Eteplirsen in the treatment of Duchenne muscular dystrophy

Figures & data

Figure 1 Eteplirsen is an exon-skipping therapeutic.

Notes: Eteplirsen (green bar) specifically recognizes exon 51 of the DMD gene. Upon binding, it influences the splicing machinery to skip exon 51 from the mature mRNA transcript. This restores the reading frame of DMD, allowing for successful translation of a shortened but functional dystrophin protein. Shown above is a case where eteplirsen is used to treat a DMD patient with a deletion spanning exons 49 and 50. This creates an out-of-frame frameshift that introduces a premature stop codon and results in nonproduction of dystrophin.
Abbreviations: DMD, Duchenne muscular dystrophy; mRNA, messenger RNA.

Figure 2 Chemical structures for the 2′O-methyl phosphorothioate (2′O-MePS) and phosphorodiamidate morpholino oligomer (PMO) classes of antisense oligonucleotides (AOs).

Notes: Shown in relation to native DNA and RNA structures. Eteplirsen is a PMO and has the basic structure depicted above. In contrast to the negatively charged 2′O-MePS AOs, PMOs lack charge. This property is thought to be associated with the high stability of PMOs and their increased safety as a therapeutic agent.

Table 1 Information listing of all conducted, ongoing, and recruiting clinical trials on eteplirsen

ClinicalTrials. gov ID	Start month and year	Phase	Description	Participant profile, dosing scheme	Route	Status (month finished or estimated to finish)	Reference(s)
NCT00159250	October 2007	I/II	Single-blind, placebo-controlled, nonrandomized, dose-ranging study testing primarily for safety and tolerability, secondarily for efficacy of local treatment with eteplirsen	Seven patients, two cohort groups; one low-dose (0.09 mg) cohort of two patients, one high-dose (0.9 mg) cohort of five patients; patients all male, 10–16 years old at enrollment	Intramuscular	Complete (March 2009)	^Citation39
NCT00844597	January 2009	I/II	Open-label, non-placebo-controlled, nonrandomized, dose-ranging study testing primarily for safety and tolerability, secondarily for pharmacokinetics, efficacy of systemic treatment with eteplirsen	19 patients, six cohort groups; cohorts given either 0.5, 1, 2, 4, 10, or 20 mg/kg eteplirsen per week for at most 12 weeks; patients all male, 5–15 years old at enrollment	Intravenous	Complete (December 2010)	^Citation34
NCT01396239	July 2011	II	Double-blind, placebo-controlled, randomized, two- dose study testing for efficacy of systemic treatment with eteplirsen; safety, tolerability, pharmacokinetics also examined	12 patients, three cohort groups, four patients per cohort; cohorts given either 0 mg/kg (placebo group), 30 mg/kg, or 50 mg/kg eteplirsen per week for 24 weeks; patients all male, 7–13 years old at enrollment	Intravenous	Complete (June 2012)	^Citation35
NCT01540409	February 2012	II	Open-label, non-placebo-controlled, two-dose extension study of NCT01396239, testing for long- term efficacy, safety, and tolerability of systemic treatment with eteplirsen	Same profile as NCT01396239, except placebo cohort was converted to delayed eteplirsen-treated cohort; four patients in placebo cohort were split randomly into two subcohorts given either 30 mg/kg or 50 mg/kg eteplirsen per week; NCT01396239-treated patients continued to receive the same dose; treatment extended for an additional 212–236 weeks	Intravenous	Ongoing, not recruiting (September 2016)	^Citation27,Citation35
NCT02255552	September 2014	III	Open-label, untreated-controlled, nonrandomized study testing for efficacy of systemic treatment with eteplirsen; results from this confirmatory study will be used for the final FDA-approval decision	160 patients projected, two cohort groups, 80 patients per cohort; cohorts will either be treated with 30 mg/kg eteplirsen per week or untreated; study to run for 96 weeks; male patients 7–16 years old eligible for study enrollment	Intravenous	Recruiting (May 2019)	^Citation23
NCT02286947	November 2014	II	Open-label, uncontrolled study testing primarily for safety, tolerability, secondarily for efficacy of systemic treatment with eteplirsen in advanced-stage DMD patients	20 patients projected (actual count not reported as of writing); all enrolled patients will be given 30 mg/kg eteplirsen per week for 96 weeks; male patients 7–21 years old eligible for study enrollment	Intravenous	Ongoing, not recruiting (September 2017)	NA
NCT02420379	May 2015	II	Open-label, controlled, nonrandomized study similar to NCT02286947, but for patients with early-stage DMD	40 patients projected, two cohort groups, 20 patients per cohort; one cohort will receive 30 mg/kg eteplirsen treatment per week; other cohort will consist of patients with mutations not amenable to eteplirsen treatment (observed only); study to run for 96 weeks; male patients 4–6 y/o eligible for study enrollment	Intravenous	Recruiting (February 2018)	NA

Note: Data assembled from trial details posted on ClinicalTrials.gov (as of January 2017), and indicated references, when available.

Abbreviations: FDA, US Food and Drug Administration; NA, not applicable; DMD, Duchenne muscular dystrophy.

Table 2 Major inclusion/exclusion criteria for NCT00844597, NCT01396239/NCT01540409, and NCT02255552

Criteria	Clinical trial
	NCT00844597	NCT01396239/NCT01540409	NCT02255552
Sex, age	Male, 5–15 years	Male, 7–13 years	Male, 7–16 years
Genotype	Has confirmed out-of-frame deletion amenable to exon 51 skipping (for all trials)
Corticosteroid use	Not detailed,* as long as patient receives standard of care	Using at a stable dose for at least 24 weeks	Using at a stable dose for at least 24 weeks
Cardiac health-related drug use	Not detailed,** as long as patient receives standard of care	Using at a stable dose for at least 24 weeks and for trial duration	Not detailed
Distance walked independently	At least 25 m	Mean 180–440 m in 6 minutes	Mean of at least 300 m in 6 minutes
Respiratory function	At least 50% of predicted FVC, not requiring ventilatory assistance, stable (for all trials)
Cardiac function	LVEF ≥35%, FS ≥25%, stable state	LVEF >40%, stable state	LVEF >50%, stable state
Others	Informed consent/assent required; no significant medical conditions; must not be receiving any treatment (other than those mentioned above), experimental or otherwise, deemed to confound trial results

Notes:

* All enrollees but one were on corticosteroids. Type, dose, and dosing regimen varied among enrollees. No information given on how long patients were on corticosteroids prior to the trial.

** Three enrollees were receiving drugs known to treat cardiac symptoms at study entry. No information was given as to how long patients were on these drugs prior to the trial. One other enrollee was subjected to treatment with such drugs during the study, due to complications deemed consistent with natural Duchenne muscular dystrophy progression. Information obtained from trial details posted on ClinicalTrials.gov (as of January 2017). A more detailed and complete listing of these criteria can be found on that site.

Abbreviations: FVC, forced vital capacity; LVEF, left ventricular ejection fraction; FS, fractional shortening.

Table 3 Key efficacy data from NCT01396239/NCT01540409

Assay	Parameter measured	Dose#	Sample size (N)	Results
Immunostaining on muscle biopsies	% dystrophin-positive fibers	30 mg/kg weekly	4	+22.9% from BL at week 24 (P≤0.002); +51.7% from BL at week 48 (P≤0.001)
		50 mg/kg weekly Combined	4 11	Not tested at week 24; +42.9% from BL at week 48 (P≤0.008) 17.4% at week 180,* range 1.42%–33%
Western blot	% dystrophin protein of normal levels	Combined	11	0.93% at week 180,* range 0%–2.47%
6-minute walk test	Independent walking distance in 6 minutes	30 mg/kg weekly	4	No significant difference from placebo/delayed cohort at week 48
		50 mg/kg weekly	4	87.4 m difference in distance decline from placebo/delayed cohort at week 48 (P≤0.001)
		Combined	4	67.3 m difference in distance decline from placebo/delayed cohort at week 48 (P≤0.001)
			12	151 m difference in distance decline from matched historical controls at year 3 (P<0.01)
Pulmonary	% pMIP	Combined	12	−2.2% from BL at year 3**
function tests	% pMEP	Combined	12	−5% from BL at year 3**
	% pFVC	Combined	12	−9.4% from BL at year 3**

Notes:

# For the “combined” dose, data from the 30 mg/kg, 50 mg/kg, and placebo/delayed cohorts were compiled for analysis;

* BL comparison not suitable;

** comparison to matched historical controls not possible, significance not determined either. Information obtained from clinical trial results and from the US Food and Drug Administration summary review of eteplirsen.^23,27,35 Results provided are average values unless otherwise stated.

Abbreviations: BL, baseline; pMIP, predicted maximum inspiratory pressure; pMEP, predicted maximum expiratory pressure; pFVC, predicted forced vital capacity.

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