Spark Therapeutics, Inc.

Transcription

1 Spark Therapeutics, Inc. Corporate Overview November

2 Forward looking statements This presentation contains "forward looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the company's product candidates, including LUXTURNA TM (voretigene neparvovec), SPK 7001, SPK 9001 and SPK 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. 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) our BLA or MAA for LUXTURNA may not be approved by the FDA or EMA respectively; (ii) the data from our Phase 3 clinical trial of LUXTURNA may not support labeling for all biallelic RPE65 mutations other than Leber congenital amaurosis (LCA); (iii) the improvements in functional vision demonstrated by LUXTURNA in our clinical trials may not be sustained over extended periods of time; (iv) interim data from our SPK 7001 Phase 1/2 clinical trial, including data to be generated from our recently expanded cohort, may not support further development of this product candidate; (v) our early preliminary clinical results for our product candidate, SPK 8011, for hemophilia A may not be sustained or sufficient to support further development; (vi) we may be unsuccessful in achieving higher factor VIII activity levels through dose escalation in our phase 1/2 clinical trial of SPK 8011; (vii) our lead SPK FIX product candidate, SPK 9001, may not produce sufficient data in our Phase 1/2 clinical trial to warrant further development; (viii) our early preliminary data in our phase 1/2 clinical trial of SPK 8011 have yet to be audited and therefore are subject to confirmation in connection with a clinical trial audit; and (ix) any one or more of our product candidates in preclinical or clinical development will not successfully be developed and commercialized. 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. LUXTURNA TM is the trademark of Spark Therapeutics, Inc. 2

3 Spark is a fully integrated gene therapy platform company seeking to challenge the inevitability of genetic disease Validated gene therapy platform: human proof of concept data in 3 programs in the retina (LUXTURNA TM [voretigene neparvovec]) and hemophilia (SPK 8011 and SPK 9001) Investigational LUXTURNA represents the first marketing application for a gene therapy for a genetic disease in the U.S. with FDA action expected in January 2018; MAA validated by EMA Unanimous October 2017 FDA Advisory Committee vote (16 0) in favor of approval Investigational SPK 8011 for hemophilia A preliminary Phase 1/2 data provide proof of concept: 5 participants infused to date at three doses: 5x10 11 vg/kg (n=2); 1x10 12 vg/kg (n=2); and 2x10 12 vg/kg (n=1) Factor VIII (FVIII) levels of 14% and 11% seen in first 2 participants at initial dose, as of August 1 No spontaneous bleeds or serious adverse events (SAEs) reported as of August 1, including no FVIII inhibitors and no thrombotic events Investigational SPK 9001 for hemophilia B preliminary Phase 1/2 data: predictable results leading to a reduction of 96% in ABR 1 and 99% in AIR 2 as of 6/5/17 with cumulative follow up of 9.6 patient years; no SAEs to date Investigational SPK 7001 Phase 1/2 trial in choroideremia ongoing $575 million in cash, cash equivalents and marketable securities at September 30 1 Annualized bleeding rate; 2 Annualized infusion rate The safety and efficacy of investigational LUXTURNA (voretigene neparvovec) have not been demonstrated. 3

4 Investigational LUXTURNA (voretigene neparvovec) under regulatory review and positioned potentially to be the first gene therapy for a genetic disease in the U.S. 4

5 LUXTURNA under FDA and EMA regulatory review potential to be first approved gene therapy for a genetic disease in U.S. Proposed US Indication: LUXTURNA for the treatment of patients with vision loss due to confirmed biallelic RPE65 mutation associated retinal dystrophy FDA Ad Com unanimously (16 0) recommended approval of LUXTURNA FDA pre approval inspection completed without critical observations PDUFA date of Jan. 12, 2018 MAA validated by European Medicines Agency Gain in functional vision based on MLMT 1 in 93% (27/29) of Phase 3 participants at 1 year with 72% achieving maximum improvement (to 1 lux) no product related SAEs observed 3 year data (n=20) and 4 year data (n=4) from Phase 3 add evidence to durability of effect; no statistically significant signs of a waning of therapeutic effect 1 Multi luminance mobility test. The safety and efficacy of investigational LUXTURNA (voretigene neparvovec) have not been demonstrated. 5

6 Spark is taking an innovative and patient centric approach to launch preparation for investigational LUXTURNA PATIENT IDENTIFICATION CONVERSION PATIENT EXPERIENCE MARKET ACCESS Build a system to continually identify appropriate patients Prepare the market to receive LUXTURNA by developing and communicating the story of gene therapy and IRD therapy Establish a seamless system to support appropriate patient care across the patient journey Obtain/establish quality coverage and appropriate reimbursement for LUXTURNA across all channels IDYourIRD has been well received Ongoing education on IRD, and importance of genetic testing and onetime gene therapies Treatment Centers identified to support appropriate patient care, and will be trained postapproval Tested multiple approaches to valuing long term functional improvements to vision Continue to ID and process patient kits Promotional messaging platform & tools are being finalized for approval & launch Patient Services system & processes are being developed for launch; supply and distribution plan in late stage development Standard and innovative approaches to access being explored; development of patient support programs in progress The safety and efficacy of investigational LUXTURNA (voretigene neparvovec) have not been demonstrated. 6

7 Natural history of biallelic RPE65 mutations characterized by early, profound and continuous visual decline Unaffected vision Impaired VA and visual field (VF) Impaired visual acuity (VA) Impaired VA, VF and light sensitivity 7 Private and Confidential

8 Investigational LUXTURNA (voretigene neparvovec) Phase 3 trial participant: Functional vision significantly impaired at baseline CH 41: baseline visit at 4 lux (Fail) Source: Spark Phase 3 trial source data The safety and efficacy of investigational LUXTURNA (voretigene neparvovec) have not been demonstrated. 8

9 Investigational LUXTURNA (voretigene neparvovec) Phase 3 trial: Improved functional vision, as measured by primary endpoint*, through a one time administration CH 41: 1 year visit after LUXTURNA administration at 4 lux (Pass) *Multi luminance mobility test (MLMT) Source: Spark Phase 3 trial source data Note: The videos of CH 41 are representative of the mean MLMT improvement demonstrated in the intervention group in the Phase 3 trial. The safety and efficacy of investigational LUXTURNA (voretigene neparvovec) have not been demonstrated. 9

10 Investigational LUXTURNA (voretigene neparvovec) Phase 3 clinical data: Results from a varied set of endpoints Secondary endpoint: Full field light sensitivity threshold White light [ log10(cd.s/m 2 )] Mean FST: white light, averaged over both eyes (mitt) BL D30 D90 D180 Y1 Y2 BL D30 D90 D180 Y1 p <0.001 at one year Abbreviation: BL = baseline, FST = full field light sensitivity threshold mitt population for 301 study. Intervals are +/ one standard error Mean MLMT: lux score/level, bilateral (mitt) 1 lux 4 lux 10 lux 50 lux 125 lux 250 lux 400 lux Abbreviation: BL = baseline, MLMT = multi luminance mobility test mitt population for 301 study. Intervals are +/ one standard error Gain in functional vision based on MLMT in 93% (27/29) of Phase 3 participants at 1 year with 72% achieving maximum improvement (to 1 lux) No product related SAEs or deleterious immune responses 1 >150 fold average improvement in light sensitivity (FST) BL D30 D90 D180 Y1 Y2 BL D30 D90 D180 Y1 p=0.004 at one year Another secondary endpoint, visual acuity, did not reach statistical significance; 9 letter improvement (p=0.17) Visual Field (VF) improved on two measures with a near doubling in Goldmann VF Lux score Primary endpoint Goldmann III4e (sum total degrees) Additional protocolspecified endpoint Mean Goldmann Visual Field III4e: both eyes (mitt) Abbreviation: BL = baseline, mitt population for 301 study. Intervals are +/ one standard error BL D30 D90 D180 Y1 Y2 BL D30 D90 D180 Y1 p=0.006 at one year Source: Spark data presented at The Retina Society, October 2015; Spark data on file (unpublished). (1) One SAE (serious adverse event) in one eye deemed related to surgical procedure The safety and efficacy of investigational LUXTURNA (voretigene neparvovec) have not been demonstrated. 10

11 Data support potential value of a one time administration of investigational LUXTURNA (voretigene neparvovec) to deliver longer term results Health economic (HEOR) modeling is an important approach to assessing value HEOR modeling should include direct costs, quality of life, indirect costs and durability of effect Indirect costs have significant economic consequences 70% of working age Americans who are blind are unemployed Substantial caregiver and societal costs, such as lost wages and increased educational costs Value conclusions from ongoing HEOR modeling corroborated independently by society (e.g., long term disability, court cases) 3 year data (n=20) and 4 year data (n=4) from Phase 3 add evidence to durability of effect; no statistically significant signs of a waning of therapeutic effect Mean MLMT: lux score/level, bilateral (mitt) 301 and 302 study lux score/level, injected eye 102 cohort 1 lux 6 4 lux 10 lux 50 lux 125 lux 250 lux 400 lux Source: Spark data presented at The Retina Society, October 2015; The Lancet; Spark data on file (unpublished). *Spark data on file. Lux score Abbreviation: BL = baseline, MLMT = multi luminance mobility test mitt population for 301 study. Intervals are +/ one standard error BL D30 D90 D180 Y1 Y2 Y3 BL D30 D90 D180 Y Original intervention (n = 20) 301 Control/intervention (n = 9) 102 (n = 8) Mean FST: white light, averaged over both eyes (mitt) 301 and 302 study white light, injected eye 102 cohort White light [ log10(cd.s/m 2 )] BL D30 D90 D180 Y1 Y2 Y3 Y4 BL D30 D90 D180 Y1 Abbreviation: BL = baseline, FST = full field light sensitivity threshold, mitt population for 301 study. Intervals are +/ one standard error The safety and efficacy of investigational LUXTURNA (voretigene neparvovec) have not been demonstrated. 301 Original intervention (n = 20) 301 Control/intervention (n = 9) 102 (n = 8) Y4

12 Investigational LUXTURNA (voretigene neparvovec) Phase 3 safety overview years 1 and 2: No product related SAEs Most common treatment emergent ocular adverse events Number of participants (n=29) Increased intraocular pressure 5 Cataracts 4 Retinal tear 3 Retinal deposit* 3 Macular hole 2 Transient and mild eye inflammation 2 Eye pain 2 Eye pruritus 2 Procedure related serious adverse event Number of participants (n=29) Loss of foveal function (visual acuity) right eye 1 *Asymptomatic, self limiting, subretinal precipitates Sources: Russell et al. Abstract presented at: Retina Society 48th Annual Scientific Meeting; October 7 11, 2015; Paris, France. Data on file. Spark Therapeutics, Inc. The safety and efficacy of investigational LUXTURNA (voretigene neparvovec) have not been demonstrated. 12

13 Demonstrated leadership in applying gene therapy technology to hemophilia 13

14 Spark objectives for developing an optimized gene therapy for hemophilia Safety Low, effective dose to reduce risk of SAEs Restore hemostasis by leveraging innate biology rather than bypassing normal physiological pathways Factor activity levels >12% at all times reduces risk of bleeds and need for chronic infusions No thrombosis or inhibitors Predictable and consistent results Participants within an acceptable factor activity range >12% and below levels that could introduce new safety risks Sustained factor expression Without the troughs that characterize regular infusions of protein therapeutics Reduce treatment burden and improve QoL Note: Black lines are medians; shaded areas interquartile ranges. Source: Adapted from den Uijl IE et. al. Haemophilia 2011; 17(6):

15 Spark is two for two in achieving proof of concept in hemophilia gene therapy Safety SPK 9001 for hemophilia B No SAEs reported, including no FIX inhibitors and no thrombotic events as of June 5, 2017 SPK 8011 for hemophilia A No SAEs reported, including no FVIII inhibitors and no thrombotic events as of August 1, 2017 Evidence of predictability and consistency Predictability of results: No confirmed bleeds observed in initial 10 participants in 9.6 cumulative years of follow up, as of June 5 11/11 participants with >12% FIX activity Consistent FIX activity levels achieved All participants well within an acceptable range Initial 2 treated participants achieved 14% and 11% FVIII activity, as of August 1, at dose of 5x10 11 vg/kg No spontaneous bleeds reported Evidence of sustainability Sustained FIX expression with 1 participant out 18 months post infusion and 4 others out over one year as of June 5 First participant out over 5 months, second participant out ~3 months post infusion as of August 1 Data as of June 5 th, 2017 (latest update) for SPK 9001 and August 1 st, 2017 for SPK Note: Two SPK 9001 trial participants experienced asymptomatic, transient elevation in liver enzymes, or decline in FIX activity, potentially indicative of an immune response to the Spark100 capsid. Both received a tapering course of corticosteroids (now completed) after which their ALTs returned to baseline, while factor IX activity levels have remained stable. As of June 5th, neither participant had experienced a bleed nor taken factor concentrates. Source: SPK 8011 preliminary initial Phase 1/2 data per investigator reporting; and therefore are subject to confirmation in connection with a clinical trial audit. Factor activity refers to FVIII:C values from local labs. 15

16 Preliminary SPK 9001 Phase 1/2 data in hemophilia B: Consistent and sustained FIX activity within target range in initial 10 participants 12 weeks 1 year 90% FIX:C Activity (% of normal) 75% 60% 45% 30% 15% 30% 79%* 25% 18% 16%* 44% 43% 38% 24% 33% 100 IU/kg EHL-rFIX, BeneFIX, or MonoNine 0% Months post vector administration Source: Spark data as of June 5, 2017; Participant 1 80 week data as of June 22, FIX:C Activity = circulating factor IX activity level EHL rfix Extended half life recombinant factor IX *These two participants experienced asymptomatic, transient elevation in liver enzymes, or decline in FIX activity, potentially indicative of an immune response to the Spark100 capsid. Both received a tapering course of corticosteroids (now completed) after which their ALTs returned to baseline, while factor IX activity levels remained stable. As of June 5 th, neither participant had experienced a bleed nor taken factor concentrates. 16

17 Preliminary SPK 9001 Phase 1/2 data in hemophilia B: Predictable results for initial 10 participants in FIX activity target range Annualized Bleeding Rate First ten participants free of confirmed bleeds Participant 1 Participant 2 Participant 3 Participant 4 Participant 5 Participant 6 Participant 7 Participant 8 Participant 9 Participant 10 Participant 1 Participant 2 Participant 3 Participant 4 Participant 5 Participant 6 Participant 7 Participant 8 Participant 9 Participant 10 Prior 1 year 0 0 4* Pre-trial bleed Suspected bleed After vector infusion (22-80 weeks) Nine of the ten initial participants have not taken factor IX concentrates to prevent or control bleeding events since vector administration FIX infusions: prior 1 yr. vs. after vector administration Participant 1 Participant 2 Participant 3 Participant 4 Participant 5 Participant 6 Participant 7 Participant 8 Participant 9 Participant 10 Prior 1 year Prophylaxis infusion On-demand infusion Infusion for suspected bleed * Participant 1 Participant 2 Participant 3 Participant 4 Participant 5 Participant 6 Participant 7 Participant 8 Participant 9 Participant 10 After vector infusion (22-80 weeks) Note: SPK 9001 data as of last visit prior to June 5, 2017; most recent update. SPK 8011 data as of August 1, *SPK 9001 Participant 3 self infused factor concentrates for suspected ankle bleed on Day 2 after vector infusion and self administered precautionary infusions another nine times between Dec. 2, 2016 and Jan 2, 2017 for persistent knee pain. Participant has not used factor concentrates since Jan. 2. **SPK 8011 Participant 1 infused factor following an emergency dental extraction in Week 6 post infusion, while Participant 3 infused factor subsequent to a traumatic ankle injury on Day 2 post infusion. No documented use for either participant of additional factor concentrates through 8/1. 17

18 Preliminary SPK 8011 Phase 1/2 data in hemophilia A as of August 1: First 2 participants stable with double digit FVIII activity; doseescalation ongoing 15% 14% FVIII:C Activity (% of normal) 12% 9% 6% 3% 8% Two additional participants have been dosed since last update on August 1. Participant 4 received same dose as participant 3 (1x10 12 vg/kg), with participant 5 receiving the next dose of 2x10 12 vg/kg. Next data update to be provided at ASH. 11% 0% Days post vector administration Note: Data as of 8/1/17; Subject 1 infused factor following an emergency dental extraction in Week 6 post infusion. Reading shortly thereafter recorded 19% activity level; excluded from this graph due to factor infusion proximity. Subject 3 infused factor subsequent to a traumatic ankle injury on Day 2 post infusion; Day 7 read deemed not to be impacted by any residual Factor from infusion. Factor activity refers to FVIII:C values from local labs. 18 Private and Confidential

19 Fully integrated AAV gene therapy platform 19

20 Spark has programs across 3 target tissues, with 4 candidates in clinical trials and 3 with human proof of concept Preclinical Phase 1/2 Phase 3 Registration INHERITED RETINAL DISEASES (IRDs) LUXTURNA (voretigene neparvovec): IRD due to biallelic RPE65 mutations* SPK 7001: Choroideremia LHON 1 Undisclosed LIVER MEDIATED DISEASES SPK 8011: Hemophilia A SPK 9001: Hemophilia B Undisclosed (Genethon) NEURODEGENERATIVE DISEASES CLN2 disease 2 Huntington s disease Cutting edge vector design State of the art manufacturing expertise Innovative scientific and regulatory strategies Strong commitment to improve patient care 1 Leber hereditary optic neuropathy; 2 A form of Batten Disease. *BLA filing under review in the US; MAA validated by EMA. 20

21 Interim data from ongoing SPK 7001 P1/2 trial in CHM: No productrelated SAEs with 15 participants dosed; follow up ongoing Choroideremia is slow progressing, affecting ~12,500 males in US / EU5 To study safety, initiated 2 year Phase 1/2 trial in 10 participants with later stage disease SPK 7001 administration resulted in no product related SAEs At interim analysis 1, 4/10 later stage participants showing non statistically significant indications of efficacy on 1 or more endpoints Non significance of results may be due to duration of follow up and later stage of disease in this cohort Completed enrollment in additional cohort of 5 participants at an earlier stage of disease hrep1: crep1 mrna Ratio of REP1 levels in preclinical model Control Goal = x 10" µg/eye Source: Spark unpublished preclinical data. Next steps: Conduct analysis at 2 year timepoint on first 10 participants 1 At time of interim analysis, had 1 year of follow up on 5 participants, 18 months of follow up on 4 and the targeted 2 year data for 1 21

22 Spark s AAV manufacturing platform is the product of years of experience and optimization Manufacturing processes in use Purpose built, multi suite, in house cgmp facility Adherent cell culture (HEK293 mammalian cell line), transient transfection process Implemented a scalable all column downstream purification process Technology capable of being scaled linearly 50+ sub lots manufactured to date at Spark 24 assays developed for, and being used in, production of LUXTURNA Sufficient scale for IRDs (including LUXTURNA TM ) and Hemophilia B Processes currently being implemented Proof of concept achieved in a fully scalable, serum free suspension cell culture system utilizing our current HEK293 cell line Natural AAV hosts produce higher specificactivity vectors vs. non mammalian cells Reduces risk of potentially immunogenic residual impurities and pathogenicity and requirement for helper viruses Maintains product continuity Leverages current quality systems Ongoing scale up and implementation of new upstream process Designed to support anticipated requirements for potential Hemophilia A and other future potential gene therapy products 22

23 Recent and upcoming clinical and regulatory catalysts Preclinical Phase 1/2 Phase 3 INHERITED RETINAL DISEASES (IRDs) Registration LUXTURNA (voretigene neparvovec): IRD due to biallelic RPE65 mutations* SPK 7001: Choroideremia LIVER MEDIATED DISEASES SPK 8011: Hemophilia A SPK 9001: Hemophilia B IRD catalysts May 2017: Interim SPK 7001 readout July 2017: LUXTURNA BLA acceptance and filing August 2017: Completed FDA PAI August 2017: LUXTURNA MAA validation October 2017: Unanimous Ad Com vote (16 0) in favor of LUXTURNA approval January 2018: LUXTURNA PDUFA date Liver mediated disease catalysts July 2017: SPK 9001 update on P1/2 data in hemophilia B August 2017: Initial topline readout of P1/2 dose escalation study of SPK 8011 in hemophilia A ASH 2017: Presentation of interim data from P1/2 study of SPK 8011 in hemophilia A *BLA filing under review in the US; MAA validated by EMA. 23