Eteplirsen showed safety, efficacy over 2 years in Duchenne muscular dystrophy

PHILADELPHIA – Eteplirsen safely maintained its beneficial effect on walking speeds for certain patients with Duchenne muscular dystrophy for more than 2 years and was the first drug to show stabilized diaphragm function over the same period.

The investigational gene therapy drug had a stabilizing effect on patients’ walking speed over the course of 120 weeks regardless of whether they started it earlier or later in the open-label extension of the initial 24-week, randomized trial, but those who started treatment earlier maintained a higher walking speed, Dr. Jerry R. Mendell said at the annual meeting of the American Academy of Neurology.

Coinvestigator Dr. Edward M. Kaye of Sarepta Therapeutics, the study sponsor, presented in-depth safety and pharmacokinetics data that showed no significant treatment-related adverse events with eteplirsen in the small study. No patients have discontinued or disrupted treatment, and no laboratory evidence of toxicity has been seen to date.

The initial 24-week, double-blind, randomized, placebo-controlled study involved four patients who were given the equivalent of 30 mg/kg eteplirsen weekly, four given 50 mg/kg eteplirsen weekly, and four given placebo. At the start of the open-label extension study, two of the placebo-treated patients were transitioned to 30 mg/kg weekly and two to 50 mg/kg weekly.

All patients underwent muscle biopsy at baseline, followed by biopsies at 12 weeks in two of the high-dose patients and in two of the placebo-treated patients, and at 24 weeks in the four patients taking 30 mg/kg weekly and in two placebo-treated patients.

"This design permitted a comparison between high dose over a shorter time interval and low dose over a longer time interval," said Dr. Mendell of the Center for Gene Therapy at Nationwide Children’s Hospital, Columbus, Ohio.

All patients underwent a biopsy at 1 year (48 weeks) in the open-label extension (Ann. Neurol. 2013;74:637-47).

By 48 weeks, the mean percentage of dystrophin-positive muscle fibers was 34% in the placebo/30 mg/kg delayed-treatment group, 43% in the placebo/50 mg/kg delayed-treatment group, 42% in the 50-mg/kg group, and 52% in the 30-mg/kg group.

Distance traveled on the 6-minute walk test began to diverge between active and placebo-treated patients at 12 weeks and stabilized at 24 weeks among those who received active treatment, but continued to decline until 36 weeks for placebo-treated patients who started treatment at 24 weeks.

At 120 weeks, the patients who had received continuous treatment with eteplirsen declined by a mean of 14 m on the 6-minute walk test since baseline, compared with a decline of 79 m in those who underwent delayed treatment with eteplirsen. In comparison, studies of the natural history of Duchenne muscular dystrophy (DMD) have shown steady declines on the 6-minute walk test, ranging from 30 to 115 m at 1 year and 97 to 125 m at 2 years.

There was "remarkable stability" in diaphragm function over the course of treatment with eteplirsen, "which is quite different from the natural history of untreated patients," Dr. Mendell said. In all 12 patients, maximal expiratory pressure remained stable, going from a mean of 90% of predicted at baseline to 95% at 120 weeks. The same was true for maximal inspiratory pressure, moving from 79% of expected at baseline to 80% at 120 weeks. In contrast, the natural history of untreated DMD shows that pulmonary function declines substantially over time: by 3.9%/year for maximal inspiratory pressure after starting at 90% of predicted at 9 years of age, and by 3.6%/year after starting at 45% of predicted at 9 years of age (Pediatr. Pulmonol. 2014;49:473-81).

Eteplirsen was created to help patients with a deletion of exon 51 in dystrophin, which causes a nonfunctional dystrophin protein. The drug is a charge-neutral phosphorodiamidate morpholino oligomer (PMO) that targets the 13% of DMD patients with this mutation by directing alternative splicing of the dystrophin gene through its ability to bind to exon 51 of dystrophin pre-mRNA. This restores transcription and translation of a truncated, yet functional, dystrophin protein, such as those found in Becker muscular dystrophy.

The neutral charge of eteplirsen helps it to avoid binding to serum proteins, which is one of the problems that have occurred with phosphorothioate antisense oligonucleotide-based drugs. Phosphorothioate antisense drugs have also been linked to immune activation, hepatotoxicity, thrombocytopenia, coagulopathy, renal toxicity, and proteinuria. But Dr. Kaye reported that eteplirsen is mainly excreted by the kidneys, has a half-life of about 3 hours, and showed no evidence of those problems. Only 13 of 453 urine protein assessments tested positive, but all were low, transient, and resolved spontaneously.

"The reason that this is important is there has actually been very little human data until recently, despite the fact that [PMOs have] been around for over 30 years. Most of the work has been done in animals and in research laboratories, and it’s only until recently that people have been exposed to the drug," Dr. Kaye said.

The study was funded by Sarepta Therapeutics. Dr. Kaye and two coauthors are employees of the company. Dr. Mendell had no relevant disclosures.

[email protected]

PHILADELPHIA – Eteplirsen safely maintained its beneficial effect on walking speeds for certain patients with Duchenne muscular dystrophy for more than 2 years and was the first drug to show stabilized diaphragm function over the same period.

The investigational gene therapy drug had a stabilizing effect on patients’ walking speed over the course of 120 weeks regardless of whether they started it earlier or later in the open-label extension of the initial 24-week, randomized trial, but those who started treatment earlier maintained a higher walking speed, Dr. Jerry R. Mendell said at the annual meeting of the American Academy of Neurology.

Coinvestigator Dr. Edward M. Kaye of Sarepta Therapeutics, the study sponsor, presented in-depth safety and pharmacokinetics data that showed no significant treatment-related adverse events with eteplirsen in the small study. No patients have discontinued or disrupted treatment, and no laboratory evidence of toxicity has been seen to date.

The initial 24-week, double-blind, randomized, placebo-controlled study involved four patients who were given the equivalent of 30 mg/kg eteplirsen weekly, four given 50 mg/kg eteplirsen weekly, and four given placebo. At the start of the open-label extension study, two of the placebo-treated patients were transitioned to 30 mg/kg weekly and two to 50 mg/kg weekly.

All patients underwent muscle biopsy at baseline, followed by biopsies at 12 weeks in two of the high-dose patients and in two of the placebo-treated patients, and at 24 weeks in the four patients taking 30 mg/kg weekly and in two placebo-treated patients.

"This design permitted a comparison between high dose over a shorter time interval and low dose over a longer time interval," said Dr. Mendell of the Center for Gene Therapy at Nationwide Children’s Hospital, Columbus, Ohio.

All patients underwent a biopsy at 1 year (48 weeks) in the open-label extension (Ann. Neurol. 2013;74:637-47).

By 48 weeks, the mean percentage of dystrophin-positive muscle fibers was 34% in the placebo/30 mg/kg delayed-treatment group, 43% in the placebo/50 mg/kg delayed-treatment group, 42% in the 50-mg/kg group, and 52% in the 30-mg/kg group.

Distance traveled on the 6-minute walk test began to diverge between active and placebo-treated patients at 12 weeks and stabilized at 24 weeks among those who received active treatment, but continued to decline until 36 weeks for placebo-treated patients who started treatment at 24 weeks.

At 120 weeks, the patients who had received continuous treatment with eteplirsen declined by a mean of 14 m on the 6-minute walk test since baseline, compared with a decline of 79 m in those who underwent delayed treatment with eteplirsen. In comparison, studies of the natural history of Duchenne muscular dystrophy (DMD) have shown steady declines on the 6-minute walk test, ranging from 30 to 115 m at 1 year and 97 to 125 m at 2 years.

There was "remarkable stability" in diaphragm function over the course of treatment with eteplirsen, "which is quite different from the natural history of untreated patients," Dr. Mendell said. In all 12 patients, maximal expiratory pressure remained stable, going from a mean of 90% of predicted at baseline to 95% at 120 weeks. The same was true for maximal inspiratory pressure, moving from 79% of expected at baseline to 80% at 120 weeks. In contrast, the natural history of untreated DMD shows that pulmonary function declines substantially over time: by 3.9%/year for maximal inspiratory pressure after starting at 90% of predicted at 9 years of age, and by 3.6%/year after starting at 45% of predicted at 9 years of age (Pediatr. Pulmonol. 2014;49:473-81).

Eteplirsen was created to help patients with a deletion of exon 51 in dystrophin, which causes a nonfunctional dystrophin protein. The drug is a charge-neutral phosphorodiamidate morpholino oligomer (PMO) that targets the 13% of DMD patients with this mutation by directing alternative splicing of the dystrophin gene through its ability to bind to exon 51 of dystrophin pre-mRNA. This restores transcription and translation of a truncated, yet functional, dystrophin protein, such as those found in Becker muscular dystrophy.

The neutral charge of eteplirsen helps it to avoid binding to serum proteins, which is one of the problems that have occurred with phosphorothioate antisense oligonucleotide-based drugs. Phosphorothioate antisense drugs have also been linked to immune activation, hepatotoxicity, thrombocytopenia, coagulopathy, renal toxicity, and proteinuria. But Dr. Kaye reported that eteplirsen is mainly excreted by the kidneys, has a half-life of about 3 hours, and showed no evidence of those problems. Only 13 of 453 urine protein assessments tested positive, but all were low, transient, and resolved spontaneously.

"The reason that this is important is there has actually been very little human data until recently, despite the fact that [PMOs have] been around for over 30 years. Most of the work has been done in animals and in research laboratories, and it’s only until recently that people have been exposed to the drug," Dr. Kaye said.

The study was funded by Sarepta Therapeutics. Dr. Kaye and two coauthors are employees of the company. Dr. Mendell had no relevant disclosures.

[email protected]

PHILADELPHIA – Eteplirsen safely maintained its beneficial effect on walking speeds for certain patients with Duchenne muscular dystrophy for more than 2 years and was the first drug to show stabilized diaphragm function over the same period.

The investigational gene therapy drug had a stabilizing effect on patients’ walking speed over the course of 120 weeks regardless of whether they started it earlier or later in the open-label extension of the initial 24-week, randomized trial, but those who started treatment earlier maintained a higher walking speed, Dr. Jerry R. Mendell said at the annual meeting of the American Academy of Neurology.

Coinvestigator Dr. Edward M. Kaye of Sarepta Therapeutics, the study sponsor, presented in-depth safety and pharmacokinetics data that showed no significant treatment-related adverse events with eteplirsen in the small study. No patients have discontinued or disrupted treatment, and no laboratory evidence of toxicity has been seen to date.

The initial 24-week, double-blind, randomized, placebo-controlled study involved four patients who were given the equivalent of 30 mg/kg eteplirsen weekly, four given 50 mg/kg eteplirsen weekly, and four given placebo. At the start of the open-label extension study, two of the placebo-treated patients were transitioned to 30 mg/kg weekly and two to 50 mg/kg weekly.

All patients underwent muscle biopsy at baseline, followed by biopsies at 12 weeks in two of the high-dose patients and in two of the placebo-treated patients, and at 24 weeks in the four patients taking 30 mg/kg weekly and in two placebo-treated patients.

"This design permitted a comparison between high dose over a shorter time interval and low dose over a longer time interval," said Dr. Mendell of the Center for Gene Therapy at Nationwide Children’s Hospital, Columbus, Ohio.

All patients underwent a biopsy at 1 year (48 weeks) in the open-label extension (Ann. Neurol. 2013;74:637-47).

By 48 weeks, the mean percentage of dystrophin-positive muscle fibers was 34% in the placebo/30 mg/kg delayed-treatment group, 43% in the placebo/50 mg/kg delayed-treatment group, 42% in the 50-mg/kg group, and 52% in the 30-mg/kg group.

Distance traveled on the 6-minute walk test began to diverge between active and placebo-treated patients at 12 weeks and stabilized at 24 weeks among those who received active treatment, but continued to decline until 36 weeks for placebo-treated patients who started treatment at 24 weeks.

At 120 weeks, the patients who had received continuous treatment with eteplirsen declined by a mean of 14 m on the 6-minute walk test since baseline, compared with a decline of 79 m in those who underwent delayed treatment with eteplirsen. In comparison, studies of the natural history of Duchenne muscular dystrophy (DMD) have shown steady declines on the 6-minute walk test, ranging from 30 to 115 m at 1 year and 97 to 125 m at 2 years.

There was "remarkable stability" in diaphragm function over the course of treatment with eteplirsen, "which is quite different from the natural history of untreated patients," Dr. Mendell said. In all 12 patients, maximal expiratory pressure remained stable, going from a mean of 90% of predicted at baseline to 95% at 120 weeks. The same was true for maximal inspiratory pressure, moving from 79% of expected at baseline to 80% at 120 weeks. In contrast, the natural history of untreated DMD shows that pulmonary function declines substantially over time: by 3.9%/year for maximal inspiratory pressure after starting at 90% of predicted at 9 years of age, and by 3.6%/year after starting at 45% of predicted at 9 years of age (Pediatr. Pulmonol. 2014;49:473-81).

Eteplirsen was created to help patients with a deletion of exon 51 in dystrophin, which causes a nonfunctional dystrophin protein. The drug is a charge-neutral phosphorodiamidate morpholino oligomer (PMO) that targets the 13% of DMD patients with this mutation by directing alternative splicing of the dystrophin gene through its ability to bind to exon 51 of dystrophin pre-mRNA. This restores transcription and translation of a truncated, yet functional, dystrophin protein, such as those found in Becker muscular dystrophy.

The neutral charge of eteplirsen helps it to avoid binding to serum proteins, which is one of the problems that have occurred with phosphorothioate antisense oligonucleotide-based drugs. Phosphorothioate antisense drugs have also been linked to immune activation, hepatotoxicity, thrombocytopenia, coagulopathy, renal toxicity, and proteinuria. But Dr. Kaye reported that eteplirsen is mainly excreted by the kidneys, has a half-life of about 3 hours, and showed no evidence of those problems. Only 13 of 453 urine protein assessments tested positive, but all were low, transient, and resolved spontaneously.

"The reason that this is important is there has actually been very little human data until recently, despite the fact that [PMOs have] been around for over 30 years. Most of the work has been done in animals and in research laboratories, and it’s only until recently that people have been exposed to the drug," Dr. Kaye said.

The study was funded by Sarepta Therapeutics. Dr. Kaye and two coauthors are employees of the company. Dr. Mendell had no relevant disclosures.

[email protected]