Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

被引：401

作者：

Mendell, Jerry R. ^{[1
,2
,3
]}

Goemans, Nathalie ^{[4
]}

Lowes, Linda P. ^{[1
,3
]}

Alfano, Lindsay N. ^{[1
,3
]}

Berry, Katherine ^{[1
,3
]}

Shao, James ^{[5
]}

Kaye, Edward M. ^{[5
]}

Mercuri, Eugenio ^{[6
]}

Hamid, Hoda Abdel ^{[19
]}

Byrne, Barry J. ^{[20
]}

Connolly, Anne M. ^{[21
,22
]}

Dracker, Robert A. ^{[23
]}

Frank, L. Matthew ^{[24
,25
]}

Heydemann, Peter T. ^{[26
]}

O'Brien, Kevin C. ^{[27
]}

Sparks, Susan E. ^{[28
]}

Specht, Linda A. ^{[29
]}

Rodino-Klapac, Louise ^{[30
,31
,32
]}

Sahenk, Zarife ^{[30
,31
,32
]}

Al-Zaidy, Samiah ^{[30
,31
,32
]}

Cripe, Linda H. ^{[30
,31
,32
]}

Lewis, Sarah ^{[30
,32
]}

Pane, M. ^{[6
]}

Mazzone, E. ^{[6
]}

Messina, Sonia ^{[7
]}

Vita, G. L. ^{[7
]}

D'Amico, A. ^{[8
]}

Bertini, E. S. ^{[8
]}

Berardinelli, A. ^{[9
]}

Torrente, Y. ^{[10
]}

Magri, F. ^{[10
]}

Comi, G. P. ^{[10
]}

Baranello, G. ^{[11
]}

Mongini, T. ^{[12
]}

Pini, A. ^{[13
]}

Battini, R. ^{[14
]}

Pegoraro, E. ^{[15
]}

Bruno, C. ^{[16
]}

Politano, L. ^{[17
]}

Previtali, S. ^{[18
]}

机构：

[1] Nationwide Childrens Hosp, Columbus, OH USA

[2] Ohio State Univ, Dept Pediat & Neurol, Columbus, OH 43210 USA

[3] Paul D Wellstone Muscular Dystrophy Cooperat Res, Rochester, NY USA

[4] Univ Hosp Leuven, Leuven, Belgium

[5] Sarepta Therapeut, Cambridge, MA USA

[6] Univ Cattolica Sacro Cuore, Rome, Italy

[7] Univ Messina, Messina, Italy

[8] Infant Jesus Hosp, Rome, Italy

[9] Casimiro Mondino Fdn, Pavia, Italy

[10] Univ Milan, Milan, Italy

[11] Neurol Inst Carlo Besta, Milan, Italy

[12] Univ Turin, Turin, Italy

[13] Maggiore Hosp, Bologna, Italy

[14] Stella Maris Inst, Pisa, Italy

[15] Univ Padua, Padua, Italy

[16] Ist Giannina Gaslini, Genoa, Italy

[17] Univ Naples 2, Naples, Italy

[18] Ist Sci San Raffaele, Dept Neurol, I-20132 Milan, Italy

[19] Univ Pittsburgh, Div Pediat Neurol, Pittsburgh, PA USA

[20] Univ Florida, Sch Med, Pediat Mol Genet & Microbiol, Gainesville, FL USA

[21] Washington Univ, Dept Neurol, Neurol & Pediat, St Louis, MO USA

[22] Washington Univ, Dept Pediat, Neurol & Pediat, St Louis, MO 63130 USA

[23] Summerwood Pediat Infusacare Med Serv, Syracuse, NY USA

[24] Eastern Virginia Med Sch, Norfolk, VA USA

[25] Childrens Hosp Kings Daughters, Norfolk, VA USA

[26] Rush Univ Med Ctr, Div Child Neurol, Dept Pediat & Neurol, Chicago, IL USA

[27] Univ Calif Irvine, Miller Childrens Hosp Long Beach, Irvine, CA USA

[28] Carolinas Med Ctr, Levine Childrens Hosp, Clin Gen Dept Pediat, Charlotte, NC 28203 USA

[29] Dartmouth Hitchcock Med Ctr, Pediat Neurol, Lebanon, NH USA

[30] Nationwide Childrens Hosp, Columbus, OH USA

[31] Ohio State Univ, Dept Pediat Neurol, Columbus, OH USA

[32] Paul D. Wellstone Muscular Dystrophy Cooperat, Rochester, NY USA

来源：

ANNALS OF NEUROLOGY | 2016年 / 79卷 / 02期

关键词：

6-MINUTE WALK TEST; EXON SKIPPING THERAPY; NATURAL-HISTORY; TOXICOLOGY EVALUATION; DISEASE PROGRESSION; PULMONARY-FUNCTION; LIFE EXPECTANCY; END-POINTS; RESTORATION; RNA;

D O I：

10.1002/ana.24555

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

ObjectiveTo continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). MethodsAmbulatory DMD patients who were 7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype. ResultsAt 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. InterpretationOver 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257-271

引用

页码：257 / 271

页数：15

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