Sarepta Therapeutics : LBP.22 Mercuri et al. Safety tol and PK of etep in pts 6-48 mon with DMD

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There were no treatment-relateddiscontinuations or deaths, and no kidney toxicity was observed

1 serious TEAE, mild bronchiolitis, was reported in Cohort 2 and unrelated to treatment

3 patients experienced treatment-relatedTEAEs (vomiting, localized edema, flushing), all mild in severity

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• Shifts from baseline in serum chemistry values were not clinically significant

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All TEAEs were mild or moderate in severity

-Allpatients experienced at ≥1 TEAE, with the most common (≥50% of patients) consistent with those commonly seen in pediatric populations

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Safety

Eteplirsen was well tolerated in patients as young as 6 months of age, with no new safety signals after 96 weeks of treatment and no discernable difference between Cohort 1 and 2

LBP.22 Presented at the 2021 World Muscle Society Virtual Congress, September 20−24, 2021

Safety, Tolerability, and Pharmacokinetics of Eteplirsen in Patients 6-48 Months Old With Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping

E. Mercuri,1 A.M. Seferian,2 L. Servais,2-4 N. Deconinck,5,6 H. Stevenson,7 L. East,7 W. Zhang,7 S. Upadhyay,7 F. Muntoni8,9

1Pediatric Neurology Unit, Università Cattolica del Sacro Cuore Roma, Rome, Italy and Nemo Clinical Centre, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; 2I-Motion Institute, Hôpital Armand Trousseau, Paris, France; 3Division of Child Neurology, Centre de Références des Maladies Neuromusculaires, Department of Pediatrics, University Hospital Liège & University of Liège, Liège, Belgium; 4MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK; 5Centre de Référence Neuromusculaire and Paediatric Neurology Department, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, 1020 Brussels, Belgium; 6Neuromuscular Reference Center, UZ Gent, Ghent, Belgium; 7Sarepta Therapeutics, Inc., Cambridge, MA, USA; 8Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health, London, UK; 9National Institute for Health Research, Great Ormond Street Hospital Biomedical Research Centre, London, UK

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Objective	CONCLUSIONS
To evaluate the safety, tolerability,	• This was the first clinical trial of eteplirsen in patients aged 6-48 months, the youngest population of patients with DMD in a clinical trial to date
and pharmacokinetics of eteplirsen
treatment in male patients with Duchenne	• The safety experience in this study was consistent with the known safety profile of eteplirsen
muscular dystrophy (DMD) aged 6-48 months
• Eteplirsen was well tolerated in this young patient population with no evidence of kidney toxicity
who have a confirmed mutation of the DMD
gene amenable to exon 51 skipping in	- All treatment-emergent adverse events (TEAEs) were mild or moderate, and none led to death or discontinuation of study drug
Study 4658-102 (NCT03218995)	• Infusion-related reaction is an important identified risk; all infusion-related reactions were nonserious and consistent with those previously reported
Key Takeaway
• Eteplirsen pharmacokinetics were consistent between both cohorts and aligned with expectations based on previous clinical experience in boys with DMD older than 4 years of age

The safety and pharmacokinetic results

from Study 4658-102 contribute to

the body of evidence supportingBACKGROUND the early use of eteplirsen

in boys with DMD

• Progressive and irreversible muscle damage begins at birth in patients with DMD due to the absence of dystrophin protein1,2

• Motor development in patients ≤7 years of age often masks muscle degeneration, commonly leading to delayed diagnosis, while those >7 years of age tend to exhibit progressive deterioration and declining ambulatory function3-7
• Initiating treatment early before significant muscle degeneration has occurred may improve clinical outcomes8-10
• Eteplirsen is indicated to treat patients with DMD who have a mutation in the dystrophin gene amenable to exon 51 skipping6,11
• Previous studies in patients >4 years of age indicate eteplirsen is well tolerated and attenuates pulmonary and ambulatory decline compared with mutation- matched natural history cohorts6,11-14

STUDY DESIGN

RESULTS

Treatment Exposure

• Patients received a mean of
• 1. eteplirsen infusions (Cohort 1, 94.6; Cohort 2, 90.8); mean of 85.1 infusions at the 30-mg/kg dose
• 9/15 (60%) patients had an implantable venous access device port placed during the study
• Mean time on eteplirsen was
• 1. weeks (1.85 years), representing a total of 27.8 patient-yearsa of eteplirsen exposure (N=15)

aPatient years on eteplirsen is calculated as: (last treatment date - first treatment date + 7)/365.25.

Summary of TEAEs

	Cohort 1	Cohort 2	Total
	Age 24 to 48 months	Age 6 to <24 months
	(N=15)
Participants with ≥1 TEAE, n (%)	(n=9)	(n=6)
Any TEAE	9 (100)	6 (100)	15 (100)
TEAE related to study drug	2 (22.2)	1 (16.7)	3 (20.0)
Serious TEAE	0	1 (16.7)	1 (6.7)
Serious TEAE related to study drug	0	0	0
TEAE leading to discontinuation	0	0	0
TEAE leading to death	0	0	0
Number of TEAEs by severity
Mild	234	165	399
Moderate	5	12	17
Severe	0	0	0

TEAEs occurring in ≥50% of patients

	Cohort 1	Cohort 2	Total
Participants with TEAE by	Age 24 to 48 months	Age 6 to <24 months
(N=15)
preferred term, n (%)	(n=9)	(n=6)
Pyrexia	7 (77.8)	6 (100)	13 (86.7)
Cough	7 (77.8)	5 (83.3)	12 (80.0)
Nasopharyngitis	7 (77.8)	5 (83.3)	12 (80.0)
Vomiting	8 (88.9)	4 (66.7)	12 (80.0)
Diarrhea	5 (55.6)	3 (50.0)	8 (53.3)
Rhinitis	4 (44.4)	4 (66.7)	8 (53.3)

Study 4658-102 is a Phase 2, multicenter, open-label,dose-escalation study in the youngest population of patients with DMD in a clinical trial to date

Study Population

• Male patients 6-48 months of age with DMD amenable to exon 51 skipping
• • Cohort 1: aged 24-48 months
  • Cohort 2: aged 6 to <24 months
• Enrollment for Cohort 2 began after the first 3 Cohort 1 patients completed
  ≥12 infusions and all available safety data was reviewed

Once-weekly eteplirsen IV (up to 96 weeks)

Screening	Target dose: 30 mg/kg	EOS
visit
10-weekdose-titration period:
2, 4, 10, 20, 30 mg/kg
Study Endpoints
• Primary: Safety and tolerability	• Secondary: Pharmacokinetics

Pharmacokinetics

Pharmacokinetic characteristics of eteplirsen were consistent between both cohorts and aligned with expectations based on clinical experience in the older population

• Tmax of eteplirsen was estimated to be 0.4-0.6 hours after dosing, consistent across both cohorts and all dose levels
• Cmax and AUClast values increased with increasing dose level through 20 mg/kg and remained similar to the pharmacokinetic exposure parameters at 30 mg/kg on Weeks 10 and 24
• Variability was high across all dose levels, with overall geometric CV% values ranging from 82.8% to 136% for Cmax and 41.7% to 113% for AUClast
• At 30 mg/kg, eteplirsen exposure was consistent between cohorts, with Cohort 1 Cmax and AUClast values 1.1-1.5-fold of those observed in Cohort 2
• Urine pharmacokinetic parameters support that urinary excretion is time-independent and a major pathway of eteplirsen clearance

Key plasma and urine eteplirsen pharmacokinetic parameters

			Cohort 1					Cohort 2
	2 mg/kg	10 mg/kg	20 mg/kg	30 mg/kg	30 mg/kg	2 mg/kg	10 mg/kg	20 mg/kg	30 mg/kg	30 mg/kg
Parameter	(Week 2)	(Week 6)	(Week 8)	(Week 10)	(Week 24)	(Week 2)	(Week 6)	(Week 8)	(Week 10)	(Week 24)
Cmax, μg/mL -	n=8	n=9	n=9	n=9	n=8	n=5	n=6	n=6	n=6	n=6
geo. mean	9.67	46.5	63.3	93.7	78.2	4.22	17.2	85.0	63.8	59.7
(geo. CV%)	(75.9%)	(72.3%)	(123%)	(55.5%)	(92.2%)	(120%)	(192%)	(67.6%)	(124%)	(82.7%)
Tmax, h −	n=8	n=9	n=9	n=9	n=8	n=5	n=6	n=6	n=6	n=6
0.58	0.58	0.78	0.58	0.63	0.58	0.72	0.73	0.92	0.72
median (range)
(0.17, 2.67)	(0.47, 4.25)	(0.50, 2.75)	(0.50, 1.48)	(0.42, 6.83)	(0.42, 0.67)	(0.58, 3.32)	(0.53, 1.17)	(0.50, 2.75)	(0.58, 1.83)
AUClast, μg*h/mL -	n=8	n=9	n=9	n=9	n=8	n=5	n=6	n=6	n=6	n=6
geo. mean	13.8	56.1	92.1	119	100	6.13	27.8	81.4	85.0	89.6
(geo. CV%)	(118%)	(57.2%)	(94.7%)	(30.8%)	(42.5%)	(73.1%)	(113%)	(89.6%)	(114%)	(43.8%)
Ae(0-4h), µg -	n=3	n=7	n=6	n=8	n=7	n=3	n=6	n=5	n=6	n=4
7720	56,000	102,000	263,000	239,000	1430	28,700	65,600	94,700	147,000
mean (SD)
(9060)	(73,300)	(108,000)	(209,000)	(140,000)	(1390)	(24,100)	(47,900)	(68,500)	(132,000)
Fe(0-4h), % −	n=3	n=7	n=6	n=8	n=7	n=3	n=6	n=5	n=6	n=4
27.2	32.2	32.1	50.9	52.5	6.81	29.7	35.2	33.6	45.5
mean (SD)
(33.8)	(40.9)	(31.0)	(35.2)	(33.4)	(7.07)	(27.7)	(26.6)	(27.9)	(41.4)

EOS=end of study; IV=intravenous.

Ae(0-4h)=amount of unchanged drug excreted in urine 0-4h after dosing; AUClast=area under the curve from time 0 to last quantifiable concentration; Cmax=maximum plasma concentration; CV=coefficient of variance; Fe(0-4h)=fraction of drug excreted in urine 0-4h after dosing; geo.=geometric; Tmax=time of Cmax.

REFERENCES	ACKNOWLEDGMENTS & DISCLOSURES
1. Ciafaloni E, et al. J Pediatr. 2009;155(3):380-5. 2. Birnkrant DJ, et al. Lancet Neurol. 2018;17:251-67. 3. Brogna C, et al. PLoS One. 2019;14:e0218683. 4. McDonald CM, et al. Muscle Nerve. 2010;42(6):966-74.	The authors and Sarepta Therapeutics, Inc., thank the patients and their families. Study 4658-102 (NCT03218995) was funded by Sarepta Therapeutics, Inc. Editorial support was provided by Kristin M. Allan, PhD, of Eloquent Scientific
5.	Mazzone ES, et al. PLoS One. 2013;8(1):e52512. doi: 10.1371/journal.pone.0052512. 6. Mendell JR, et al. J Neuromusc Dis. 2021. doi: 10.3233/JND-200548. 7. Coratti G, et al. PLoS One. 2021;16(6):e0253882.	Solutions, and was funded by Sarepta Therapeutics, Inc. Disclosures: EM has received consultant fees from Sarepta Therapeutics, Inc. AMS has no conflicts to disclose. LS has participated on advisory boards for Sarepta Therapeutics, Inc.
8.	Kwon JM, et al. Muscle Nerve. 2016;54:186-91. 9. Beckers P, et al. Sci Rep. 2021;11:3011. doi: 10.1038/s41598-021-82725-z. 10. Ke Q, et al. World J Pediatr. 2019;15(3):219-25. 11. McDonald CM, et al. J	ND has participated on advisory boards for Sarepta Therapeutics, Inc. HS, LE, WZ, and SU are employees of Sarepta Therapeutics, Inc, and may own stock/options in the company. FM has received consultant fees and speaker honoraria
Neuromusc Dis. 2021; doi: 10.3233/JND-210643. 12. Mendell JR, et al. Ann Neurol. 2016;79:257-71. 13. Mendell JR, et al. Ann Neurol. 2013;74(5):637-47. 14. clinicaltrials.gov. NCT02420379.	from Sarepta Therapeutics, Inc.

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- All were mild in severity and most (43/44) were assessed as unrelated to study drug by the investigator

- The most common (≥20% of patients) were rhinorrhea, diarrhea, cough, vomiting, and pyrexia

• No adverse events of thrombocytopenia, hepatotoxicity, or hypersensitivity were reported

• No kidney toxicity was observed; screening for kidney toxicity yielded a single laboratory abnormality, deemed unrelated to treatment (Cohort 2)

- Laboratory abnormality: Patient had low creatinine clearance (59.8 mL/min) at screening and Week 24 prior to eteplirsen administration (56.9 mL/min); clearance values were otherwise normal throughout the study, and the patient completed the study

aDefined as events, reported with a start during or within 24 hours after an infusion, that were medically reviewed by a pharmacovigilance specialist and physician to determine if they met infusion-relatedcriteria.

80% of patients experienced ≥1 adjudicated infusion-relatedreactiona

ADDITIONAL SAFETY DETAILS

Adverse events relevant to identified or potential risks:

		PATIENT DETAILS
					Patient disposition
										Enrolled
		Baseline characteristics
									N=15
			Cohort 1	Cohort 2	Total
			Age 24-48 months	Age 6 to <24 months
			(N=15)
		Characteristic	(n=9)	(n=6)
		Cohort 1	Cohort 2
		, months	36.8 (8.2)	16.0 (7.1)	28.5 (12.9)			(24 to 48 months)	(6 to <24 months)
		Age						n=9
		Height/length, cm	96.6 (6.4)	77.1 (6.1)	88.8 (11.6)			n=6
		Weight, kg	16.3 (2.7)	10.6 (2.4)	14.0 (3.8)
		BMI, kg/m2	17.4 (1.8)	17.5 (1.7)	17.4 (1.7)
10-week eteplirsen dose titration
		Time since DMD diagnosis, months	12.3 (6.7)	7.8 (8.0)	10.5 (7.3)
						2, 4, 10, 20, 30 mg/kg
		Corticosteroid type, n (%)	2 (22.2)		2 (13.3)					(N=15)
		Deflazacort	0
		Prednisone	0	0	0
				48-96-week eteplirsen 30 mg/kg
		No corticosteroids taken	7 (77.8)	6 (100)	13 (86.7)
						(N=15)
		Corticosteroid frequency, n (%)	2 (22.2)		2 (13.3)
		Continuous	0
		Completed
		Intermittent	0	0	0
						N=15
		Values are mean (SD) unless otherwise noted. BMI=body mass index.

Presented at the 2021 World Muscle Society Virtual Congress, September 20−24, 2021