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Sarepta Therapeutics Announces Eteplirsen Demonstrates Sustained Benefit on Walking Test Through 74 Weeks in Phase IIb Study in Duchenne Muscular Dystrophy
04/05/13 8:30 AM EDT
After 74 weeks, patients in the 30 mg/kg and 50 mg/kg dose cohorts who were able to perform the 6MWT (modified Intent-to-Treat or mITT population; n=6) showed a statistically significant treatment benefit of 65.2 meters (p ≤ 0.004) when compared to the placebo/delayed-treatment cohort (n=4). The eteplirsen-treated patients in the mITT population demonstrated less than a 5 percent decline (13.4 meters) from baseline in walking ability. After experiencing a substantial decline earlier in the study, the placebo/delayed-treatment cohort also demonstrated stabilization in walking ability from week 36 through 74, the period in which meaningful levels of dystrophin were likely produced, with a less than 10 meter decline over this timeframe.
"We are encouraged to see a continued stabilization of walking ability in patients treated with eteplirsen for nearly one and a half years," said
Through 74 weeks, eteplirsen was well tolerated and there were no clinically significant treatment-related adverse events, serious adverse events, hospitalizations or discontinuations. As previously reported at 62 weeks, one patient had a transient elevation of urine protein on a laboratory urine dipstick test, which resolved and resulted in no clinical symptoms. The patient continued treatment without interruption and remained free of proteinuria through week 74.
Across both the eteplirsen (mITT) and placebo/delayed-treatment cohorts, there is evidence of continued stabilization on clinical laboratory tests, echocardiogram, pulmonary function tests and muscle strength.
Summary of Additional 6MWT Analyses
Patients performed two 6MWT evaluations on consecutive days at time points coinciding with a muscle biopsy procedure at baseline and weeks 12, 24 and 48. All other evaluations were a single 6MWT. The pre-specified primary analysis included the maximum distance walked at those clinic visits where repeated tests were taken. Other analyses of the repeated 6MWT results assessed mean, minimum, and day 1 (first measure) scores. Results from these additional 6MWT analyses confirm the robust treatment effect observed in the primary analysis.
Summary of 6MWT: Eteplirsen (mITT) versus Placebo/Delayed-Treatment to Week 74*
Analysis of Repeated 6MWT Values | Baseline 6MWT (meters) | Adjusted Mean 6MWT Change from Baseline (meters) | Estimated Treatment Benefit (Eteplirsen Minus Placebo/delayed-Tx) | P-Value | ||||
Maximum Score Eteplirsen (n=6) |
399.7 | -13.4 | 65.2 m | ≤ 0.004 | ||||
Maximum Score Placebo/delayed-Tx (n=4) |
394.5 | -78.6 | ||||||
Mean Score Eteplirsen (n=6) |
388.6 | -2.2 | 62.4 m | ≤ 0.007 | ||||
Mean Score Placebo/delayed-Tx (n=4) |
380.3 | -64.6 | ||||||
Minimum Score Eteplirsen (n=6) |
377.5 | +9.0 | 59.6 m | ≤ 0.015 | ||||
Minimum Score Placebo/delayed-Tx (n=4) |
366.0 | -50.6 | ||||||
Day 1 Score Eteplirsen (n=6) |
379.7 | +6.6 | 62.2 m | ≤ 0.013 | ||||
Day 1 Score Placebo/delayed-Tx (n=4) |
371.5 | -55.6 | ||||||
*All analyses are based on a Mixed Model Repeated Measures test.
About the Phase IIb Eteplirsen Program (Studies 201 and 202)
Study 201 was a randomized, double-blind, placebo-controlled clinical study conducted at
At Week 25, all patients rolled over to Study 202, a long-term open-label extension study, and placebo-treated patients initiated eteplirsen treatment at 30 mg/kg (n=2) or 50 mg/kg (n=2).
The primary efficacy endpoint in Study 201 and Study 202 was the increase in novel dystrophin as assessed by muscle biopsy at weeks 12 and 24 and at week 48, respectively. The primary clinical endpoint was the 6MWT, a well-accepted measure of ambulation and clinical function in DMD. Long-term follow up in Study 202 continues to evaluate safety and clinical outcomes including the 6MWT every 12 weeks.
About the 6-Minute Walk Test (6MWT)
The 6-minute walk test (6MWT) was developed as an integrated assessment of cardiac, respiratory, circulatory, and muscular capacity (
About the Statistical Methodology and the Modified Intent-to-Treat (mITT) Population
The Mixed Model Repeated Measures (MMRM) test was used for all statistical analyses of the 6MWT results, including for all subgroups. Analysis of Covariance (ANCOVA) for ranked data was used when the assumptions of normality of the dependent variable (the change in 6MWT distance from baseline) were violated. Baseline 6MWT scores and duration since DMD diagnosis were included as covariates.
The mITT population used in the 6MWT analyses consisted of 10 of the 12 enrolled patients, including 4 patients in the 50 mg/kg cohort, 2 patients in the 30 mg/kg cohort and 4 patients in the placebo/delayed-treatment cohort. Two patients in the 30 mg/kg cohort showed rapid disease progression upon enrollment and lost ambulation by week 24, and thus were excluded.
About Duchenne Muscular Dystrophy
DMD is an X-linked rare, degenerative neuromuscular disorder causing severe progressive muscle loss and premature death. One of the most common fatal genetic disorders, DMD affects approximately one in every 3,500 boys worldwide. A devastating and incurable muscle-wasting disease, DMD is associated with specific errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fiber function. Progressive muscle weakness eventually spreads to the arms, neck and other areas. Eventually, this progresses to complete paralysis and increasing difficulty in breathing due to respiratory muscle dysfunction requiring ventilation support, as well as cardiac dysfunction leading to heart failure. The condition is terminal, and death usually occurs before the age of 30.
About Sarepta's Proprietary Exon-Skipping Platform Technology
Eteplirsen is Sarepta's lead drug candidate that is designed to address the underlying cause of DMD by enabling the production of a functional dystrophin protein. Data from clinical studies of eteplirsen in DMD patients have demonstrated a broadly favorable safety and tolerability profile and restoration of dystrophin protein expression.
Eteplirsen uses Sarepta's novel phosphorodiamidate morpholino oligomer (PMO)-based chemistry and proprietary exon-skipping technology to skip exon 51 of the dystrophin gene enabling the repair of specific genetic mutations that affect approximately 13 percent of the total DMD population. By skipping exon 51, eteplirsen may restore the gene's ability to make a shorter, but still functional, form of dystrophin from messenger RNA, or mRNA. Promoting the synthesis of a truncated dystrophin protein is intended to improve, stabilize or significantly slow the disease process and prolong and improve the quality of life for patients with DMD.
Sarepta is also developing other PMO-based exon-skipping drug candidates intended to treat additional patients with DMD.
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Forward-Looking Statements and Information
This press release contains forward-looking statements. These forward-looking statements generally can be identified by use of words such as "believes or belief," "anticipates," "plans," "expects," "will," "intends," "potential," "possible," "advance" and similar expressions. These forward-looking statements include statements about the development of eteplirsen and its efficacy, potency and utility in the treatment of DMD and the potential for the creation of novel dystrophin to lead to significant clinical benefit over a longer course of treatment.
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