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Spark Therapeutics, Inc.
Jefferies 2016 Global Healthcare Conference June 10, 2016
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Forward-looking statements
This presentation includes ‘‘forward-looking statements,” within the meaning of the Private Securities Litigation Reform Act of 1995, that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, expectations regarding the clinical development of our product candidates, future operations, future financial position, future revenue, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘estimate,’’ ‘‘expect,’’ ‘‘intend,’’ ‘‘may,’’ ‘‘plan,’’ ‘‘predict,’’ ‘‘project,’’ ‘‘target,’’ ‘‘potential,’’ ‘‘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. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make as a result of a variety of risks and uncertainties, including those described in the ‘‘Risk Factors’’ section of our public filings with the Securities and Exchange Commission. We do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.
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Validated gene therapy platform: proof-of-concept data in the eye and liver Expertise in selection, design, manufacture and formulation of highly optimized therapies
Voretigene neparvovec for RPE65-mediated inherited retinal diseases (IRDs) Pivotal, randomized, controlled Phase 3 (P3) trial was statistically and clinically significant 1 year data from P3 crossover and 2 year data from P3 patients expected in mid-2016 Rolling BLA initiated with path to potential approval in 2017
Hemophilia B data at initial low dose demonstrate consistent, disease-modifying levels of factor IX activity without the need for immunosuppression FIX activity as % normal sustained: 1st patient at 28% (18 weeks); 2nd patient at 30% (7 weeks) Expanded dataset on first cohort to be presented June 11 at EHA
Expect to file IND for Hemophilia A in 2H16
Choroideremia, another IRD, initial efficacy data from P1/2 trial expected 2H16 Expect to file IND for Batten disease, our initial CNS target, in 2H16
$275 million in cash at March 31, 2016
Spark is a fully integrated gene therapy platform company developing transformative therapies for severe genetic diseases
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Spark’s validated platform has successfully delivered gene therapies with proof-of-concept data in the eye and liver
Inherited retinal
dystrophies (Eye)
Liver-associated
disease (Liver)
Neuro-degenerative
diseases (CNS)
Voretigene neparvovec (RPE65-mediated
IRDs)
SPK-CHM (Choroideremia)
SPK-9001
(Hemophilia B)
Best-in-Class Selection and Design
Proven Vector Manufacturing
Regulatory and Clinical Innovation
Shaping Commercial Model
SPK-FVIII (Hemophilia A)
SPK-TPP1 (TPP1 deficiency, a form of Batten
disease)
Leading capabilities in selection, design, manufacture and formulation of highly optimized AAV gene therapies – Expect readouts from 5 clinical programs
across 3 therapeutic franchises by 1H17
SPK-9001 data demonstrate consistent, disease-altering levels of factor IX activity
Similar design, dose range and translation of PC data, SPK-9001 may inform SPK-FVIII – Expect to file IND for SPK-FVIII in 2H16
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Liver: Recently released first-in-human clinical data from SPK-FIX program
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Objectives of a gene therapy for hemophilia
Sustained factor activity levels >12% to reduce risk of bleeds and need for chronic therapy
Consistent results across patients increases prospect of benefit for all appropriate patients
Lack of, or minimal need for, steroids increases maximum sustained activity level
Lowest possible dose decreases risk of immune response and lowers manufacturing hurdles / cost
Note: Black lines are medians; shaded areas interquartile ranges. Source: den Uijl IE et al. Haemophilia 2011; 17(6):849-53.
Annual number of joint bleeds according to factor activity
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Spark’s lead hemophilia B candidate, SPK-9001, was highly optimized by leveraging platform capabilities
Best-in-Class Selection and Design
Proven Vector Manufacturing
Regulatory and Clinical Innovation
Shaping Commercial Model
Novel bioengineered AAV capsid may
increase addressable patient population
Single-stranded, codon optimized cassette
may yield more homogeneous, potent,
and pure product
High-activity variant may enable clinically-
relevant, long-term FIX activity levels
Use of empty capsids may increase
addressable patient population 30%
40%
50%
60%
AAV2 AAV5 AAV8 Spark 100
% of AAV-Permissive hemophilia B patients % of AAV-permissive Hemophilia B Patients
Source: Spark data presented at ISTH, June 2015: 60 human sera from hemophilia B patients.
Disease-altering activity levels
Allows starting at a low dose
Potential to avoid need for steroids
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Clinical data on SPK-9001 demonstrate consistent, disease-altering levels of factor IX activity
Source: European Hematology Association 21st Congress, late breaking abstract 771, June 11 2016
First 3 subjects at initial low dose 5x1011 vg/kg
FIX activity rose consistently and was sustained above disease-altering levels
– First: 28% of normal at 18 weeks – Second: 30% of normal at 7 weeks – Third: 16% of normal at 3 weeks
Well-tolerated and have not needed, or received, immunosuppression
All subjects have been free from regular clotting factor infusions
Expanded dataset on first cohort to be presented June 11 at European Hematology Association meeting
0
10
20
30
40
0 7 14 21 28 35 42 49 56 63 70 77 84Fa
ctor
IX A
ctiv
ity (%
of n
orm
al)
Days post vector administration
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SPK-FVIII preclinical data demonstrate potential to meet product objectives and benefit of continued optimization
Source: Spark data presented at ASH, December 2015. Source: Spark data presented at ASH, December 2015.
Note: Ɛ denotes the development of inhibitors to human FVIII, an anticipated result with this preclinical model. Data: Spark Therapeutics, Inc., unpublished
Low dose High dose
SPK1
00-F
VIII
SPK2
00-F
VIII
Candidate is a codon optimized, B-domain-deleted FVIII gene
Two different novel bioengineered AAV vectors, SPK100 and SPK200, have shown therapeutic levels of expression in non-human primates (NHPs) at clinically-relevant doses
SPK200 capsid appears to have superior transduction efficiency in NHPs with ~2x higher FVIII levels
Source: Spark data presented at ASGCT, May 2016. Source: Spark data presented at ASGCT, May 2016.
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Given common product design, dose range and translation of preclinical data, SPK-FIX may inform SPK-FVIII
Preclinical data has been a predictor of human factor levels
Dose range may define immune response in humans
Expect to initiate a Phase 1/2 clinical trial in 2H16 with initial efficacy in 1H17
FIX Activity Levels in Non-Human Primates
Source: Spark data presented at ISTH, June 2015.
5x1011 vg/kg
FIX Activity Levels in Subjects
Source: European Hematology Association 21st Congress, late breaking abstract 771, June 11 2016
2x1012 vg/kg
FVIII Activity Levels in Non-Human Primates
Source: Spark data presented at ASGCT, May 2016.
Note: Ɛ denotes the development of inhibitors to human FVIII, an anticipated result with this preclinical model. Data: Spark Therapeutics, Inc., unpublished
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Eye: Initiated BLA submission of voretigene neparvovec for RPE65-mediated IRDs
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Statistically and clinically significant voretigene neparvovec P3 results; durability of benefit for over 3 years
Abbreviation: BL = baseline, MT = mobility test mITT population for 301 study. Intervals are +/- one standard error
Mean MT: lux score/level, bilateral (mITT) – 301 trial lux score/level, injected eye – 102 trial
301 Intervention (n = 20) 301 Control (n = 9)
102 (n = 8)
Abbreviation: BL = baseline, FST = full-field light threshold sensitivity testing mITT population for 301 study. Intervals are +/- one standard error
301 Intervention (n = 20)
301 Control (n = 9) 102 (n = 8)
Mean FST: white light, averaged over both eyes (mITT) – 301 trial white light, injected eye – 102 trial
65% of intervention subjects (no controls) passed at 1 lux at year one, demonstrating maximum improvement measurable
100-fold improvement in light sensitivity, on average
No product-related serious adverse events or deleterious immune responses
Durability of benefit 3 years post-injection in subjects in the 102 trial that would have met eligibility criteria for the P3 trial (102 cohort)
Source: Spark data presented at The Retina Society, October 2015.
1 lux
4 lux
10 lux
50 lux
125 lux
250 lux
400 lux
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Restoring functional vision through a one-time administration of voretigene neparvovec
CH-41: baseline visit at 4 lux (Fail) CH-41: 1-year visit after voretigene neparvovec administration at 4 lux (Pass)
Note: The videos of CH-41 are representative of the mean improvement demonstrated in the intervention group in the Phase 3 trial. Source: Spark Phase 3 trial source data.
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Voretigene neparvovec is uniquely positioned to be the first therapeutic for RPE65-mediated IRDs
Expect to complete BLA submission for voretigene neparvovec in the second half of 2016, and MAA in early 2017
Clinical and regulatory progress
Orphan Product Designation from FDA and EMA for LCA and RP due to RPE65
FDA Breakthrough Therapy Designation
Rolling BLA process initiated; nonclinical component submitted in April 2016
1-year data on Phase 3 crossover subjects (302 trial) expected mid-2016
2-year data on Phase 3 intervention subjects (301 trial) expected mid-2016
4-year data on 102 cohort expected 4Q16
Shaping a patient-centric, commercial model
Estimated prevalent population: 3,500 in US and EU5
Additional opportunities in EU23, Latin America and Asia
Investments in genetic testing for IRDs and stakeholder education will confirm and identify potential eligible patients
Continued regulatory discussions about a label that would capture patients with RPE65 mutations (and only those)
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SPK-CHM leverages voretigene neparvovec with initial efficacy data expected in 2H16
Choroideremia affects an estimated 12,500 males in the US and EU5, or ~3.5x the voretigene neparvovec population
Recently completed enrollment of second dose cohort in Phase 1/2 trial
– No product-related SAEs observed during trial – Preclinical data suggest current clinical dose
should be therapeutically optimal
Following successful approach with voretigene neparvovec to select optimal endpoints for registration trial in consultation with regulators
Advancing preclinical programs targeting LHON and RHO-adRP while continuing to evaluating additional IRD targets (>220 genes implicated)
0
25
50
75
100
125
Control 5 x 10" µg/eye
hRep
1: c
Rep1
mRN
A
Ratio of REP1 levels in preclinical model
1 Goal = 1
105
Source: Spark unpublished preclinical data.
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SPK-TPP1: Establishing a proprietary approach for gene therapy delivery to the brain
CSF bathes the central nervous system, providing extensive bio-distribution of TPP1
Expect to initiate a clinical trial in 2H16 with initial efficacy data in the 1H17, creating the potential for other genes to be expressed in CSF
TPP1 deficiency is a fatal neurodegenerative disease affecting children
Estimated prevalence of 750-1000 and incidence of 100 annually in US and EU5
In preclinical studies, administration of SPK-TPP1 to the ventricles leads to expression of TPP1 in the cerebral spinal fluid
SPK-TPP1 demonstrated potential to delay onset and progression of disease in a well-established model of TPP1 deficiency
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Significant number of data readouts and regulatory milestones expected across 5 clinical candidates through mid-2017
SPK-CHM (Choroideremia)
SPK-9001 (Hemophilia B)
SPK-FVIII (Hemophilia A)
SPK-TPP1 (TPP1 deficiency, a form
of Batten disease)
Rolling BLA submission: non-clinical module
BLA submission completed
302 trial (Phase 3 crossover subjects): 1-yr data
301 trial: 2-year data
102 cohort: 4-year data
MAA submission completed
Initial efficacy data
Additional efficacy data
Clinical trial initiated Initial efficacy data
Clinical trial initiated
Initial efficacy data
2016 2017
2H16
2H16
2H16
1H17
2H16
1H17
Milestones
Voretigene neparvovec
(RPE65-mediated IRDs) IRDs
Liver
CNS
4Q16
Early
Mid-2016
Mid-2016
2H16
Initial efficacy data
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