Exondys 51™ - eteplirsen Manufacturer: Sarepta Therapeutics, Inc. FDA Approval Date: September 19, 2016 Meredith Tilley, PharmD Candidate

Exondys 51™ - eteplirsen Objectives At the end of this presentation participants will be able to: Appropriately recommend Exondys 51™ - eteplirsen Effectively educate patients on the purpose, proper use and potential adverse effects of Exondys 51™ - eteplirsen

Exondys 51™ - eteplirsen Clinical Application Indications: Treatment of Duchenne muscular dystrophy (DMD) in patients with a mutation of the DMD gene that is amenable to exon 51 skipping Place in therapy: As the first medication approved for DMD, Exondys 51 is a promising first line treatment Exondys 51 [package insert].

Exondys 51™ - eteplirsen Duchenne Muscular Dystrophy Rare genetic disorder that primarily affects boys Presents in early childhood and is characterized by progressive muscle weakness and an absence of dystrophin Heart and respiratory muscle are affected by early teens One of 9 types of muscular dystrophy X linked recessive inheritance pattern- carried by the mother Very rarely seen in females- Life expectancy- most do not survive past teenage years, but some are beginning to live into their early 30s MDA. DMD. Assessed 2016.

Exondys 51™ - eteplirsen Clinical Application Contraindications/Black Box Warnings: None Warnings/Precautions: Exondys 51 [package insert].

Exondys 51™ - eteplirsen Clinical Application Pregnancy: No human or animal data Lactation: Exondys 51 [package insert].

Exondys 51™ - eteplirsen Drug Facts Pharmacology: Antisense oligonucleotide Binds to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patinets that are amenable to exon 51 skipping This allows for production of an internally truncated dystrophin protein Exondys 51 [package insert].

Exondys 51™ - eteplirsen Drug Facts Pharmacokinetics: A Cmax occurs near the end of infusion (1.1-1.2 hours) and follows linear kinetics D Volume of distribution= 600 ml/kg and is between 6-17% protein bound M Not metabolized by hepatic microsomes E t1/2= 3-4 hours. Clearance was 339 ml/hr/kg after 12 weeks of therapy Exondys 51 [package insert].

Exondys 51™ - eteplirsen Drug Interactions Does NOT significantly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 Does NOT induce CYP2B6, CYP3A4, or CYP1A2 NOT a substrate or inhibitor for OAT1, OAT3, OCT1, OCT2, OATP1b1, OATP1B3, P- gp, BCRP, MRP2, and BSEP Exondys 51 [package insert].

Exondys 51™ - eteplirsen Adverse Effects Common Adverse Effects: (eteplirsen%)[placebo%] Balance disorder (38%)(0%) Vomiting (38%)(0%) Contact dermatitis (25%)(0%) Exondys 51 [package insert].

Exondys 51™ - eteplirsen Monitoring Parameters Efficacy Monitoring: 6-minute walk test Muscle tissue dystrophin levels Toxicity Monitoring: Monitor for adverse reactions Exondys 51 [package insert].

Exondys 51™ - eteplirsen Prescription Information Dosing: 30 mg/kg once weekly as a 35-60 minute IV infusion Cost: – $300,000 per year Source: MarketWatch. Accessed 10/24/2016 Exondys 51 [package insert].

Exondys 51™ - eteplirsen Literature Review Title: Eteplirsen for the treatment of DMD Purpose To test eteplirsen’s ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT) Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Study Design: Phase 1: 24- week, randomized, double-blind, placebo- controlled phase 3 trial Phase 2: Long-term, open-label extension study 8 boys on 18-25 mg/day deflazacort 1 boy on 20 mg/day prednisone 2 boys on 25 mg/day prednisone 1 boy on 75 mg prednisone on Fridays and Saturdays Cardiac and pulmonary functions were stable Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Inclusion Criteria: Males aged 7-13 Confirmed DMD deletions correctable by skipping exon 51 6MWT distance of 200-400 meters Stable on glucocorticoids for >24 weeks 8 boys on 18-25 mg/day deflazacort 1 boy on 20 mg/day prednisone 2 boys on 25 mg/day prednisone 1 boy on 75 mg prednisone on Fridays and Saturdays Cardiac and pulmonary functions were stable Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Interventions Phase 1: Placebo (n=4) Eteplirsen 30 mg/kg/wk (n=4) Eteplirsen 50 mg/kg/wk (n=4) Phase 2: Eteplirsen 30 mg/kg/wk (n=2) Eteplirsen 50 mg/kg/wk(n=2) Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Primary Endpoints Dystrophin production 6MWT Safety profile Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Patient Demographics Placebo/Delayed Eteplirsen (n=4) Eteplirsen 30 mg/kg (n=4) Eteplirsen 30 mg/kg (n=2) Eteplirsen 50 mg/kg (n=4) Male 4 (100%) 2 (100%) Age 8.5 9.3 9.5 Height, cm 119.3 130.5 124.0 121.3 Weight, kg 30.6 34.8 30.0 29.0 Race, White 3 (75%) 1 (50%) 6MWT, m 394.5 355.3 407.0 396.0 Non white patients were Asian 30 mg/kg- older, taller, and heavier, 40 m less on 6MWT Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Results: Dystrophin Wk 12, mean change from BL, (p-value) Wk 24, Wk 48, All eteplirsen, 8 N/A 47.3 (<0.001) Eteplirsen 30 mg/kg, 4 ND 22.9 (<0.002) 51.7 (<0.001) Eteplirsen 50 mg/kg, 4 0.8 (NS) 42.9 (<0.008) Placebo/Delayed Eteplirsen, 4 -4.0 37.7 (<0.009) Eteplirsen 30 mg/kg, 2 -7.48 33.6 Eteplirsen 50 mg/kg, 2 -0.6 41.8 BL- baseline ND- not done NS- not significant Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Results: 6MWT Placebo 30 mg/kg 50 mg/kg Week 24 Change from BL -25.8 m -128.2 m -0.3 m Week 48 -68.4 m -153.4 m NS +21.0 m (p<0.016) Large decline at 24/48 wks in the 30 mg/kg group was due to 2 patients that were older, which has a faster rate of disease progression (if you took them out, the mean change in BL was +14.2 m at 24 wks and +19.9 at 48 wks) Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Results: Safety Well tolerated No changes in vital signs, PE, ECG, echocardiogram, or PFTs No changes in chemistries, hematology, coagulation, LFTs, or renal function Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Limitations Small sample sized (n=12) No long term data Is the data clinically significant? Did not help those with rapidly progressing disease Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Literature Review Author’s conclusions Potentially safe and effective for disease modifying therapy for patients already on glucocorticoids Increases dystrophin production in all patients treated >12 weeks Mendell JR, et al. Ann Neurol. 2013;74(5):637-47.

Exondys 51™ - eteplirsen Summary Exondys 51, eteplirsen, is the first drug approved to treat patients with DMD and is a promising treatment option for these patients Exondys 51 is dosed as a 30 mg/kg once weekly IV infusion over 35-60 minutes The most common adverse reactions seen with eteplirsen include balance disorders, vomiting, and contact dermatitis Eteplirsen has a low potential for drug-drug interactions

Exondys 51™ - eteplirsen References http://www.exondys51.com/ Exondys 51 [package insert]. Cambridge, MA: Sarepta Therapeutics, Inc; 2016. Duchenne Muscular Dystrophy. (2016). Accessed November 2, 2016, from https://www.mda.org/disease/duchenne- muscular-dystrophy Mendell JR, Rodino-klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74(5):637- 47.