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

2. 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

3. 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].

4. 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.

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

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

7. 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].

8. Exondys 51™ - eteplirsen Drug Facts
Pharmacokinetics: A
Cmax occurs near the end of infusion
( 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].

9. 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].

10. 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].

11. 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].

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

13. 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):

14. 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 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):

15. Exondys 51™ - eteplirsen Literature Review
Inclusion Criteria:
Males aged 7-13
Confirmed DMD deletions correctable by skipping exon 51
6MWT distance of meters
Stable on glucocorticoids for >24 weeks
8 boys on 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):

16. 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):

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

18. 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):

19. 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):

20. Exondys 51™ - eteplirsen Literature Review
Results:
6MWT
Placebo
30 mg/kg
50 mg/kg
Week 24
Change from BL
-25.8 m m
-0.3 m
Week 48
-68.4 m 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 m at 24 wks and at 48 wks)
Mendell JR, et al. Ann Neurol. 2013;74(5):

21. 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):

22. 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):

23. 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):

24. 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 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

25. Exondys 51™ - eteplirsen References
Exondys 51 [package insert]. Cambridge, MA: Sarepta Therapeutics, Inc; 2016.
Duchenne Muscular Dystrophy. (2016). Accessed November 2, 2016, from muscular-dystrophy
Mendell JR, Rodino-klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74(5):