The Experts below are selected from a list of 945 Experts worldwide ranked by ideXlab platform
Edward M Kaye - One of the best experts on this subject based on the ideXlab platform.
-
longitudinal effect of Eteplirsen versus historical control on ambulation in duchenne muscular dystrophy
Annals of Neurology, 2016Co-Authors: Jerry R Mendell, Nathalie Goemans, Linda Lowes, L Alfano, Katherine Berry, James Shao, Edward M Kaye, Eugenio MercuriAbstract:Objective To 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). Methods Ambulatory 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. Results At 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. Interpretation Over 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
-
pp09 16 2691 Eteplirsen a phosphorodiamidate morpholino oligomer pmo for the treatment of duchenne muscular dystrophy dmd 3 2 year update on six minute walk test 6mwt pulmonary function testing pft and safety
European Journal of Paediatric Neurology, 2015Co-Authors: Edward M Kaye, Jerry R Mendell, Linda Lowes, Zarife Sahenk, Kandice Roush, A.m. Gomez, Vinod Malik, Louise R Rodinoklapac, L Alfano, Kevin M FlaniganAbstract:Background/Objective DMD, a rare, degenerative, X-linked recessive genetic disease is mostly caused by frame-shift mutations in the dystrophin gene, preventing production of dystrophin protein. Eteplirsen, an investigational PMO designed to enable production of internally truncated yet functional dystrophin in boys amenable to exon 51-skipping, was evaluated in previously conducted clinical studies (33, 28, and 201), and is currently being evaluated in ongoing clinical trials. Methods Twelve eligible boys aged 7–13 years were randomized 1:1:1 to Eteplirsen 30/50 mg/kg/wk, or placebo for 24 weeks. All patients transitioned into an ongoing open-label extension trial at Week 25 with Eteplirsen 30/50 mg/kg. Efficacy endpoints included 6MWT, PFT, and %-dystrophin positive fibers. Safety assessments included AE recording, ECG, ECHO, and safety laboratory testing. Results After 3.2 years of treatment, all patients previously evaluable on 6MWT (mITT; n=10) showed continued ambulation. A 65.4 meter treatment benefit (p≤0.017) on 6MWT through Week 168 was observed for patients in the Eteplirsen treated cohort (n=6) compared with the placebo/delayed-treatment cohort (n=4). After declining on average 7.6 meters/month baseline through Week 36, the placebo/delayed-treatment cohort experienced a decline of 2.2 meters/month and the Eteplirsen cohort a decline of 1.9 meters/month in the timeframes in which meaningful levels of dystrophin were likely produced (Week 36–168 for the Placebo/delayed-treatment cohort and Week 12–168 for the Eteplirsen cohort). All 12 patients demonstrated PFT stability baseline through Week 168, including MIP (+11.1%, p=NS), MEP (+13.5%, p=NS), and MIP/MEP %-predicted (-2.4%/-6.3%, p=NS). No deaths, discontinuations, treatment-related SAEs, immune activation including infusion reactions, or clinically significant abnormal laboratory, ECG, or ECHO findings were reported. Conclusion The observed slowed decline in walking distance and sustained pulmonary function contrasts with rapid declines in ambulation and pulmonary capacity observed in DMD natural history of boys this age. Eteplirsen was well tolerated after 3.2 years of weekly infusions.
-
Pharmacokinetic Properties of Chronic Administration of Eteplirsen in the Treatment of Boys with Duchenne Muscular Dystrophy (DMD) (P7.043)
Neurology, 2015Co-Authors: Jihad Saoud, J. Zhang, L Warner, C Kincaid, P Duda, Edward M KayeAbstract:OBJECTIVE: The objective of this analysis is to examine the pharmacokinetic profiles of Eteplirsen, a PMO designed to skip exon 51, following long-term administration in patients with DMD. BACKGROUND: DMD is a rare, degenerative, recessive, X-linked genetic disease that results in progressive muscle loss and premature death. It is caused by mutations in the dystrophin gene that disrupt the reading frame of the encoded mRNA and prevent production of dystrophin protein. Exon skipping by PMOs is a promising, disease-modifying approach to DMD and Eteplirsen is an investigational PMO designed to enable functional dystrophin production in boys amenable to exon 51 skipping (~13[percnt] of total DMD). DESIGN/METHODS: Twelve boys aged 7-10 years with eligible genotypes were randomized 1:1:1 to weekly IV Eteplirsen 30 mg/kg, 50 mg/kg, or placebo for 24 weeks (4658-us-201). All patients transitioned into an ongoing open-label extension, 4658-us-202, with 30 or 50 mg/kg. Blood samples for determination of the pharmacokinetic properties of Eteplirsen through up to 152 weeks of treatment as determined by HPLC/FL analysis of plasma samples. RESULTS: The plasma half-life of Eteplirsen was found to be between 3-4 hours for both cohorts, similar to that observed at Week 12 in 4658-us-201. Due to rapid decline in concentrations over 24 hours, little if any accumulation due to weekly dosing was expected and none was observed. There were no notable differences in Cmax, AUC, and CL at Weeks 12 and 152. PK profiles were similar to those previously reported in the DMD population after a 1-hour IV infusion of Eteplirsen in a phase Ib study (AVI-4658-28). CONCLUSIONS: The pharmacokinetic profile of Eteplirsen at 152 weeks showed concordance with previously conducted Phase I and II studies. Due to the short half-life and rapid decline in concentrations, accumulation was not observed with the current once weekly IV dosing schedule. Study Supported by: Sarepta Therapeutics Disclosure: Dr. Saoud has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Zhang has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Warner has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Kincaid has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Duda has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Kaye has received personal compensation for activities with Sarepta Therapeutics as an employee.
-
in vitro pharmacokinetic evaluation of Eteplirsen srp 4045 and srp 4053 three phosphorodiamidate morpholino oligomers pmo for the treatment of patients with duchenne muscular dystrophy dmd p5 061
Neurology, 2015Co-Authors: Peter Sazani, Jay S Charleston, T. Magee, C. Shanks, J. Zhang, M. Carver, Jihad Saoud, Edward M KayeAbstract:BACKGROUND: DMD is a rare, X-linked recessive, degenerative neuromuscular disorder that causes severe progressive muscle loss leading to premature death. The disease is caused by mutations in the DMD gene that disrupt the reading frame of the encoded dystrophin mRNA resulting in a lack of dystrophin, a protein that plays a key structural role in muscle fibers. Sarepta’s Phosphorodiamidate Morpholino Oligomer (PMO) chemistry and exon-skipping technology directs alternative splicing of the dystrophin pre-mRNA to restore the mRNA reading frame and enable translation of an internally truncated yet functional dystrophin protein. Eteplirsen, Sarepta’s lead investigational exon-skipping drug candidate, is designed to address deletion mutations amenable to exon 51 skipping (13[percnt] of total DMD population). SRP-4045 and SRP-4053 are additional exon skipping drug candidates in development designed to skip exons 45 or 53 respectively, addressing an additional 16[percnt] of the total DMD population (~8[percnt] each). DESIGN/METHODS: Studies conducted to evaluate the in vitro pharmacokinetic properties of each PMO include plasma protein binding and metabolic stability in hepatic microsomes of mice, rats, monkeys, and humans. Induction and inhibition of cytochrome P450 isoenzymes were also evaluated. RESULTS: Pharmacokinetic profiles for the three PMOs were similar. Each exhibited low protein binding in all species, no evidence of in vitro metabolism by hepatic microsomes, no extensive inhibition of the major drug metabolizing cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, and no induction of CYP1A2, CYP2B6, or CYP3A4 at biologically relevant concentrations in vitro. CONCLUSIONS: The in vitro pharmacokinetic profiles of Eteplirsen, SRP-4045 and SRP-4053 were similar and showed no significant interaction with total serum protein or metabolic enzymes. Study Supported by: Sarepta Therapeutics Disclosure: Dr. Sazani has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Magee has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Charleston has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Shanks has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Zhang has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Carver has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Saoud has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Kaye has received personal compensation for activities with Sarepta Therapeutics as an employee.
-
In Vitro Pharmacokinetic Evaluation of Eteplirsen, SRP-4045, and SRP-4053; Three Phosphorodiamidate Morpholino Oligomers (PMO) for the Treatment of Patients with Duchenne Muscular Dystrophy (DMD) (P5.061)
Neurology, 2015Co-Authors: Peter Sazani, Jay S Charleston, T. Magee, C. Shanks, J. Zhang, M. Carver, Jihad Saoud, Edward M KayeAbstract:BACKGROUND: DMD is a rare, X-linked recessive, degenerative neuromuscular disorder that causes severe progressive muscle loss leading to premature death. The disease is caused by mutations in the DMD gene that disrupt the reading frame of the encoded dystrophin mRNA resulting in a lack of dystrophin, a protein that plays a key structural role in muscle fibers. Sarepta’s Phosphorodiamidate Morpholino Oligomer (PMO) chemistry and exon-skipping technology directs alternative splicing of the dystrophin pre-mRNA to restore the mRNA reading frame and enable translation of an internally truncated yet functional dystrophin protein. Eteplirsen, Sarepta’s lead investigational exon-skipping drug candidate, is designed to address deletion mutations amenable to exon 51 skipping (13[percnt] of total DMD population). SRP-4045 and SRP-4053 are additional exon skipping drug candidates in development designed to skip exons 45 or 53 respectively, addressing an additional 16[percnt] of the total DMD population (~8[percnt] each). DESIGN/METHODS: Studies conducted to evaluate the in vitro pharmacokinetic properties of each PMO include plasma protein binding and metabolic stability in hepatic microsomes of mice, rats, monkeys, and humans. Induction and inhibition of cytochrome P450 isoenzymes were also evaluated. RESULTS: Pharmacokinetic profiles for the three PMOs were similar. Each exhibited low protein binding in all species, no evidence of in vitro metabolism by hepatic microsomes, no extensive inhibition of the major drug metabolizing cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, and no induction of CYP1A2, CYP2B6, or CYP3A4 at biologically relevant concentrations in vitro. CONCLUSIONS: The in vitro pharmacokinetic profiles of Eteplirsen, SRP-4045 and SRP-4053 were similar and showed no significant interaction with total serum protein or metabolic enzymes. Study Supported by: Sarepta Therapeutics Disclosure: Dr. Sazani has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Magee has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Charleston has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Shanks has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Zhang has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Carver has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Saoud has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Kaye has received personal compensation for activities with Sarepta Therapeutics as an employee.
Jerry R Mendell - One of the best experts on this subject based on the ideXlab platform.
-
Comparison of Long-term Ambulatory Function in Patients with Duchenne Muscular Dystrophy Treated with Eteplirsen and Matched Natural History Controls.
Journal of neuromuscular diseases, 2021Co-Authors: Jerry R Mendell, Craig M. Mcdonald, Eugenio Mercuri, Nathalie Goemans, Linda Lowes, Navid Khan, Nanshi Sha, Helen Eliopoulos, Lindsay AlfanoAbstract:Background Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with Eteplirsen (EXONDYS 51 ®) is established. Once-weekly Eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with Eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. Objective Compare long-term ambulatory function in Eteplirsen-treated patients versus controls. Methods Study 201/202 included 12 Eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. Results At Years 3 and 4, Eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of Eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, Eteplirsen-treated patients had milder NSAA decline than controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. Conclusion In this retrospective matched control study, Eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.
-
comparison of long term ambulatory function in patients with duchenne muscular dystrophy treated with Eteplirsen and matched natural history controls
Journal of neuromuscular diseases, 2021Co-Authors: Craig M. Mcdonald, Eugenio Mercuri, Jerry R Mendell, Nathalie Goemans, Navid Khan, Nanshi Sha, Helen Eliopoulos, L LowesAbstract:BACKGROUND Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with Eteplirsen (EXONDYS 51®) is established. Once-weekly Eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with Eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. OBJECTIVE Compare long-term ambulatory function in Eteplirsen-treated patients versus controls. METHODS Study 201/202 included 12 Eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. RESULTS At Years 3 and 4, Eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of Eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, Eteplirsen-treated patients demonstrated milder NSAA decline versus controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. CONCLUSION In this retrospective matched control study, Eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.
-
Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy.
Journal of neuromuscular diseases, 2019Co-Authors: Navid Khan, Jerry R Mendell, Linda Lowes, Helen Eliopoulos, Lixin Han, Erik K Henricson, T. Bernard Kinane, Heather Gordish-dressman, Craig M. McdonaldAbstract:BACKGROUND Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. OBJECTIVE Evaluate the effects of Eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. METHODS Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and
-
Duchenne Muscular Dystrophy Exon-Skipping Trials
Muscle Gene Therapy, 2019Co-Authors: Jerry R Mendell, Zarife Sahenk, Louise R. Rodino-klapacAbstract:This chapter demonstrates an alternative mode of molecular therapy with the goal of restoring the DMD gene to achieve clinical improvement using antisense oligonucleotides (AONs). Preclinical studies were successful in mdx mice showing persistent production of dystrophin at significant levels in large numbers of muscle fibers. These experimental studies led to the clinical introduction of a 2′-O-methyl-phosphorothioate oligonucleotide (2’OMePS) and a phosphorodiamidate morpholino oligonucleotide (PMO) to induce skipping of one or more exons, restoring the reading frame and allowing for the production of a BMD-like dystrophin. This chapter reviews the clinical trial experience, the side effect profiles, and the basis for FDA approval of the PMO product, introduced as Eteplirsen. Following approval the product is identified as Exondys 51®. The results of the long-term, 36-month clinical trial are described. The findings included a change in the rate of decline and prolonged ambulation in DMD boys compared to natural history controls. Exondys 51™ represents the first drug other than deflazacort (Emflaza®) ever approved for DMD.
-
Eteplirsen treatment attenuates respiratory decline in ambulatory and non ambulatory patients with duchenne muscular dystrophy
Journal of neuromuscular diseases, 2019Co-Authors: Navid Khan, Jerry R Mendell, Linda Lowes, Helen Eliopoulos, Lixin Han, Bernard T Kinane, Heather Gordishdressman, Erik K Henricson, Craig M. McdonaldAbstract:BACKGROUND Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. OBJECTIVE Evaluate the effects of Eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. METHODS Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change. RESULTS FVC% p annual change was greater for CINRG DNHS Exon 51 controls (- 6.00) versus patients in studies 201/202, study 204, and study 301 (- 2.19, P < 0.001; - 3.66, P 0.004; and - 3.79, P 0.017, respectively). FVC% p annual change in all Eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (- 5.67) and All CINRG DNHS (- 5.56) cohorts (P < 0.05, all comparisons). CONCLUSIONS Significant, clinically meaningful attenuation of FVC%p decline was observed in Eteplirsen-treated patients versus CINRG DNHS controls.
Linda Lowes - One of the best experts on this subject based on the ideXlab platform.
-
Comparison of Long-term Ambulatory Function in Patients with Duchenne Muscular Dystrophy Treated with Eteplirsen and Matched Natural History Controls.
Journal of neuromuscular diseases, 2021Co-Authors: Jerry R Mendell, Craig M. Mcdonald, Eugenio Mercuri, Nathalie Goemans, Linda Lowes, Navid Khan, Nanshi Sha, Helen Eliopoulos, Lindsay AlfanoAbstract:Background Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with Eteplirsen (EXONDYS 51 ®) is established. Once-weekly Eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with Eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. Objective Compare long-term ambulatory function in Eteplirsen-treated patients versus controls. Methods Study 201/202 included 12 Eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. Results At Years 3 and 4, Eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of Eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, Eteplirsen-treated patients had milder NSAA decline than controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. Conclusion In this retrospective matched control study, Eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.
-
Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy.
Journal of neuromuscular diseases, 2019Co-Authors: Navid Khan, Jerry R Mendell, Linda Lowes, Helen Eliopoulos, Lixin Han, Erik K Henricson, T. Bernard Kinane, Heather Gordish-dressman, Craig M. McdonaldAbstract:BACKGROUND Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. OBJECTIVE Evaluate the effects of Eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. METHODS Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and
-
Eteplirsen treatment attenuates respiratory decline in ambulatory and non ambulatory patients with duchenne muscular dystrophy
Journal of neuromuscular diseases, 2019Co-Authors: Navid Khan, Jerry R Mendell, Linda Lowes, Helen Eliopoulos, Lixin Han, Bernard T Kinane, Heather Gordishdressman, Erik K Henricson, Craig M. McdonaldAbstract:BACKGROUND Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. OBJECTIVE Evaluate the effects of Eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. METHODS Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change. RESULTS FVC% p annual change was greater for CINRG DNHS Exon 51 controls (- 6.00) versus patients in studies 201/202, study 204, and study 301 (- 2.19, P < 0.001; - 3.66, P 0.004; and - 3.79, P 0.017, respectively). FVC% p annual change in all Eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (- 5.67) and All CINRG DNHS (- 5.56) cohorts (P < 0.05, all comparisons). CONCLUSIONS Significant, clinically meaningful attenuation of FVC%p decline was observed in Eteplirsen-treated patients versus CINRG DNHS controls.
-
Eteplirsen a phosphorodiamidate morpholino oligomer pmo for duchenne muscular dystrophy dmd longitudinal comparison to external controls on six minute walk test 6mwt and loss of ambulation loa s42 004
Neurology, 2017Co-Authors: J.r. Mendell, Nathalie Goemans, Linda Lowes, Louise R Rodinoklapac, L Alfano, K Berry, S Moody, Emily Naughton, Eugenio MercuriAbstract:Objective: PMO Eteplirsen is designed to skip exon 51, restore the reading frame, and induce production of internally-shortened dystrophin in patients amenable to exon 51-skipping. Background: DMD, a rare, degenerative, X-linked disease occurring in ~1:5000 males worldwide results in progressive muscle loss and premature death. DMD is primarily caused by whole exon deletions resulting in a shift of the dystrophin mRNA reading frame that prevents production of functional dystrophin protein. Design/Methods: Analysis of 6MWT performance over 4 years compared boys treated with 30 or 50 mg/kg/wk Eteplirsen IV (N=12) versus a group of comparable, untreated external controls (N=13) as defined by age, corticosteroid use, and genotype. Results: At Year 4, a statistically significant treatment benefit of 162 meters on 6MWT was observed in Eteplirsen-treated patients versus external controls (p=0.0005). Sensitivity analyses of 6MWT with covariates including baseline 6MWT, age and glucocorticoid use resulted in differences >150 meters between the groups that were statistically significant (p Kaplan-Meier estimates of Loss of Ambulation (LOA) showed that 85% of the external control patients lost ambulation versus 17% of Eteplirsen-treated patients at Year 4 (log-rank p=0.011). Median age to LOA in the external cohort was 12.9 years. The Eteplirsen-treated patients had not reached median age of LOA as 10/12 were still ambulatory at Year 4; however, the median age of Eteplirsen-treated patients at this time point was 13.4. No major safety signal was observed. Data from the final study time-point will be presented. Conclusions: Eteplirsen slowed DMD progression as evidenced by a 162 meter advantage on the 6MWT compared to external control patients (p=0.0005) at Year 4. In addition, there was a reduction in risk of loss of ambulation in the Eteplirsen treated patients (p=0.011). The 6MWT and LOA data reported here were not included in the US prescribing information for Eteplirsen by the Food & Drug Administration. Study Supported by: Sarepta Therapeutics, Inc. DMD Italian Network University Hospitals, Leuven Disclosure: Dr. Mendell has received personal compensation for activities with Sarepta Therapeutics, Inc. Dr. Goemans has received personal compensation for activities with PRC, Biomarin, Biogen, and Italofarmaca as a consultant, speaker, and advisory board member. Dr. Rodino-Klapac has nothing to disclose. Dr. Lowes has received personal compensation for activities with AveXis, Inc., Bristol-Myers Squibb, Sarepta Therapeutics, and Pfizer as a consultant. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Moody has received personal compensation for activities with Sarepta Therapeutics, Inc. Ms. Naughton has received personal compensation for activities with Sarepta Therapeutics. Dr. Mercuri has nothing to disclose. Dr. Italian Network has nothing to disclose.
-
Eteplirsen, a Phosphorodiamidate Morpholino Oligomer (PMO) for Duchenne Muscular Dystrophy (DMD): Clinical Update and Longitudinal Comparison to External Controls on Six-Minute Walk Test (6MWT) (S28.001)
Neurology, 2016Co-Authors: J. Mendell, Nathalie Goemans, Linda Lowes, Lindsay Alfano, Louise R. Rodino-klapac, Zarife Sahenk, Sarah Lewis, K Berry, Ellyn L Peterson, Kim ShontzAbstract:Objective: DMD, a rare, degenerative, X-linked genetic disease results in progressive muscle loss and premature death, occurring in ~1:3500-5000 males worldwide. DMD is primarily caused by frameshift-causing whole-exon mRNA deletions that prevent production of dystrophin protein. Eteplirsen, a PMO, is designed to induce production of internally-shortened dystrophin in patients amenable to exon 51-skipping. Methods: In a 24-week double-blind placebo-controlled study, twelve 12 boys aged 7-13 years were randomized to weekly intravenous infusions of 30/50 mg/kg Eteplirsen or placebo, rolling-over to an ongoing open-label extension study (1:1 30/50 mg/kg). Clinical outcome measures included 6MWT and dystrophin expression. Routine safety assessments and cardiac monitoring were conducted. External control (EC) data were obtained from the DMD Italian Network and the Leuven Neuromuscular Research Center. A cohort (N=13) comparable to the Eteplirsen-treated boys was defined based on age at baseline, corticosteroid use, and genotype. 3 year longitudinal data were used for comparative analysis of 6MWT performance. Results: At Year 3, a statistically-significant treatment benefit of 151 meters on 6MWT was observed in Eteplirsen-treated patients compared with EC (p
Toshifumi Yokota - One of the best experts on this subject based on the ideXlab platform.
-
Molecular Diagnosis and Novel Therapies for Neuromuscular Diseases.
Journal of personalized medicine, 2020Co-Authors: Rika Maruyama, Toshifumi YokotaAbstract:With the development of novel targeted therapies, including exon skipping/inclusion and gene replacement therapy, the field of neuromuscular diseases has drastically changed in the last several years. Until 2016, there had been no FDA-approved drugs to treat Duchenne muscular dystrophy (DMD), the most common muscular dystrophy. However, several new personalized therapies, including antisense oligonucleotides Eteplirsen for DMD exon 51 skipping and golodirsen and viltolarsen for DMD exon 53 skipping, have been approved in the last 4 years. We are witnessing the start of a therapeutic revolution in neuromuscular diseases. However, the studies also made clear that these therapies are still far from a cure. Personalized genetic medicine for neuromuscular diseases faces several key challenges, including the difficulty of obtaining appropriate cell and animal models and limited its applicability. This Special Issue “Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases” highlights key areas of research progress that improve our understanding and the therapeutic outcomes of neuromuscular diseases in the personalized medicine era.
-
Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy
Gene Therapy, 2020Co-Authors: Kasia Dzierlega, Toshifumi YokotaAbstract:Duchenne muscular dystrophy (DMD) is one of the most common lethal muscle-wasting disorders affecting young boys caused by mutations in the DMD gene. Exon skipping has emerged as a promising therapy for DMD. Antisense oligonucleotides (AONs) are designed to induce the skipping of exon(s), in order to restore the reading frame, and therefore, allow for dystrophin expression. Eteplirsen and golodirsen, AONs for DMD exons 51 and 53 skipping, have been recently approved by the FDA. Viltolarsen, an AON for DMD exon 53 skipping, was approved in Japan earlier this year. Although promising, the efficacy of Eteplirsen and AON sequence employed remain controversial. In addition, exon skipping faces challenges including the applicability and delivery. This article reviews and discusses exon skipping and the current advances being made in the field, on drugs, multi-exon skipping, sequence design, and applicability. We also discuss challenges and future directions that will facilitate the development of exon skipping therapy.
-
Quantitative Evaluation of Exon Skipping in Immortalized Muscle Cells In Vitro.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Kenji Rowel Q. Lim, Toshifumi YokotaAbstract:Exon skipping through the use of antisense oligonucleotides (AOs) is currently one of the most promising approaches for treating Duchenne muscular dystrophy (DMD). While we now have a number of AO drug candidates in clinical trials, we are still faced with issues of poor or controversial efficacy in some of these drugs. This is the case with Eteplirsen, an exon 51-skipping AO that is the first and only FDA-approved drug for DMD to date. Effective procedures must, therefore, be set up for the in vitro screening of potential AOs for DMD treatment. Here, we describe one such procedure using immortalized DMD patient-derived muscle cells. Aside from allowing for the quantitative evaluation of candidate AOs based on their exon skipping efficiency and dystrophin protein rescue levels, these immortalized cells are stable, pure, easy to grow, and not subject to confounding by senescence-related issues. This procedure enables a more reliable screening of AOs prior to their entry in clinical trials and greatly facilitates the search for more efficacious candidate exon skipping AOs for DMD treatment.
-
Invention and Early History of Exon Skipping and Splice Modulation.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Kenji Rowel Q. Lim, Toshifumi YokotaAbstract:Since its discovery in 1977, much has been known about RNA splicing and how it plays a central role in human development, function, and, notably, disease. Defects in RNA splicing account for at least 10% of all genetic disorders, with the number expected to increase as more information is uncovered on the contribution of noncoding genomic regions to disease. Splice modulation through the use of antisense oligonucleotides (AOs) has emerged as a promising avenue for the treatment of these disorders. In fact, two splice-switching AOs have recently obtained approval from the US Food and Drug Administration: Eteplirsen (Exondys 51) for Duchenne muscular dystrophy, and nusinersen (Spinraza) for spinal muscular atrophy. These work by exon skipping and exon inclusion, respectively. In this chapter, we discuss the early development of AO-based splice modulation therapy-its invention, first applications, and its evolution into the approach we are now familiar with. We give a more extensive history of exon skipping in particular, as it is the splice modulation approach given the most focus in this book.
-
In Vivo Evaluation of Multiple Exon Skipping with Peptide-PMOs in Cardiac and Skeletal Muscles in Dystrophic Dogs
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Rika Maruyama, Yoshitsugu Aoki, Shin'ichi Takeda, Toshifumi YokotaAbstract:Exon skipping is an emerging approach to treating Duchenne muscular dystrophy (DMD), one of the most common lethal genetic disorders. Exon skipping uses synthetic antisense oligonucleotides (AONs) to splice out frame-disrupting exon(s) of DMD mRNA to restore the reading frame of the gene products and produce truncated yet functional proteins. The FDA conditionally approved the first exon-skipping AON, called Eteplirsen (brand name ExonDys51), targeting exon 51 of the DMD gene, in late 2016. Using a cocktail of AONs, multiple exons can be skipped, which can theoretically treat 80-90% of patients with DMD. Although the success of multiple exon skipping in a DMD dog model has made a significant impact on the development of therapeutics for DMD, unmodified AONs such as phosphorodiamidate morpholino oligomers (PMOs) have little efficacy in cardiac muscles. Here, we describe our technique of intravenous injection of a cocktail of peptide-conjugated PMOs (PPMOs) to skip multiple exons, exons 6 and 8, in both skeletal and cardiac muscles in dystrophic dogs and the evaluation of the efficacy and toxicity.
Em Kaye - One of the best experts on this subject based on the ideXlab platform.
-
Longitudinal effect of Eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy
2016Co-Authors: Goemans N, L Alfano, Lp Lowes, Berry K, Shao J, Em Kaye, Mercuri E, Ha Hamid, Bj ByrneAbstract:Objective To 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). Methods Ambulatory 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. Results At 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. Interpretation Over 3 years of follow-up, Eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC
-
pp09 16 2691 Eteplirsen a phosphorodiamidate morpholino oligomer pmo for the treatment of duchenne muscular dystrophy dmd 3 2 year update on six minute walk test 6mwt pulmonary function testing pft and safety
European Journal of Paediatric Neurology, 2015Co-Authors: Em Kaye, Jerry R Mendell, L Lowes, Zarife Sahenk, Kandice Roush, A.m. Gomez, Vinod Malik, Louise R Rodinoklapac, L Alfano, Kevin M FlaniganAbstract:Background/Objective DMD, a rare, degenerative, X-linked recessive genetic disease is mostly caused by frame-shift mutations in the dystrophin gene, preventing production of dystrophin protein. Eteplirsen, an investigational PMO designed to enable production of internally truncated yet functional dystrophin in boys amenable to exon 51-skipping, was evaluated in previously conducted clinical studies (33, 28, and 201), and is currently being evaluated in ongoing clinical trials. Methods Twelve eligible boys aged 7–13 years were randomized 1:1:1 to Eteplirsen 30/50 mg/kg/wk, or placebo for 24 weeks. All patients transitioned into an ongoing open-label extension trial at Week 25 with Eteplirsen 30/50 mg/kg. Efficacy endpoints included 6MWT, PFT, and %-dystrophin positive fibers. Safety assessments included AE recording, ECG, ECHO, and safety laboratory testing. Results After 3.2 years of treatment, all patients previously evaluable on 6MWT (mITT; n=10) showed continued ambulation. A 65.4 meter treatment benefit (p≤0.017) on 6MWT through Week 168 was observed for patients in the Eteplirsen treated cohort (n=6) compared with the placebo/delayed-treatment cohort (n=4). After declining on average 7.6 meters/month baseline through Week 36, the placebo/delayed-treatment cohort experienced a decline of 2.2 meters/month and the Eteplirsen cohort a decline of 1.9 meters/month in the timeframes in which meaningful levels of dystrophin were likely produced (Week 36–168 for the Placebo/delayed-treatment cohort and Week 12–168 for the Eteplirsen cohort). All 12 patients demonstrated PFT stability baseline through Week 168, including MIP (+11.1%, p=NS), MEP (+13.5%, p=NS), and MIP/MEP %-predicted (-2.4%/-6.3%, p=NS). No deaths, discontinuations, treatment-related SAEs, immune activation including infusion reactions, or clinically significant abnormal laboratory, ECG, or ECHO findings were reported. Conclusion The observed slowed decline in walking distance and sustained pulmonary function contrasts with rapid declines in ambulation and pulmonary capacity observed in DMD natural history of boys this age. Eteplirsen was well tolerated after 3.2 years of weekly infusions.
-
pp09 5 2350 pharmacokinetic evaluation of Eteplirsen srp 4045 and srp 4053 three phosphorodiamidate morpholino oligomers pmos for the treatment of patients with duchenne muscular dystrophy dmd
European Journal of Paediatric Neurology, 2015Co-Authors: P. Sazani, C. Shanks, J. Zhang, M. Carver, J.s. Charleston, J. Saoud, Em KayeAbstract:Background DMD is a rare, X-linked recessive, degenerative neuromuscular disorder caused by mutations in the dystrophin gene. The most prevalent mutations result in a reading frame shift and premature translation termination, resulting in a lack of dystrophin, a protein that plays a key structural role in muscle fiber function. Exon-skipping PMOs direct alternative splicing of the dystrophin pre-mRNA to restore the mRNA reading frame and enable translation of an internally truncated yet functional dystrophin protein. Eteplirsen, an investigational exon-skipping PMO, has been dosed at up to 50 mg/kg/wk for over 3 years in a clinical study with no reported clinically significant treatment-related adverse events. Preclinical analysis enables comparison of the pharmacokinetic properties of Eteplirsen, SRP-4045, and SRP-4053, three PMOs with specific sequences developed to treat patients with mutations amenable to skipping exon 51, 45 and 53, respectively. Methods Studies conducted to evaluate the in vitro pharmacokinetic properties of Eteplirsen, SRP-4045 and SRP-4053 included analysis of plasma protein binding and metabolic stability in hepatic microsomes of mice, rats, monkeys, and humans. Induction and inhibition of cytochrome P450 isoenzymes were also assessed. Results Pharmacokinetic profiles for the three PMOs were similar across species. All three compounds showed comparable Cmax, AUC, and clearance, and displayed similar dose proportionality across the three doses examined (5, 40, and 320 mg/kg). Each exhibited low protein binding in all species, no evidence of in vitro metabolism by hepatic microsomes, no extensive inhibition of the major drug metabolizing cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, and no induction of CYP1A2, CYP2B6, or CYP3A4 at biologically relevant concentrations. Conclusions The consistent preclinical profiles and lack of any significant, sequence-specific toxicities for Eteplirsen, SRP-4045, and SRP-4053 demonstrate PMOs to be a well-tolerated therapeutic class, with potential applications in a wide variety of disease indications.
-
PP09.16 – 2691: Eteplirsen, a phosphorodiamidate morpholino oligomer (PMO) for the treatment of Duchenne muscular dystrophy (DMD): 3.2 year update on six-minute walk test (6MWT), pulmonary function testing (PFT), and safety
European Journal of Paediatric Neurology, 2015Co-Authors: Em Kaye, Jerry R Mendell, Linda Lowes, Lindsay Alfano, Louise R. Rodino-klapac, Zarife Sahenk, Kandice Roush, A.m. Gomez, Vinod Malik, Kevin M FlaniganAbstract:Background/Objective DMD, a rare, degenerative, X-linked recessive genetic disease is mostly caused by frame-shift mutations in the dystrophin gene, preventing production of dystrophin protein. Eteplirsen, an investigational PMO designed to enable production of internally truncated yet functional dystrophin in boys amenable to exon 51-skipping, was evaluated in previously conducted clinical studies (33, 28, and 201), and is currently being evaluated in ongoing clinical trials. Methods Twelve eligible boys aged 7–13 years were randomized 1:1:1 to Eteplirsen 30/50 mg/kg/wk, or placebo for 24 weeks. All patients transitioned into an ongoing open-label extension trial at Week 25 with Eteplirsen 30/50 mg/kg. Efficacy endpoints included 6MWT, PFT, and %-dystrophin positive fibers. Safety assessments included AE recording, ECG, ECHO, and safety laboratory testing. Results After 3.2 years of treatment, all patients previously evaluable on 6MWT (mITT; n=10) showed continued ambulation. A 65.4 meter treatment benefit (p≤0.017) on 6MWT through Week 168 was observed for patients in the Eteplirsen treated cohort (n=6) compared with the placebo/delayed-treatment cohort (n=4). After declining on average 7.6 meters/month baseline through Week 36, the placebo/delayed-treatment cohort experienced a decline of 2.2 meters/month and the Eteplirsen cohort a decline of 1.9 meters/month in the timeframes in which meaningful levels of dystrophin were likely produced (Week 36–168 for the Placebo/delayed-treatment cohort and Week 12–168 for the Eteplirsen cohort). All 12 patients demonstrated PFT stability baseline through Week 168, including MIP (+11.1%, p=NS), MEP (+13.5%, p=NS), and MIP/MEP %-predicted (-2.4%/-6.3%, p=NS). No deaths, discontinuations, treatment-related SAEs, immune activation including infusion reactions, or clinically significant abnormal laboratory, ECG, or ECHO findings were reported. Conclusion The observed slowed decline in walking distance and sustained pulmonary function contrasts with rapid declines in ambulation and pulmonary capacity observed in DMD natural history of boys this age. Eteplirsen was well tolerated after 3.2 years of weekly infusions.
-
PP09.5 – 2350: Pharmacokinetic evaluation of Eteplirsen, SRP-4045, and SRP-4053; Three phosphorodiamidate morpholino oligomers (PMOs) for the treatment of patients with Duchenne muscular dystrophy (DMD)
European Journal of Paediatric Neurology, 2015Co-Authors: P. Sazani, C. Shanks, J. Zhang, M. Carver, J.s. Charleston, J. Saoud, Em KayeAbstract:Background DMD is a rare, X-linked recessive, degenerative neuromuscular disorder caused by mutations in the dystrophin gene. The most prevalent mutations result in a reading frame shift and premature translation termination, resulting in a lack of dystrophin, a protein that plays a key structural role in muscle fiber function. Exon-skipping PMOs direct alternative splicing of the dystrophin pre-mRNA to restore the mRNA reading frame and enable translation of an internally truncated yet functional dystrophin protein. Eteplirsen, an investigational exon-skipping PMO, has been dosed at up to 50 mg/kg/wk for over 3 years in a clinical study with no reported clinically significant treatment-related adverse events. Preclinical analysis enables comparison of the pharmacokinetic properties of Eteplirsen, SRP-4045, and SRP-4053, three PMOs with specific sequences developed to treat patients with mutations amenable to skipping exon 51, 45 and 53, respectively. Methods Studies conducted to evaluate the in vitro pharmacokinetic properties of Eteplirsen, SRP-4045 and SRP-4053 included analysis of plasma protein binding and metabolic stability in hepatic microsomes of mice, rats, monkeys, and humans. Induction and inhibition of cytochrome P450 isoenzymes were also assessed. Results Pharmacokinetic profiles for the three PMOs were similar across species. All three compounds showed comparable Cmax, AUC, and clearance, and displayed similar dose proportionality across the three doses examined (5, 40, and 320 mg/kg). Each exhibited low protein binding in all species, no evidence of in vitro metabolism by hepatic microsomes, no extensive inhibition of the major drug metabolizing cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, and no induction of CYP1A2, CYP2B6, or CYP3A4 at biologically relevant concentrations. Conclusions The consistent preclinical profiles and lack of any significant, sequence-specific toxicities for Eteplirsen, SRP-4045, and SRP-4053 demonstrate PMOs to be a well-tolerated therapeutic class, with potential applications in a wide variety of disease indications.