Spark Therapeutics Company presentation from OIS@AAO 2015

1. 1 Private and Confidential
Spark Therapeutics, Inc.
OIS@AAO
November 12, 2015

2. 2 Private and Confidential
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. 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.

3. 3 Private and Confidential
Fully integrated company with R&D, manufacturing, commercial
Lead program, SPK-RPE65, clinically de-risked with highly statistically
significant results in pivotal, Phase 3 of RPE65-mediated blindness
 Durability data at 3 years and counting for comparable Phase 1 cohort
 Pre-commercial activities underway with BLA filing expected in 2016
Validated platform being applied across deep, growing product
development pipeline across multiple tissues and target indications
 First follow-on eye program, SPK-CHM, in Phase 1/2 trial of choroideremia
 Factor IX partnership with Pfizer, an industry leader in hemophilia
 Neurodegenerative programs to be announced in 2015 and 2016
Founded on know-how accumulated over 20 years at CHOP, including
manufacturing platform applied safely across >150 administrations
Cash at June 30, 2015: $223 million
Spark is a gene therapy company developing one-time,
life-altering treatments for debilitating genetic disorders

4. 4 Private and Confidential
Validated platform being applied across deep, growing
pipeline of AAV gene therapy candidates
REPLACE WITH JEFF’S VERSION
Worldwide rights
Worldwide rights
Worldwide rights
Worldwide rights
SPK-RPE65:
RPE65-mediated IRDs
Positive results in
pivotal, Phase 3
SPK-CHM:
Choroideremia
Phase 1/2 second
dose cohort initiated
Genable RhoNova:
RHO-adRP
Preclinical
SPK-FIX:
Hemophilia B
Phase 1/2 trial
initiated
Hemophilia A
IND-enabling study
to start in 2016
Undisclosed
IND-enabling study
to start in 2015
Preclinical Status Commercial rightsIND-enabling Phase 1/2 Phase 3Program
Collaboration
Inherited retinal dystrophies (IRDs)
Hematologic disorders
Neurodegenerative diseases
Worldwide rightsUndisclosed
IND-enabling study
to start in 2016

5. 5 Private and Confidential
Phase 3 trial design (n=31 ITT, n=29 mITT/safety)
 Mobility test (MT) change score at 1 year, bilateral
Primary
 Full-field light threshold sensitivity testing (FST), averaged over
both eyes
 MT change score, first injected eye
 Visual acuity (VA), averaged over both eyes
Secondary
Endpoint
reached at 1
year
Eligibility
screening
2nd injection
(12 ± 6 days)
Control group
n=10 ITT (9 mITT/safety)
≤ 12 months (± 30 days)
First injection
(≤ 90 days of
baseline)
Intervention
group
n=21 ITT (20
mITT/safety)
Baseline testing
Randomization
(2:1 intervention
to control)
Assignment
(balanced for age
and baseline MT
performance)
All followed control subjects (n=9) have crossed
over and received SPK-RPE65
Study fully enrolled in 2013;
randomization completed in 2014
Dosing regimen: 1.5e11 vg/eye in
300 µL
Crossover to
intervention
group
Trial endpoints

6. 6 Private and Confidential
SPK-RPE65: Measuring functional vision through a
validated mobility test
Mobility course layout (1 of 12)
The ability to design trials and clinically meaningful endpoints is a critical component of
developing a gene therapeutic for IRDs
1 Styrofoam object or cone.
2 Foam is a raised foam block.
3 Waist-high object.
Lux levels
Foam2
Foam2
Door
Raised
Grass
Grass
Hole
STY1
StopHole
Step
Start
Raised
Hole
STY1
Waste
3
Moonless summer night
or indoor nightlight
1
400
Office setting
4
Outdoor parking lot at night
or Christmas tree lights
10
An hour following sunset
in a city setting or a bus
stop at night
125
Half-an-hour before sunrise
or the interior of a shopping
mall or train or bus at night
250
Interior of an elevator
or office hallway
Outdoor train station at
night or the inside of a
stairwell
50

7. 7 Private and Confidential
Highly statistically significant Phase 3 data reported in
October 2015 (ITT efficacy population, n=31)
Primary endpoint
Endpoint Statistical significance (p-value)
Mobility test change score, bilateral p = .001
Secondary endpoint
Endpoint Statistical significance (p-value)
FST, averaged over both eyes p < .001
MT change score, first injected eye p = .001
VA, averaged over both eyes p = .17
 No serious adverse events related to SPK-RPE65
 No deleterious immune responses observed in the trial
 Procedure-related adverse events consistent with prior trials
Adverse events

8. 8 Private and Confidential
BL D30 D90 D180 Y1
Study visit
Phase 3 trial results of SPK-RPE65: MT and FST
(mITT/safety population, n=29)
65% of intervention subjects (no controls) passed at 1
lux, demonstrating maximum improvement possible
100-fold improvement in light sensitivity in subjects
receiving SPK-RPE65
0
1
2
3
4
5
6
BL D30 D90 D180 Y1
Luxscore,bilateral
Study visit
Intervention Control
Mean MT lux score/level, bilateral (mITT)
N (Intervention)=20
N (Control)=9
P-value=0.004
Abbreviations: BL=baseline
Intervals are +/- one standard error
Maximum Improvement
1 lux
4 lux
10 lux
50 lux
125 lux
250 lux
400 lux -4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
Whitelight,botheyes[(log10(cd.s/m2)]
Intervention Control
Mean FST: white light, averaged over both eyes (mITT)
N (Intervention)=20
N (Control)=9
P-value=0.001
Abbreviations: BL=baseline, FST=Full-field light threshold sensitivity testing
Intervals are +/- one standard error

9. 9 Private and Confidential
Durability of effect of SPK-RPE65: MT change score over 3
years
Durability of benefit demonstrated out 3 years post-injection on MT in entire cohort of 102 trial
subjects which would have qualified for Phase 3
Mean MT lux score/level, 102-injected eye
Abbreviation: BL=baseline
Intervals are +/- one standard error, N=8
Day 30: N=7 due to incomplete follow-up
0
1
2
3
4
5
6
BL D30 D90 D180 Y1
Luxscore,bilateral
Study visit
Intervention Control
Mean MT lux score/level, bilateral (mITT)
N (Intervention)=20
N (Control)=9
P-value=0.004
0
1
2
3
4
5
6
BL D30 D90 D180 Y1 Y2 Y3
Luxscore,102-injectedeye
1 lux
4 lux
10 lux
50 lux
125 lux
250 lux
400 lux
Maximum Improvement
Study visit
Maximum Improvement
Abbreviations: BL=baseline
Intervals are +/- one standard error

10. 10 Private and Confidential
Durability of effect of SPK-RPE65: FST over 3 years
BL D30 D90 D180 Y1
Study visit
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
Whitelight,botheyes[(log10(cd.s/m2)]
Intervention Control
Mean FST: white light, averaged over both eyes (mITT)
N (Intervention)=20
N (Control)=9
P-value=0.001
Mean FST: white light, 102-injected eye
-30
-20
-10
0
10
BL W4 W8D90 D180 Y1 Y2 Y3
MeanFST,102-injectedeyeAbbreviation: BL: Baseline, FST=Full-field light threshold sensitivity testing
Intervals are +/- one standard error, N=8
Year 3: N=5 due to pending monitoring
Durability of benefit demonstrated out 3 years post-injection by FST in entire cohort of 102 trial
subjects which would have qualified for Phase 3
Study visit
Abbreviations: BL=baseline, FST=Full-field light threshold sensitivity testing
Intervals are +/- one standard error

11. 11 Private and Confidential
SPK-RPE65: Market opportunity and commercialization
model
 An estimated 3,500 patients in US and EU5
– ~6% to 11% of LCA patients (LCA2)1
– ~1% to 3% of RP patients (RP20)
 Received Orphan Product Designation in US and EU for LCA and
RP due to RPE65 mutations
– Currently seeking expansion of designation to all RPE65-
mediated IRDs
 100% of worldwide rights retained by Spark
 Commercialization through patient-centric approach and Centers
of Excellence (COE) for treating IRDs
 Payor dialogue underway and BLA submission anticipated in
2016
SPK-RPE65 has the potential to be the first gene therapy approved in the US for the treatment of
a genetic disease and the first approved pharmacologic treatment for any IRD
0
1,000
2,000
3,000
4,000
5,000
6,000
US and EU5
Estimated Prevalence of
RPE65-mediated IRDs
RP20
LCA2
Source: Spark calculations based on incidence/prevalence
from Genetics Home Reference and commissioned market
research.
1 Note: All clinical trials of SPK-RPE65 have included only subjects diagnosed with LCA2.

12. 12 Private and Confidential
SPK-RPE65 creates a platform for addressing additional
IRDs
Product
candidate
Gene
Vector
capsid
Expression
cassette
Route of
administration
Target cells in retina
Manufacturing
process
Commercialization
model
SPK-RPE65 RPE65 AAV2 CBA Sub-retinal RPE Scaled COE
SPK-CHM CHM AAV2 eCBA Sub-retinal RPE Scaled COE
RhoNova
RHO-r
RHO-s
AAV5 Undisclosed Sub-retinal Photoreceptors Scaled COE
 SPK-CHM: Choroideremia affects an estimated 12,500 males in the US and EU5; 3.5x the SPK-RPE65 population
– Currently enrolling in Phase 1/2 trial; first dose cohort complete with no product-related SAEs
 RhoNova: Addresses RHO-adRP and utilizes a novel dual-vector gene therapy strategy: (i) suppress the mutant
rhodopsin gene and (ii) replace with normal gene resistant to suppressor
– License, supply and development consultancy agreements with tiered, mid-single-digit royalties
 Evaluating additional IRD targets (over 220 genes implicated in IRDs) and new technologies (i.e., Clearside
suprachoroidal space microinjector) to expand and enhance platform

13. 13 Private and Confidential
Proven track record of moving the concept of gene
therapy toward a therapeutic reality for patients
2013 2016 est.
• SPK-RPE65: Submit
BLA in US
• SPK-FIX: Phase 1/2
proof-of-concept
results
• Hemophilia A:
Initiate IND-enabling
study
• Follow-on CNS:
Initiate IND-enabling
study
2015 est.
 $185 million IPO
 SPK-CHM: Phase 1/2
trial initiated
 Clearside Biomedical
microinjector option
 SPK-FIX: Phase 1/2
trial initiated
 SPK-RPE65: Positive
Phase 3 results
• Lead CNS: Preclinical
POC data published
• Lead CNS program:
IND-enabling study
initiated
2014
 Collaboration with
Genable on RhoNova
 $73 million Series B
 SPK-RPE65: FDA
granted breakthrough
 Opened facility
supporting corporate,
R&D, manufacturing
 SPK-FIX: Executed
Pfizer collaboration
 Recruited industry
executives including
CCO and CFO
 Acquired rights to IP
and programs from
CHOP,Penn, Iowa
 $10 million Series A
 Recruited gene
therapy pioneers
from CHOP
 SPK-RPE65: Phase 3
fully recruited
 Hemophilia B human
POC with
predecessor vector