Spark Therapeutics, Inc.: 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, 2018-01-24 22:00 CET (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. 

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