fully integrated, commercial company committed to discovering, developing and delivering gene therapies, we challenge the inevitability of genetic diseases, including blindness, hemophilia, lysosomal storage disorders and neurodegenerative diseases. We have successfully applied our technology in the first FDA-approved gene therapy in the U.S. for a genetic disease, and currently have three programs in clinical trials, including 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, and follow us on Twitter and LinkedIn.

Spark Therapeutics 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 SPK-3006 program. 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) the data for SPK-3006 IND-enabling studies may not be sustained; (ii) continuous exposure to GAA via gene therapy may not result in more stable clearance of glycogen; (iii) AAV-mediated liver gene transfer of secretable GAA may not result in lower immunogenicity to GAA or sustain plasma levels of GAA to provide increased uptake in muscle tissue or efficient clearance of glycogen; (iv) AAV gene transfer does not have a greater therapeutic response and a lower immunogenicity profile compared to native GAA expressed by the liver or native GAA expressed directly in muscle tissue; (v) our preliminary results of scale-up to non-human primates supporting the initiation of clinical studies of SPK-3006 in humans may not be sustained; (vi) we may not submit an IND application or Clinical Trial Application or initiate a U.S. and EU Phase 1/2 clinical trial in adult patients when expected or at all. 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 U.S. 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.