Spark Therapeutics, Inc. - Jefferies · expectations disclosed in the forward-looking statements we...

1 Private and Confidential

Spark Therapeutics, Inc.

Jefferies 2016 Global Healthcare Conference June 10, 2016


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.


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


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


Liver: Recently released first-in-human clinical data from SPK-FIX program


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

12


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


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


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.


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


Eye: Initiated BLA submission of voretigene neparvovec for RPE65-mediated IRDs


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


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.


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)


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.


CNS: A third tissue type targeted by Spark’s gene therapy platform


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


Spark: A gene therapy platform capable of numerous near-term catalysts


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


2016 2017

2H16

2H16

2H16

1H17

2H16

1H17

Milestones

Voretigene neparvovec

(RPE65-mediated IRDs) IRDs

Liver

CNS

4Q16

Early

Mid-2016

Mid-2016

2H16


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