P.289 Open-Label Evaluation of Eteplirsen in Patients With Duchenne Muscular Dystrophy Amenable to 51 Skipping: PROMOVI Trial Craig McDonald,1 Perry Shieh,2 Hoda Z. Abdel-Hamid,3 Anne M. Connolly,4 Navid Khan,5 Erica Koenig,5 Deb Steiner,5 Jyoti Malhotra,5 Wenfei Zhang,5 Baoguang Han,5 Emma Ciafaloni6; on behalf of the PROMOVI Clinical Investigators 1University of California Davis Health System and School of Medicine, Sacramento, CA; 2David Geffen School of Medicine at UCLA, Los Angeles, CA; 3UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA; 4St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO; 5Sarepta Therapeutics, Inc., Cambridge, MA; 6University of Rochester Medical Center, Rochester, NY

BACKGROUND RESULTS RESULTS RESULTS

• Duchenne muscular dystrophy (DMD) is a fatal, X-linked • 78 of 79 patients who received eteplirsen completed 96 weeks Table 3. Baseline Characteristics for 6MWT Matched Comparator Safety: PROMOVI Consistent With Study 201/202 neuromuscular disease caused by mutations1 of treatment; baseline characteristics are shown in Table 1 Analysis: PROMOVI vs Study 201/202 • Adverse events (AEs) reported in PROMOVI reflected those • Eteplirsen binds to exon 51 of dystrophin pre-mRNA to allow PROMOVI Study 201/202 observed in other PMO studies, with no major differences; a skipping of exon 51, restore the mRNA reading frame, and allow Table 1. Baseline Characteristics: Treated Group (Efficacy Set) Characteristic (n=42) (n=12) overall, once-weekly eteplirsen IV appeared to be well tolerated 9.0 ± 2.1 9.5 ± 1.2 translation of a truncated dystrophin protein1-3 Characteristic Eteplirsen IV 30 mg/kg/wk (N=79) Age, years • The majority of the treatment-emergent AEs (TEAEs) reported (7.0, 13.0) (7.4, 11.0) Age, years 9.1 ± 2.0 (7.0, 16.0) were mild or moderate in severity • Clinical trials of eteplirsen have demonstrated a significant 389.3 ± 41.9 363.2 ± 42.2 increase in dystrophin accumulation, and indicate 6MWT distance, m • No treatment-related discontinuations due to TEAEs Standing height, cm 125.5 ± 9.0 (106.0, 148.5) (301.0, 450.0) (256.0, 416.0) • AEs observed among patients who received eteplirsen and those eteplirsen may slow muscle deterioration, prolong ambulation, 25.0 ± 4.2 24.9 ± 4.9 Time since DMD diagnosis, months 53.3 ± 33.3 (5.5, 147.1) NSAA total score in the untreated control group were generally consistent with and preserve pulmonary function in patients with DMD with (17.0, 31.0) (17.0, 31.0) Corticosteroid treatment, n (%) AEs observed in a younger population with DMD and in patients 2-5 5.2 ± 0.8 6.2 ± 1.5 eligible genetic Deflazacort 22 (27.8) 10-m run, s (3.8, 7.2) (3.9, 8.7) with DMD receiving chronic corticosteroid treatment Prednisone 57 (72.2) — 43.0 ± 28.4 52.1 ± 24.1 One treatment-related serious AE of urticaria was observed Duration of corticosteroid use, months OBJECTIVE Corticosteroid schedule, n (%) (5.7, 120.4) (15.5, 91.7) approximately 15–20 minutes after infusion and resolved Continuous 65 (82.3) a approximately 1 hour after an IV steroid and antihistamine • To report results from the Phase 3 PROMOVI study of eteplirsen Intermittent 14 (17.7) NSAA=North Star Ambulatory Assessment. Values are mean ± SD (range). Primary efficacy subset for comparison with study 201/202, consists of all treated patients with ≥1 postbaseline assessment and baseline 6MWT distance of were administered; although the patient continued on efficacy/safety in boys with DMD amenable to exon 51 skipping 300–450 m, inclusive, baseline NSAA score 17–31, and age 7–13 years, inclusive. Values are mean ± SD (range), unless otherwise noted. eteplirsen without subsequent events and without pretreatment with corticosteroids, the event may have been METHODS Exon 51 Skipping and Dystrophin: PROMOVI Consistent With Figure 3. Mean Change From Baseline to Week 96 in 6MWT in related to drug hypersensitivity Eteplirsen-Treated Patients From Study 201/202 and PROMOVI Study 201/202 and Shows Accumulation Over Time — Overall, 8 eteplirsen-treated patients (10.1%) experienced Study Population Exon 51 skipping and increases in dystrophin were observed • Study Change From Baseline to Week 96 renal TEAEs; each was proteinuria, which resolved in all but • Confirmed DMD, amenable to exon 51 skipping 450 following eteplirsen treatment (Figure 2) (m) PROMOVI -68.9 one individual • 7–16 years of age, inclusive 400 201/202 -67.3 • Positive correlation was observed between exon 51 skipping vs — One infected venous port serious AE was reported as severe

• Stable dose of oral corticosteroids ≥24 weeks before study P Distance dystrophin (Pearson coefficient = 0.710 [ <0.001]; Spearman 350 and unrelated to treatment • Stable pulmonary function: forced vital capacity (FVC) ≥50% coefficient = 0.692 [P<0.001]) • 6-minute walk test (6MWT) distance: ≥300 m 300 Figure 2. Exon 51 Skipping and Dystrophin Accumulation in 250 CONCLUSIONS Study Design/Treatment Eteplirsen-Treated Patients a Mean (SE) 6MWT PROMOVI (n=42 ) Study 201/202 (n=12) • The PROMOVI study design is shown in Figure 1; treated 200 • PROMOVI, a large, US-based, multicenter study, contributes to the Exon 51 Skipping Dystrophin 0 12 24 36 48 60 72 84 96 patients received eteplirsen IV 30 mg/kg/wk for 96 weeks Time (weeks) growing body of evidence for eteplirsen and confirms evidence of 1.6 0.9 † † 0.630 aAt 12, 72, and 96 weeks, n=41 patients. One patient did not have a 6MWT value at Week 12, but did at later visits. † 1.091 0.8 0.532* 0.578† treatment effect and safety profile seen in study 201/202 Figure 1. Study Design 1.4 1.047 Another patient withdrew after Week 48. 1.2 0.7 • PROMOVI control arm did not retain sufficient patients, Treated group (amenable to exon 51 skipping) % Skipping † 0.6 Biopsy 0.724 Randomization to muscle biopsy schedule 51 1 FVC%p: PROMOVI Consistent With Study 201/202 in Slowing precluding statistically and clinically meaningful comparisons (40% of patients; 0.5 Biopsy 0.8 0.588† 0.303* Pulmonary Annual Decline 20% at Weeks 72 and 96 each) 0.4 0.244 • PROMOVI included a flawed comparison of eteplirsen-treated (all patients) Biopsy Biopsy 0.6 FVC%p data were compared to study 201/202 and the CINRG 10 (20% of patients) (40% of patients) 0.3 • 0.186 patients vs a mismatched control arm that consisted entirely of weeks 0.4 0.2 DNHS exon 51 cohort, matched for baseline characteristics Mean (SE) Exon Mean (SE) Exon

Mean(SE) % Normal Dystrophin patients with mutations not amenable to exon 51 skipping Eteplirsen IV 30 mg/kg/wk R 0.2 0.1 (Table 4) (n=79) Baseline Week 24 Week 48 Week 72 Week 96 0 0 — Inadequate choice of control group became clear only Baseline Week 24 Week 48 Week 72 Week 96 Baseline Week 24 Week 48 Week 72 Week 96 • Compared with the untreated CINRG DNHS exon 51 cohort, after study initiation, as emerging natural history data Control group (not amenable to exon 51 skipping) Time (weeks) Time (weeks) eteplirsen-treated patients experienced a significant, clinically Untreated (n=30) Absolute Difference of Means Fold Absolute Difference of Means Fold meaningful attenuation in pulmonary function decline (P<0.001; demonstrated patients with different mutations have different (Week 96 vs baseline) Changea P-Valueb (Week 96 vs baseline) Changea P-Valueb ) disease trajectories6-8 Study Endpoints 0.956 18.74 <0.001 0.516 7.02 <0.001 Figure 4 *P-value <0.05. †P-value <0.001. — The annual rate of decline in FVC%p was -3.3 based on ulnar • increased post treatment, demonstrating target • Primary: change from baseline to Week 96 in 6MWT distance aCalculated from scatter plot (not shown) of change from baseline dystrophin level vs change from baseline in b calculated height and -3.1 based on standing height engagement, and dystrophin protein accumulate