Sarepta Therapeutics, Inc. · NASDAQ:SRPT
Sarepta Therapeutics — Technical Presentation (May 2018)
59 slides from Sarepta Therapeutics's technical presentation, May 3, 2018
Slide 1: Eteplirsen CHMP Oral Explanation
Eteplirsen AVI BioPharma CHMP Oral Explanation Date: 24 April 2018 Exhibit 99.2 The information presented to the CHMP included clinical efficacy and other data that were excluded from the FDA approved product labeling for EXONDYS 51® (eteplirsen). Sarepta Therapeutics, Inc. makes no recommendation f
Slide 2: Attendees
Attendees Name Position AVI BioPharma Douglas Ingram President & Chief Executive Officer Shamim Ruff, MSc Sr. Vice President, Chief Regulatory Affairs Officer Helen Eliopoulos, MD Executive Director, Regulatory Affairs Diane Frank, PhD Sr. Director, Translational Development Chris Mix, MD VP, Clinic
Slide 3: Proposed Indication for DMD
Proposed Indication for DMD DMD is a rare, fatal disease Result from inability to produce dystrophin Proposed indication is in a subpopulation of DMD Treatment of Duchenne muscular dystrophy (DMD) in ambulatory patients 4 years and older who have a confirmed mutation of the DMD gene that is amenable
Slide 4: What You Will Hear Today
What You Will Hear Today Eteplirsen: Induces exon skipping and produces functional dystrophin Consistently slows disease progression Multiple studies and endpoints 115 DMD subjects (~ 28% of the eligible population in Europe) Favorable safety profile and well tolerated Commitment to a confirmatory t
Slide 5: Dystrophin Quantification: Proof of Eteplirsen Mechanism of Action
Dystrophin Quantification: Proof of Eteplirsen Mechanism of Action Craig M. McDonald, MD Study Chair, CINRG Duchenne Natural History Study Professor and Chair, Dept. Physical Medicine & Rehabilitation Professor of Pediatrics Director, Neuromuscular Disease Clinics University of California at Davis S
Slide 6: Goal of Eteplirsen: Production of Functional Truncated Dystrophin Protein
Goal of Eteplirsen: Production of Functional Truncated Dystrophin Protein The truncated dystrophin proteins produced by eteplirsen are functional and the same proteins produced from conception in Becker muscular dystrophy patients (near normal life expectancy) The goal of eteplirsen is not to produc
Slide 7: What Amount of Dystrophin is Clinically Relevant?
What Amount of Dystrophin is Clinically Relevant? Low levels of truncated dystrophin are naturally present in exon 44 skip amenable patients with DMD – an experiment in nature Exon 44 skip amenable patients have levels of dystrophin which are similar to those seen with pharmacologic exon skipping (2
Slide 8: Similar Quantity of Truncated Dystrophin in Eteplirsen and Exon 44 Amenable Patients
Similar Quantity of Truncated Dystrophin Protein Seen in Both Eteplirsen Treated Patients and Exon 44 Amenable Patients *Untreated Exon 51-amenable EC for Study 201/202 Week 180. †Untreated Exon 44-amenable from Anthony K, et al. Neurology. 2014;83(22):2062-2069. Study 201/202 P<0.001 Exon 51–Amenab
Slide 9: Eteplirsen Produces Dystrophin Which Accumulates Over Time
0.08% 0.93% 0.16% 0.44% Week 48 Study 301 Week 180 Study 201/202 P=0.007 P=0.008 Treated (N=12) Baseline (N=12) Treated (N=11) Untreated (N=9) 2.8-fold increase 11.6-fold increase Eteplirsen Produces Dystrophin Which Accumulates Over Time Validated Western Blot
Slide 10: Major Objections Related to Dystrophin
Major Objections Related to Dystrophin Objection Eteplirsen MAA The very modest increase in dystrophin production (mean 0.93% WB of normal dystrophin in study 201/202 and 0.44% in study 301) Clinical relevance of the dystrophin produced is confirmed Levels observed in Study 201/202 are similar to ex
Slide 11: Untreated DMD Patient: Typical Attempted Run
8 Year Old Untreated DMD Patient: Typical Attempted Run Steroid Treated Since Age 4; 6MWD = 330 Meters
Slide 12: Review of Clinical Data
Review of Clinical Data Helen Eliopoulos MD Executive Director, Regulatory Affairs
Slide 13: Eteplirsen DMD Clinical Program: Trials Contribute to Efficacy
Eteplirsen DMD Clinical Program: 3 Trials Contribute to Efficacy Phase 1 Phase 2 Phase 3 Study 33 Single IM Dose N=7 Study 28 IV Dose Ranging N=19 Study 201/202 (4-Year) Age 7-13; N=12 Study 204 (2 Year) Age 7-21; N=24 Study 203 Age 4-6; N=26 Study 301 (2-Year) Age 7-16; N=79 Study 102 Age 0.5-48 mo
Slide 14: Clinical Efficacy Focuses on Phases of Decline in DMD
Clinical Efficacy Focuses on Phases of Decline in DMD Standard of Care: Glucocorticoid Use 7 Years 20 Years 13 Years 10 Years Pulmonary Linear Decline (FVC%p) 10-18 years Mechanical Ventilation Early Mortality Ambulatory Decline: ≥7 years (6MWT & NSAA)
Slide 15: Rigorous Identification of Most Appropriate External Controls
Rigorous Identification of Most Appropriate External Controls 12 DMD Registries and Untreated Controls identified Only 3 of 12 prospectively collected ambulatory or pulmonary endpoints Long term data for endpoints Patient level data available for genotyping Registry (Patients) Six Minute Walk Test (
Slide 16: Ambulatory Data vs Primary EC
Ambulatory Data vs Primary EC Six-Minute Walk Test (6MWT) Loss of Ambulation (LOA) North Star Ambulatory Assessment (NSAA)
Slide 17: Identification of Primary External Control for Ambulatory Outcomes
Identification of Primary External Control (EC) for Ambulatory Outcomes from Italian Telethon and Leuven Centers Genetically Confirmed Amenable to Exon Skipping Exon 51 Skip Amenable Patients N=185 Italian Telethon and Leuven NMRC Pre-specified Criteria Based on Study 201/202 Corticosteroid treatmen
Slide 18: Primary EC Comparable to Studies 201/202 & 301
Primary EC Comparable to Studies 201/202 & 301 Parameter Primary EC N=12 Study 201/202 N=12 Study 301 N=60 Mean Age (years) 9.5 9.4 9.6 Mean 6MWT (m) 362.8 363.2 376.2 Mean NSAA 22.8 24.9 21.9 Corticosteroid Type Deflazacort 8 (67%) 8 (67%) 17 (28%) Prednisone 4 (33%) 4 (33%) 43 (72%) Key Baseline C
Slide 19: Primary EC and Study 201/202 Received High Standard of Care
Primary EC and Study 201/202 Received High Standard of Care Frequency of Physical Therapy (Days/wk or Usage) Primary EC: N=12 (Patients) Study 201/202 N=12 (Patients) 4-6 4 2 2-3 8 3 ≤1 0 5 None 0 2
Slide 20: Study 201/202 vs Primary EC: Individual 6MWT Over Years
Study 201/202 vs Primary EC: Individual 6MWT Over 4 Years Δ=147 m* p=0.007 Δ=165 m* p=0.001 ANCOVA with a covariate for Baseline 6MWT. *Δ= Difference in Mean Change from Baseline. Eteplirsen Study 201/202 (N=12) Primary EC (N=12)
Slide 21: Probability of Remaining Ambulatory: Kaplan-Meier Estimates
Probability of Remaining Ambulatory Kaplan-Meier Estimates for Study 201/202 vs Primary EC Eteplirsen (N=12) Primary External Control (N=12) Year 4 Estimate Study 201/202 = 83% Primary EC = 12% Log-rank p=0.007 BL Year 1 Year 2 Year 3 Year 4 Study 201/202 12 10 10 10 10 Primary EC 12 12 9 6 1 Probab
Slide 22: Study 201/202 vs Italian Telethon: Slowing of NSAA
Eteplirsen Study 201/202 vs Italian Telethon: Slowing of NSAA Directionally Consistent with 6MWT ∆3.4 (p=0.333) ∆ = Difference in mean change from baseline. # NSAA Activity 1 Stand 2 Walk 3 Stand from chair 4/5 Stand on one leg (right/left) 6/7 Climb box step (right/left) 8/9 Descend box step (right
Slide 23: Externally Controlled Trials Can be Persuasive
ICH E10 (2.5.4 Validity of Inference from External Controls) Externally Controlled Trials Can be Persuasive: Comparison of Study 201/202 vs Primary EC Disease has a well documented, highly predictable course DMD declines are well characterized for homogenous populations Covariates influencing the ou
Slide 24: Study 301 Interim Analysis of 6MWT and NSAA vs Primary EC
Study 301 Interim Analysis of 6MWT and NSAA vs Primary EC: Directionally Favoring Eteplirsen Patients at Year 2 ∆38.8 m (p=0.354) Eteplirsen-Treated (N=60) Primary EC (N=12) Mean (meters, ± SE) Mean Score 6MWT NSAA ∆3.8 (p=0.053) Eteplirsen-Treated (N=60) Italilan Telethon (N=9) For reference: Year
Slide 25: Pulmonary Data vs CINRG Control: FVC% Predicted
Pulmonary Data vs CINRG Control: Forced Vital Capacity % Predicted (FVC%p) (% FVC in healthy individuals normalized to age & height)
Slide 26: CINRG Duchenne Natural History Study
CINRG Duchenne Natural History Study Global (20 Centres) – 3 in EU (Sweden, Italy and UK) Study Period: 2006 – Present Largest prospective multicenter DMD natural history cohort N= 397 patients with pulmonary data CINRG website. www.cinrgresearch.org/. Accessed March 17, 2018. Registry (# of Patient
Slide 27: Pulmonary Outcomes Evaluated Addressing CHMP Feedback
Eteplirsen Pulmonary Outcomes Evaluated in 2 Ways Addressing CHMP Feedback Slope Model: FVC%p annual change by age (10 to <18 years) Studies 201/202, 301 & 204 Evaluated eteplirsen effects on patients who are expected to decline Time on Study 201/202: Change of FVC%p over 4 years Statistical analyse
Slide 28: Identification of CINRG Comparator for Slope Model Analysis
Identification of CINRG Comparator for Slope Model Analysis (Ages 10 to < 18 years) Genotyped Exon 51 CINRG Registry Patients N=397 Slope Model Criteria Glucocorticoid Tx FVC%p assessments for ages of 10 to < 18 years N=148 N=20
Slide 29: Slope Model: Ages 10 to <18 yrs vs Exon 51 CINRG EC
Slope Model: Ages 10 to <18 yrs vs Exon 51 CINRG EC Annual Change (FVC%p, -SE) P-value vs CINRG < 0.001 0.004 0.017 N/A
Slide 30: Identification of CINRG Comparator for Time on Study 201/202
Identification of CINRG Comparator for Time on Study 201/202 Over 4 Years Genotyped Exon 51 CINRG Registry Patients N=397 Slope Model Criteria Glucocorticoid Tx FVC%p assessments for ages of 10 to < 18 years N=148 N=20 Time on Study Criteria Glucocorticoid Tx BL Age of 7-13 years BL FVC%p of 84-124%
Slide 31: Time on Study 201/202: Change of FVC%p vs Genotyped CINRG EC
77.4% 87.5% Time on Study 201/202: Change of FVC%p vs Genotyped CINRG EC (N=67) Patients Aged 7-13 Years Change from Baseline Mean (SE) FVC%p By Year Absolute difference ~10% in FVC%p at Year 4 Years
Slide 32: Clinical Efficacy Has Been Convincingly Demonstrated
Clinical Efficacy Has Been Convincingly Demonstrated Major Objections Eteplirsen MAA Evidence from the 24 week placebo control period of Study 201 is weak Short treatment duration of placebo did not enable differentiation of effect Study 201/202 and interim analysis of 301 compared with external con
Slide 33: Eteplirsen Safety Experience is Favorable
Eteplirsen Safety Experience is Favorable and Generally Consistent with Pediatric DMD 171 clinical patients* (309 patient-years at ≥30 mg/kg); 106 patients with ≥ 2 years Infusion-related reactions; most commonly mild headache, rash, vomiting 1 SUSAR urticaria, resolved with no recurrence 263 post-m
Slide 34: Benefit Risk of Eteplirsen
Benefit Risk of Eteplirsen Craig M. McDonald, MD Study Chair, CINRG Duchenne Natural History Study Professor and Chair, Dept. Physical Medicine & Rehabilitation Professor of Pediatrics Director, Neuromuscular Disease Clinics University of California at Davis School of Medicine
Slide 35: Study 201/202: Eteplirsen Slows Disease Progression Across Multiple Endpoints
Study 201/202: Eteplirsen Slows Disease Progression Across Multiple Endpoints 6MWT NSAA FVC%p LOA BL 1 2 3 4 BL 1 2 3 4 BL 1 2 3 BL 1 2 3 4 Years Years Years Years
Slide 36: Declining FVC%p Linked to Clinically Meaningful Thresholds and Risk of Death
Declining FVC%p Linked to Clinically Meaningful Thresholds and Risk of Death (Based on CINRG Data) Modified from † Mayer, et al. 2017; CINRG Data: McDonald CM, et al. 2018. FVC%p Mean (SEM) PFT Value Age (years) Nocturnal hypoventilation Increased risk of death Clinical Progression Intervention Cont
Slide 37: Eteplirsen Slows the Rate of Pulmonary Decline Across Three Studies
Eteplirsen Slows the Rate of Pulmonary Decline Across Three Studies P-value vs CINRG < 0.001 0.004 0.017 N/A Annual Change (FVC%p, -SE)
Slide 38: Clinical Experience with Eteplirsen: Three Youngest Patients
Clinical Experience with Eteplirsen (Prof. McDonald): Three Youngest Patients Treated for > 3 Years 7.5 yrs (Study 203) 8.5 yrs (Study 203) 10 yrs (Study 301)
Slide 39: Questions
Questions Shamim Ruff, MSc (Moderator) Sr. Vice President, Chief Regulatory Affairs Officer
Slide 40: Backup Slides Displayed at Oral Explanation Q&A
Backup Slides Displayed at Oral Explanation Q&A
Slide 41: Similar Eteplirsen Benefit over Primary Comparator, Independent of Steroid Initiation
Study 201/202: Similar Eteplirsen Benefit over Primary Comparator, independent of age of steroid initiation and regimen Parameter Eteplirsen Combined 201/202 Studies (N=12) Primary External Control (amenable to Exon 51 skipping) (N=12) Age at Steroid Start 5.2 6.5 Corticosteroid Type Deflazacort 8 (
Slide 42: Study 201/202 vs Primary EC: Significant Benefit at Years 3 and 4
Δ=147 m* p=0.007 Δ=165 m* p=0.001 6MWT Study 201/202 vs Primary EC: Significant Benefit at Years 3 and 4 ANCOVA with a covariate for Baseline 6MWT. *Δ= Difference in Mean Change from Baseline. Both Groups Overlap at BL & Through Year 1 Mean 6MWT Distance (meters, ± SE)
Slide 43: Primary EC Comparable to CINRG Exon Cohort on LOA
Primary EC Comparable to CINRG Exon 51 Cohort on LOA CINRG, Exon 51, on steroids (N=37) Primary EC, Exon 51, on steroids (N=12) Probability of Remaining Ambulant 1.00 0.75 0.50 0.25 0.00 Years of Age 0 5 10 15 20 Median age of LOA was 13 years for both groups Kaplan-Meier Survival Estimate Data prov
Slide 44: Eteplirsen Preserves Ambulation: Comparison to EC and CINRG
Eteplirsen Preserves Ambulation: Comparison to EC and CINRG Exon 51 CINRG, Exon 51, on steroids (N=37) Eteplirsen, Exon 51, on steroids (N=12) Primary EC, Exon 51, on steroids (N=12) Data provided by CINRG and Primary External Control. Years of Age Probability of Remaining Ambulant Kaplan-Meier Surv
Slide 45: Proportion of Patients Who Lost Ambulation Consistent Between Studies
Proportion of Patients Who Lost Ambulation Was Consistent Between Study 201/202 and 301 *Interim analysis. Only patients who completed full 96 weeks of eteplirsen treatment, with 6MWT were included in denominator (n=35). Proportion of Patients with Loss of Ambulation (%) Proportion of Patients with
Slide 46: Study 201/202 vs Primary EC 6MWT Adjusting for Rise Time
Study 201/202 vs Primary EC 6MWT Adjusting for Ability to Rise, Rise Time For 201/202 vs Primary EC, there are only 1-2 patients in each group who were unable to rise independently at Baseline Therefore, an analysis adjusting for ability to rise was not feasible An analysis was conducted adjusting f
Slide 47: Slope Model Analysis Confirms Attenuated Pulmonary Decline
Age-Based (10 to <18 years) Slope Model Analysis Confirms that Eteplirsen Attenuates the Rate of Pulmonary Decline Pts # of Tests Study 301 42 184 Exon 51 CINRG 20 88 Pts # of Tests Study 204 20 117 Exon 51 CINRG 20 88 -3.79%/Yr -6.00%/Yr -3.66%/Yr -6.00%/Yr Study 301 Study 204
Slide 48: Study 301: Eteplirsen Benefit over Biomarin Placebo
Study 301: Eteplirsen Benefit over Biomarin Placebo – Pre-specified sensitivity analysis adjusting for steroid type Parameter Study 301 Primary Efficacy (N=59) Biomarin Study 044 Placebo (N=20) Age: Mean Min, Max 9.6 (7, 16) 8.8 (7, 12) 6MWT (m): Mean Min, Max 378 (301, 450) 368 (307, 437) Steroid T
Slide 49: Contemporary Natural History Data for PFTs
Contemporary Natural History Data for PFTs (CINRG, n=397) Longitudinal Models in DMD Patients 7 Years and Older Over Time PFT assessment GC use status Change per age in 7 to 9.9 year olds Change per age in 10 to 17.9 year olds Change per age in those 18 and older N (obs) N (indiv) Coefficient (p-val
Slide 50: CINRG Comparators: Address CHMP Concerns Regarding Variable Literature
CINRG Comparators: Address CHMP Concerns Regarding Variable Literature Dec 2016 April 2017 Nov 2017 CINRG Data*: Linear Decline Ages 10-18 CHMP (Day 180): Requested Pattern over Time for Study 201/202 Dec 2017 Mar 2018 CHMP (Day 120): UDP Age Range of 7-15.5 Too Broad and Pulmonary Literature Varied
Slide 51: Difference in FVC%p Annual Change Favors Eteplirsen
Difference in FVC%p annual change favors eteplirsen vs. external controls (Slope Models, Ages 10 - <18 years) Etep. Ctrl 12 20 42 20 20 20 12 148 42 148 20 148 N
Slide 52: Study 201/202: Similar Dystrophin Response at Week 48
Study 201/202: 30 mg/kg and 50 mg/kg Resulted in Similar Dystrophin Response at Week 48 Absolute Values Each bar graph N=6 Week 48
Slide 53: CINRG: Exon vs Exon Skip Amenable LoA
CINRG: Exon 44 vs Exon 51 Skip Amenable LoA Bello et al. Neurology. 2016; 87:4(4)401-9
Slide 54: Longitudinal 6MWD: Exon Skip Amenable vs Treated/Untreated
Longitudinal 6MWD: Exon 44 Skip Amenable vs. Treated/Untreated Exon 51 Exon 44 N=8 Eteplirsen N=12 Untx Exon 51 N=12
Slide 55: Brooke Upper Extremity Functional Grade
Brooke Upper Extremity Functional Grade 1 2 3 4 5 6 Starting with arms at the sides, the patient can abduct the arms in a full circle until they touch above the head. Can raise arms above head only be flexing the elbow or using accessory muscles. Cannot raise arms above head but can raise an 8oz. gl
Slide 56: FVC is Related to Upper Limb Function in DMD
FVC is Related to Upper Limb Function in DMD CINRG Duchenne Natural History Study Data; n = 2311 observations. OHR = Overhead Reach Patients with no hand function have very low FVC McDonald et al. Lancet 2017
Slide 57: PUL Assessment Items
PUL Assessment Items 1 PUL entry item to define the starting functional level (similar to Brooke score) 4 items: HIGH LEVEL – SHOULDER DIMENSION 9 items: MID LEVEL – ELBOW DIMENSION includes timed items 8 items: DISTAL LEVEL – WRIST and HAND DIMENSION
Slide 58: Study 4658-204 PUL Middle Domain – Non Ambulatory
Study 4658-204 PUL Middle Domain – NON AMBULATORY
Slide 59: Figure 8: Clinical
Figure 8: Day 180 JRAR Clinical
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