Spark Therapeutics Enters into a Licensing and Supply Agreement for Investigational Voretigene Neparvovec Outside the U.S.

Novartis Pharmaceuticals will commercialize investigational voretigene neparvovec when and if approved in Europe and all other markets outside the U.S.; Spark Therapeutics retains U.S. commercial rights for LUXTURNA™ (voretigene neparvovec-ryzl)

Agreement leverages Novartis’ extensive ex-US ophthalmology capabilities and infrastructure to the benefit of patients outside of U.S.

Spark Therapeutics to receive $105 million as an upfront fee and is eligible to receive up to $65 million in milestone payments, as well as receive a royalty on net sales outside the U.S.

PHILADELPHIA, Jan. 24, 2018 (GLOBE NEWSWIRE) -- Spark Therapeutics (NASDAQ:ONCE), a fully integrated gene therapy company dedicated to challenging the inevitability of genetic disease, today announced it has entered into a licensing agreement with Novartis Pharmaceuticals to develop and commercialize investigational voretigene neparvovec outside the U.S., while Spark Therapeutics will continue to exclusively commercialize LUXTURNA™ (voretigene neparvovec-ryzl) in the U.S. Under the agreement, Spark Therapeutics will retain regulatory responsibility for obtaining European Medicines Agency approval for investigational voretigene neparvovec. Spark Therapeutics also entered into a separate agreement to manufacture and supply investigational voretigene neparvovec to Novartis. No other programs in Spark Therapeutics’ pipeline are part of this agreement.

Under the terms of the licensing agreement, Novartis will pay Spark Therapeutics $105 million in cash as an upfront fee. Spark Therapeutics is eligible to receive up to an additional $65 million in cash milestone payments based on near-term European Regulatory Agency (EMA) regulatory approval and initial sales outside the U.S. in certain markets. Spark Therapeutics is also entitled to receive royalty payments on net sales of investigational voretigene neparvovec outside the U.S.

“By leveraging Novartis’ large, existing commercial and medical infrastructure in ophthalmology, as well as its commitment to commercializing genetic-based medicines, we help ensure that more patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy who live outside the U.S., and importantly outside of Europe, have access to investigational voretigene neparvovec,” said Dan Faga, chief business officer, Spark Therapeutics. “We intend to use the proceeds from this transaction to continue to develop our robust pipeline of investigational gene therapies to create a path to a world where no life is limited by genetic disease.”

Indication and Important Safety Information for LUXTURNA
LUXTURNA™ (voretigene neparvovec-rzyl) is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Patients must have viable retinal cells as determined by the treating physicians.

Warnings and Precautions

• Endophthalmitis may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering LUXTURNA, and monitor for and advise patients to report any signs or symptoms of infection or inflammation to permit early treatment of any infection.
• Permanent decline in visual acuity may occur following subretinal injection of LUXTURNA. Monitor patients for visual disturbances.
• Retinal abnormalities may occur during or following the subretinal injection of LUXTURNA, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, and retinal hemorrhage. Monitor and manage these retinal abnormalities appropriately. Do not administer LUXTURNA in the immediate vicinity of the fovea. Retinal abnormalities may occur during or following vitrectomy, including retinal tears, epiretinal membrane, or retinal detachment. Monitor patients during and following the injection to permit early treatment of these retinal abnormalities. Advise patients to report any signs or symptoms of retinal tears and/or detachment without delay.
• Increased intraocular pressure may occur after subretinal injection of LUXTURNA. Monitor and manage intraocular pressure appropriately.
• Expansion of intraocular air bubbles Instruct patients to avoid air travel, travel to high elevations or scuba diving until the air bubble formed following administration of LUXTURNA has completely dissipated from the eye. It may take one week or more following injection for the air bubble to dissipate. A change in altitude while the air bubble is still present can result in irreversible vision loss. Verify the dissipation of the air bubble through ophthalmic examination.
• Cataract Subretinal injection of LUXTURNA, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression.

Adverse Reactions

• In clinical studies, ocular adverse reactions occurred in 66% of study participants (57% of injected eyes), and may have been related to LUXTURNA, the subretinal injection procedure, the concomitant use of corticosteroids, or a combination of these procedures and products.
• The most common adverse reactions (incidence ≥ 5% of study participants) were conjunctival hyperemia (22%), cataract (20%), increased intraocular pressure (15%), retinal tear (10%), dellen (thinning of the corneal stroma) (7%), macular hole (7%), subretinal deposits (7%), eye inflammation (5%), eye irritation (5%), eye pain (5%), and maculopathy (wrinkling on the surface of the macula) (5%).

Immunogenicity
Immune reactions and extra-ocular exposure to LUXTURNA in clinical studies were mild. No clinically significant cytotoxic T-cell response to either AAV2 or RPE65 has been observed. Study participants received systemic corticosteroids before and after subretinal injection of LUXTURNA to each eye, which may have decreased the potential immune reaction to either AAV2 or RPE65.

Pediatric Use
Treatment with LUXTURNA is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and LUXTURNA would potentially be diluted or lost during the cell proliferation. The safety and efficacy of LUXTURNA have been established in pediatric patients. There were no significant differences in safety between the different age subgroups.

Please see the full U.S. Prescribing Information for LUXTURNA here.

Clinical Trial Overview of LUXTURNA™ (voretigene neparvovec-rzyl)
The safety and efficacy of LUXTURNA were assessed in one open-label, dose-exploration Phase 1 safety study (n=12) and one open-label, randomized, controlled Phase 3 efficacy and safety study (n=31) in pediatric and adult participants (range 4 to 44 years) with biallelic RPE65 mutation-associated retinal dystrophy and sufficient viable retinal cells.

Of the 31 participants enrolled in the Phase 3 study, 21 were randomized to receive subretinal injection of LUXTURNA and 10 were randomized to the control (non-intervention) group. One participant in the intervention group discontinued from the study prior to treatment and one participant in the control group withdrew consent and was discontinued from the study. All nine participants randomized to the control group elected to crossover and receive LUXTURNA after one year of observation. All participants in these studies continue to be followed for long-term safety and efficacy. LUXTURNA Phase 3 clinical trial data, including data from the intervention group of all randomized participants through the one-year time point has been previously reported in (The Lancet).

The efficacy of LUXTURNA in the Phase 3 study was established based on the multi-luminance mobility test (MLMT) score change from baseline to one year. MLMT was designed to measure changes in functional vision as assessed by the ability of a participant to navigate a course accurately and at a reasonable pace at seven different levels of illumination, ranging from 400 lux (corresponding to a brightly lit office) to one lux (corresponding to a moonless summer night). Each light level was assigned a score ranging from zero to six, with a higher score indicating that a participant could pass MLMT at a lower light level. A score of negative one was assigned to participants who could not pass MLMT at a light level of 400 lux. MLMT score change was defined as the difference between the score at baseline and the score at one year with a positive score change indicating that a participant was able to complete MLMT at a lower light level. Additional clinical outcomes included white light full-field light sensitivity threshold (FST) testing and visual acuity.

LUXTURNA Phase 3 clinical study results showed a statistically significant difference between the intervention group (n=21) and control participants (n=10) at one year in median bilateral MLMT score change (intervention minus control group difference of 2; p=0.001) and median first-treated eye MLMT score change (intervention minus control group difference of 2; p=0.003). After crossing over to receive LUXTURNA, participants in the control group showed a similar response to those in the intervention group. The median bilateral MLMT score change of two was observed for the intervention group at the 30-day timepoint. This change score has been sustained for at least three years for the original intervention group and at least two years in the crossover group in the Phase 3 clinical study. In addition, participants who received LUXTURNA showed a statistically significant improvement from baseline to one year in white light FST in the intervention group compared to the control group. The change in visual acuity from baseline to one year was not significantly different between the intervention and control participants.

The U.S. Prescribing Information for LUXTURNA includes the following Warnings and Precautions: endophthalmitis; permanent decline in visual acuity; retinal abnormalities; increased intraocular pressure; expansion of intraocular air bubbles; and cataract. The most common adverse reactions (incidence ≥ 5%) were conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), macular hole, subretinal deposits, eye inflammation, eye irritation, eye pain and maculopathy (wrinkling on the surface of the macula).

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 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 www.sparktx.com, and follow us on Twitter and LinkedIn.

Spark Cautionary Note on Forward-looking Statement
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 LUXTURNA™ (voretigene neparvovec-rzyl). 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 licensing and supply agreement will not facilitate faster access to voretigene neparvovec for patients globally who do not have access to genetically based treatment options, (ii) our MAA submitted for LUXTURNA may not be approved by EMA; (iii) voretigene neparvovec may not be approved in any markets outside of the U.S.; (iv) upon approval, Novartis may not be successful in commercializing or selling voretigene neparvovec in one or more markets; and (v) we may not receive any additional milestone or royalty payments from Novartis. 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.