DART’s Phase 1b/2a Study to Determine Safety and Tolerability of Lead Drug Candidate, Help Validate New Endpoint for Future DMD Studies

by Admin 7/26/2013 10:05:00 PM

Cambridge, Mass.—July 15, 2013—DART Therapeutics Inc., an innovative, new-model biotechnology firm focused on developing therapies for Duchenne muscular dystrophy (DMD), has initiated a phase 1b/2a study of its lead drug candidate, HT-100 (delayed-release halofuginone). The phase 1b study (with a six-month 2a extension) in patients will determine the safety and tolerability of different, increasing doses of HT-100, and explore trends in a range of efficacy endpoints.

HT-100 is an orally available, small molecule drug candidate intended to reduce fibrosis and inflammation and promote healthy muscle fiber regeneration in boys with DMD. The phase 1b/2a clinical program will enroll 30 boys and young men with DMD, both ambulatory and non-ambulatory. Participating centers include University of California, Davis Medical Center (Sacramento, Calif.), Kennedy Krieger Institute, Johns Hopkins School of Medicine (Baltimore, MD), Washington University School of Medicine (St. Louis, MO), Cincinnati Children’s Hospital Medical Center (Cincinnati, Ohio) and Nationwide Children’s Hospital (Columbus, Ohio). DART expects to complete the study in mid 2014.

“Treating DMD requires a cocktail of therapies that will change over time,” said Gene Williams, CEO of DART Therapeutics. “We believe HT-100 could be a valuable part of this cocktail—even a mini-cocktail on its own—because it demonstrates potential to address many different aspects of the disease in parallel, which could make it an exceptionally important therapy for all boys living with DMD.”

DART’s study will include boys aged six through 20, an atypical age range that allows investigators to evaluate HT-100’s safety in a broad population as well as study its effect in different disease stages. Researchers will also evaluate a new endpoint that could make DMD studies faster, more precise, less expensive and inclusive of a larger group of boys. Presently, the six-minute walk (6MW) is the standard endpoint for DMD studies. However, the 6MW has shortcomings including variability and difficulty interpreting the clinical relevance of a given effect size. It also limits study participants to boys who can walk at a certain speed. There are no validated endpoints for very young boys with DMD. The proposed endpoint, electrical impedance myography (EIM), is a simple, non-invasive technique that can measure the health of a muscle and track its changes over time. As a validated endpoint for DMD, EIM would allow researchers to include a wide range of boys in studies and more effectively and rapidly understand how well a treatment is working to halt disease progression.

“Not only do we need several different categories of treatments for DMD—a therapeutic cocktail that might include different components depending on the stage of the disease—we also need new endpoints to improve the quality and speed of our clinical studies,” said Dr. Diana Escolar, Associate Professor of Neurology at Johns Hopkins School of Medicine’s Kennedy Krieger Institute, DART’s Chief Medical Officer and Study Director. “It is only through this two-pronged approach that we will succeed in our mission to make DMD a chronic, manageable disease instead of a fatal one.”



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Sarepta Therapeutics Announces Plans to Submit New Drug Application to FDA for Eteplirsen for the Treatment of Duchenne Muscular Dystrophy in First Half of 2014

by Admin 7/26/2013 10:01:00 PM

CAMBRIDGE, MA -- (Marketwired) -- 07/24/13 -- Sarepta Therapeutics, Inc. (NASDAQ: SRPT), a developer of innovative RNA-based therapeutics, today announced it plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the first half of 2014 for the approval of eteplirsen for the treatment of Duchenne muscular dystrophy (DMD). Eteplirsen is Sarepta's lead exon-skipping compound in development for the treatment of patients with DMD who have a genotype amenable to skipping of exon 51.

The decision to submit an NDA for eteplirsen in 2014 is based on productive interactions with the FDA in a meeting that occurred this week. That meeting was a follow-up to the FDA's review of two recently submitted summary documents that included data on dystrophin and clinical outcomes from the existing eteplirsen studies. The FDA stated in pre-meeting comments that the Agency is "open to considering an NDA based on these data for filing." The Agency, however, requested additional information related to the methodology and verification of dystrophin quantification. Sarepta believes the requests from the Agency can be addressed and incorporated into an NDA submission in the first half of 2014.

"We are encouraged by the feedback from the FDA and believe that data from our ongoing clinical study merits review by the Agency and will be sufficient for an NDA filing," said Chris Garabedian, president and chief executive officer of Sarepta Therapeutics. "We plan to work closely with the FDA to prepare an NDA submission in the first half of 2014 as we continue to prepare for our confirmatory study and our manufacturing scale up."

The Agency would not commit to declaring dystrophin an acceptable surrogate endpoint under the CFR 314 Subpart H Accelerated Approval pathway prior to an NDA filing and commented that a decision by the Agency to file "the NDA would not indicate that we have accepted dystrophin expression as a biomarker reasonably likely to predict clinical benefit. A filing would only indicate that the question merits review, and that we deem the data to be reviewable."

Sarepta anticipates submitting an NDA for eteplirsen in the first half of 2014; however, the exact timing of the submission will be dependent on further discussions and agreement with the FDA on the information needed for an acceptable filing. Sarepta also intends to have an End-of-Phase II meeting with the agency later this quarter to discuss the requirements for the Chemistry, Manufacturing, and Controls (CMC) section of the NDA.



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Sarepta Therapeutics Announces Eteplirsen Demonstrates a Continued Benefit on Walking Test Through 84 Weeks in Phase IIb Study in Duchenne Muscular Dystrophy

by Admin 7/17/2013 9:51:00 AM
 
Data to Be Presented Today at the Wells Fargo Securities 2013 Healthcare Conference

CAMBRIDGE, MA -- (Marketwired) -- 06/19/13 -- Sarepta Therapeutics, Inc. (NASDAQ: SRPT), a developer of innovative RNA-based therapeutics, today announced updated data from Study 202, a Phase IIb open-label extension study of eteplirsen in patients with Duchenne muscular dystrophy (DMD). Results at 84 weeks showed a continued stabilization of walking ability in eteplirsen-treated patients evaluable on the 6-minute walk test (6MWT). As previously reported, Study 202 met its primary endpoint of increased novel dystrophin as assessed by muscle biopsy at Week 48 and is now in the long-term extension phase in which patients continue to be followed for safety and clinical outcomes. Eteplirsen is Sarepta's lead exon-skipping compound in development for the treatment of patients with DMD who have a genotype amenable to skipping of exon 51.

After 84 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 46.4 meters (p≤0.045) when compared to the placebo/delayed-treatment cohort (n=4). The eteplirsen-treated patients in the mITT population demonstrated less than a 6 percent decline (20.5 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 84, the period from which meaningful levels of dystrophin were likely produced, with an increase of 3.3 meters over this timeframe. These analyses were based on the maximum 6MWT score when the test was performed on two consecutive days.

"We now have demonstrated stability of walking for over a year and a half in the original eteplirsen treatment cohort in boys who are now 11 years old on average, an age when many DMD boys have lost the ability to walk," said Chris Garabedian, president and chief executive officer of Sarepta Therapeutics. "In addition, the placebo/delayed-treatment cohort, which has now received eteplirsen for over a year, has demonstrated a stabilization in walking ability for 48 weeks compared with the precipitous decline observed earlier in the study before dystrophin was confirmed in these patients. Overall, we believe the data across all treatment cohorts are remarkably consistent and continue to support eteplirsen as a potential treatment option in DMD."

Through 84 weeks, eteplirsen was well tolerated and there were no clinically significant treatment-related adverse events, no serious adverse events, hospitalizations or discontinuations.

One boy in the placebo/delayed-treatment cohort was not able to perform the 6MWT at the Week 84 clinic visit due to a physical injury unrelated to treatment, and therefore had no 6MWT data captured at the Week 84 time point. The boy has recovered from the injury, continues to be ambulatory and is expected to be evaluated on the 6MWT at future clinic visits.

Across all patients in the eteplirsen and placebo/delayed-treatment cohorts (Intent-to-Treat or ITT population), there is evidence of continued stabilization on clinical laboratory tests, echocardiograms, pulmonary function tests and measures of 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 versus Placebo/Delayed-Treatment to Week 84*

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   -20.5   46.4†   ≤0.045†
Maximum Score 
Placebo/delayed-Tx (n=4)
  394.5   -66.8  
Mean Score
Eteplirsen (n=6)
  388.6   -9.2   43.2   NS‡
Mean Score
Placebo/delayed-Tx (n=4)
  380.3   -52.5  
Minimum Score
Eteplirsen (n=6)
  377.5   2.0   40.1   NS‡
Minimum Score
Placebo/delayed-Tx (n=4)
  366.0   -38.1  
Day 1 Score
Eteplirsen (n=6)
  379.7   -0.5   42.8   NS‡
Day 1 Score
Placebo/delayed-Tx (n=4)
  371.5   -43.3  

* All 6MWT analyses are based on a Mixed Model Repeated Measures test.
† The pre-specified primary analysis of the 6MWT results was based on the maximum score.
‡ The lack of a 6MWT score at Week 84 for the one patient with a physical injury in the placebo/delayed-treatment cohort, combined with the improvement seen in the remaining boys in this cohort, resulted in the loss of statistical significance in the additional 6MWT analyses (mean, minimum, and day 1 value assessments).

Mr. Garabedian will present these data today at the Wells Fargo 2013 Healthcare Conference at 1:50 p.m. in Boston, Mass. The presentation will be webcast live under the investor relations section of theSarepta Therapeutics website at www.sareptatherapeutics.com and will be archived there following the presentation for 90 days.



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DRISAPERSEN TREATMENT FOR DUCHENNE MUSCULAR DYSTROPHY: RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL

by Admin 4/10/2013 10:36:00 AM

John E Kraus1, Claire Wardell1, Katie Rolfe1, Joanna Nakielny1, Naashika Quarcoo1, Lia Liefaard1, Steve Hood1, Allison Morgan2, Afrodite Lourbakos2, Sjef de Kimpe2, Rosamund Wilson2, Giles Campion2 1GlaxoSmithKline, R&D, Research Triangle Park, NC, 27709, 2Prosensa, R&D, Leiden, 2333 CH, Netherlands

Introduction: Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder, ultimately lethal, caused by the absence of dystrophin protein due to mutations of the dystrophin gene. The aim of oligonucleotide therapy is to manipulate the post-transcriptional splicing process of the premRNA to restore the reading frame of the mRNA, resulting in a shortened dystrophin protein. Drisapersen is a 2'-O-methyl-phosphothioate oligo designed to skip exon 51 in the dystrophin pre-mRNA. Here we report results of an exploratory, unpowered, double blind, placebo-controlled clinical study of drisapersen.

Methods: Subjects with DMD met the following inclusion criteria: ≥5 years old; ambulant; corticosteroid-treated; rise from the floor ≤7 sec; and a dystrophin mutation correctable by exon 51 skipping. 53 subjects were randomized to 2 drisapersen dosing regimens or matched placebo (2:1). Dosing regimens: continuous (6mg/kg/wk) and intermittent (10-week cycles of 9 doses at 6mg/kg over 6 wks, and 4 wks off drug). Treatment was administered subcutaneously for 48 weeks. The primary objective was to assess the efficacy (6 Minute Walk Distance [6MWD] = primary outcome) of 2 different drisapersen dosing regimens over 24 weeks. Secondary objectives included 6MWD at 48 weeks, various timed function tests, the North Star Ambulatory Assessment [NSAA], muscle strength and safety.

Results: The continuous treatment arm (n=18) showed a clinically meaningful and statistically significant difference from placebo (n=18) on 6MWD at 24 weeks (mean, 35.09m; [95%CI, 7.59-62.60m], p=0.014), with trends supportive of efficacy in other timed function tests and the NSAA. A clinically meaningful difference from placebo (35.84m [-0.11-71.78m], p=0.051) was maintained at 48 weeks. The intermittent treatment arm (n=17) did not separate from placebo at week 24, though by week 48 there was a clinically meaningful difference from placebo on 6MWD (27.08m [-9.83-63.99m], p=0.147), supported by trends in timed function tests and the NSAA. There was little change in muscle strength at either time point for either treatment arm. Drisapersen was generally welltolerated, with the majority of adverse events related to injection site reactions and proteinuria. All patients completed the study.

Discussion: The primary objective was achieved - the continuous treatment arm showed a clinically meaningful and statistically significant difference from placebo on 6MWD at week 24. At week 48, both treatment arms showed a clinically meaningful difference from placebo on 6MWD (supported by improvement in other secondary endpoints). Drisapersen may represent an important treatment option for boys with DMD having mutations correctable by exon 51 skipping.



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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

by Admin 4/10/2013 10:28:00 AM

Data to Be Presented at the Muscular Dystrophy Association Scientific Conference

CAMBRIDGE, MA -- (Marketwired) -- 04/05/13 -- Sarepta Therapeutics, Inc. (NASDAQ: SRPT), a developer of innovative RNA-based therapeutics, today announced updated data from Study 202, a Phase IIb open-label extension study of eteplirsen in patients with Duchenne muscular dystrophy (DMD). Results at 74 weeks showed a continued stabilization of walking ability in eteplirsen-treated patients evaluable on the 6-minute walk test (6MWT). As previously reported, Study 202 met its primary endpoint of increased novel dystrophin as assessed by muscle biopsy at week 48 and is now in the long-term extension phase in which patients continue to be followed for safety and clinical outcomes. Eteplirsen is Sarepta's lead exon-skipping compound in development for the treatment of patients with DMD who have a genotype amenable to skipping of exon 51.

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 Chris Garabedian, president and chief executive officer of Sarepta Therapeutics. "These data are particularly compelling when viewed in the context of published natural history studies, which showed substantial declines on the 6-minute walk test over this timeframe in a similar ambulatory DMD population. These results continue to support the potential of eteplirsen to be a major advance in the treatment of DMD in altering the course of this progressive and irreversible disease."

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.

Jerry R. Mendell, M.D., Director of the Centers for Gene Therapy and Muscular Dystrophy atNationwide Children's Hospital and principal investigator of the Phase IIb study, will present these data in an oral presentation at the Muscular Dystrophy Association Scientific Conference on Tuesday, April 23 at 4:05 p.m. EDT in Washington, D.C. Dr. Mendell's presentation will be posted on the Sarepta website in the "Events & Presentations" section after the session is completed.



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Sarepta Therapeutics Announces Eteplirsen Meets Primary Endpoint of Increased Novel Dystrophin and Achieves Significant Clinical Benefit on 6-Minute Walk Test After 48 Weeks of Treatment in Phase IIb Study in Duchenne Muscular Dystrophy

by Admin 10/3/2012 9:45:00 AM
 

Oct 03, 2012 (Marketwire via COMTEX) --Sarepta Therapeutics (NASDAQ: SRPT), a developer of innovative RNA-based therapeutics, today announced that treatment with its lead exon-skipping compound, eteplirsen, met the primary efficacy endpoint, increase in novel dystrophin, and achieved a significant clinical benefit on the primary clinical outcome, the 6-minute walk test (6MWT) over the placebo/delayed treatment cohort in a Phase IIb extension trial in Duchenne muscular dystrophy (DMD) patients. 

Eteplirsen administered once weekly at either 30 mg/kg or 50 mg/kg for 48 weeks (n=8) resulted in a statistically significant increase (p≤0.001) in dystrophin-positive fibers to 47.0% of normal. The placebo/delayed treatment cohort, which had received 24 weeks of eteplirsen at either 30 mg/kg or 50 mg/kg following 24 weeks of placebo (n=4), also showed a statistically significant increase in dystrophin-positive fibers to 38.3% of normal (p≤0.009).

"These data represent a significant milestone and a defining moment of progress and hope for patients with DMD and their families, as well as for those of us in the scientific community who have been pursuing potential treatments for this devastating and deadly disease for decades," said Jerry Mendell, M.D., Director of the Centers for Gene Therapy and Muscular Dystrophy at Nationwide Children's Hospital and principal investigator of the Phase IIb study. Dr. Mendell added, "By addressing the underlying cause of DMD, eteplirsen has demonstrated unparalleled effects on enabling dystrophin production and slowing the progression of the disease as measured by the 6-minute walk test, with no treatment associated adverse events. While eteplirsen is targeted to DMD patients with a specific genetic mutation, I think the implications for all DMD patients with related genetic mutations are clearly evident." 

Eteplirsen administered once weekly at 50 mg/kg over 48 weeks resulted in an 89.4 meter benefit compared to patients who received placebo for 24 weeks followed by 24 weeks of treatment with eteplirsen in the open-label extension. In the predefined prospective analysis of the study's intent-to-treat (ITT) population on the primary clinical outcome measure, the change in 6MWT distance from baseline, eteplirsen-treated patients who received 50 mg/kg of the drug weekly (n=4) demonstrated an increase of 21.0 meters in distance walked from baseline (mean=396.0 meters), while patients who received placebo/delayed-eteplirsen treatment (n=4) showed a decline of 68.4 meters from baseline (mean=394.5 meters), for a statistically significant treatment benefit of 89.4 meters over 48 weeks (p=0.016, using ANCOVA for ranked data). There was no statistically significant difference between the cohort of patients who received 30 mg/kg weekly of eteplirsen and the placebo/delayed treatment cohort.

"We are extremely excited about these data, as they demonstrate that longer-term treatment with eteplirsen is translating to continued and unprecedented increases in both dystrophin production and clinical benefit across various subgroups of DMD patients involved in this study," said Chris Garabedian, President and CEO of Sarepta Therapeutics. "On a broader scale, these results signify the promise and tremendous potential of our RNA-based technology to impact and modulate disease at the genetic level, which may lead to first-ever opportunities to target serious and life-threatening rare conditions at the origin of disease." 

The safety profile of eteplirsen was evaluated across all subjects through 48 weeks and there were no treatment-related adverse events, no serious adverse events, and no discontinuations. Furthermore, no clinically significant treatment-related changes were detected on any safety laboratory parameters, including several biomarkers for renal function.

Summary of Dystrophin: Eteplirsen-Treated Patients in All Dose Groups through Week 48*

         
Treatment Arm   Mean Change from Baseline in % Dystrophin-Positive Fibers   p-value
Eterplirsen (both doses): 48 wks of Tx (n=8)   47.0   ≤0.001
  Eteplirsen 50 mg/kg (n=4)   41.7   ≤0.008
  Eteplirsen 30 mg/kg (n=4)   52.1   ≤0.001
Placebo/Delayed Tx: 24 wks of Tx (n=4)   38.3   ≤0.009
  Placebo/50 mg/kg Delayed-Tx (n=2)   42.9   ns
  Placebo/30 mg/kg Delayed-Tx (n=2)   34.2   ns
         
         

* Values based on Immunofluorescence using anti-dystrophin antibody MANDYS106

Modified Intent-to-Treat (mITT)

The 6MWT results were further analyzed using the mITT population which excluded two patients who were randomized to the 30 mg/kg weekly eteplirsen cohort who showed signs of rapid disease progression within weeks after enrollment and were unable to perform measures of ambulation beyond 24 weeks. This mITT population consisted of 10 patients (4 eteplirsen-treated patients receiving 50 mg/kg weekly, 2 eteplirsen-treated patients receiving 30 mg/kg weekly, and 4 placebo/delayed-treatment patients).

Summary of 6MWT: Eteplirsen versus Placebo/Delayed-Treatment to Week 48*

             
Treatment Arm   Mean Change from Baseline in 6MWT (meters)   Estimated Treatment Effect (Eteplirsen minus Placebo/Delayed-Tx)   p-value
Placebo/Delayed-Tx (n=4)   -60.3        
Eteplirsen 50 mg/kg (n=4)   +27.1   87.4 m   ≤0.001
Eteplirsen Both Doses (n=6)   +7.3   67.3 m   ≤0.001
Eteplirsen 30 mg/kg (n=2)   -31.5   28.8 m   ns
             

*Note: Analysis based on Mixed Model Repeated Measures test

Summary of Additional Sub-Group Analyses at Week 48*

             
Subset   Mean 6MWT Change from Baseline (meters)   Estimated Treatment Benefit (Eteplirsen minus Placebo/delayed-Tx)   p-value
             
Placebo/delayed Tx:
< 9.5 yrs at baseline
(n=2; mean=7.6 yrs)
  -42.3   58.9 m   ≤0.038
Eteplirsen:
< 9.5 yrs at baseline
(n=3; mean=8.4 yrs)
  +16.5  
Placebo/delayed Tx:
≥9.5 yrs at baseline
(n=2; mean=10.1 yrs)
  -63.5   52.1 m   ns
Eteplirsen:
≥9.5 yrs at baseline
(n=3; mean=10.4 yrs)
  -11.3  
Placebo/delayed Tx:
Higher 6MWT baseline
(n=2; mean=422m)
  -53.5   93.8 m   ≤0.001
Eteplirsen:
Higher 6MWT baseline
(n=3; mean=424m)
  +40.3  
Placebo/delayed Tx:
Lower 6MWT baseline
(n=2; mean=367m)
  -65.8   39.6 m   ns
Eteplirsen:
Lower 6MWT baseline
(n=3; mean=375m)
  -26.2  
Placebo/delayed Tx:
Genotype 49-50 deletion
(n=3; age mean=9.2 yrs,
6MWT BL mean=397m)
  -69.0   83.4 m   ≤0.001
Eteplirsen:
Genotype 49-50 deletion
(n=2; age mean=9.1 yrs,
6MWT BL mean=383m)
  +14.4  
             

 * Note: Analysis based on Mixed Model Repeated Measures test

An abstract describing the results from this Phase IIb extension study has been accepted as part of the World Muscle Society (WMS) Congress's Late-Breaking Science program in Perth, Australia during October 9 to October 13, 2012. Principal investigator, Jerry R. Mendell, M.D. of Nationwide Children's Hospital, will present the data via an oral presentation of the abstract titled, "Results at 48 Weeks of a Phase IIb Extension Study of the Exon-Skipping Drug Eteplirsen in Patients with Duchenne muscular dystrophy (DMD)." Dr. Mendell will present on October 13 at 4:00 p.m. WST UTC +8 hours/4:00 a.m. EDT. Dr. Mendell's presentation will be posted on the Sarepta website in the "Events & Presentations" section after the session is completed. In addition, Sarepta is sponsoring an educational symposium at WMS chaired by Professor Steve Wilton, PhD, Head of the Molecular Genetic Therapy Group and Director of Translational Research and Development, Australian Neuromuscular Research Institute at the University of Western Australia. Professor Wilton is a long-time collaborator of Sarepta's whose groundbreaking research has extended the use of antisense oligomers to DMD.

About Study 201 and Study 202 (Phase IIb Eteplirsen Study)

Study 4658-US-201 was conducted at Nationwide Children's Hospital in Columbus, Ohio. Twelve boys meeting the inclusion criteria being between 7 and 13 years of age with appropriate deletions of the dystrophin gene that confirm eligibility for treatment with an exon-51 skipping drug, received double-blind IV infusions of placebo (n=4), 30 mg/kg of eteplirsen (n=4), or 50 mg/kg of eteplirsen once weekly for 24 weeks (n=4). Muscle biopsies for evaluation of dystrophin were obtained at baseline for all subjects, and after 12 weeks for patients in the 50 mg/kg cohort and after 24 weeks for patients in the 30 mg/kg cohort. Two placebo patients were randomized to the 30 mg/kg cohort and two placebo patients were randomized to the 50 mg/kg cohort. This study design allowed Sarepta to investigate the relationship of dose and duration of eteplirsen treatment on the production of dystrophin over the course of the 24-week study.

Study 4658-US-202 is the extension study to 201 and continues to assess the long-term safety and efficacy of open-label eteplirsen. The four placebo patients were rolled over to open-label eteplirsen at week 24, with six patients on 30 mgs/kg, and six patients on 50 mgs/kg. Third biopsies occurred at 48 weeks in the original study 201 treated patients, and at 24 weeks, the same time point, in the original placebo patients. 6MWT was performed at 32 weeks, 36 weeks, 48 weeks and will continue to be performed every 12 weeks going forward.



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Sarepta Therapeutics Announces Significant Clinical Benefit With Eteplirsen After 36 Weeks in Phase IIb Study for the Treatment of Duchenne Muscular Dystrophy

by Admin 7/24/2012 10:46:00 AM

Jul 24, 2012 (Marketwire via COMTEX) --Sarepta Therapeutics (NASDAQ: SRPT), a developer of innovative RNA-based therapeutics, today announced that treatment with its exon-skipping compound, eteplirsen, achieved a significant clinical benefit on the primary clinical outcome, the 6-minute walk test (6MWT), over a placebo/delayed treatment cohort in a Phase IIb trial in Duchenne muscular dystrophy (DMD) patients. Eteplirsen administered once weekly at 50mg/kg over 36 weeks resulted in a 69.4 meter benefit compared to patients who received placebo for 24 weeks followed by 12 weeks of treatment with eteplirsen in the open-label extension. In the predefined prospective analysis of the study's intent-to-treat (ITT) population on the primary clinical outcome measure, the change in 6MWT distance from baseline, eteplirsen-treated patients who received 50mg/kg of the drug weekly (n=4) demonstrated a decline of 8.7 meters in distance walked from baseline (mean=396.0 meters), while patients who received placebo/delayed-eteplirsen treatment for 36 weeks (n=4) showed a decline of 78.0 meters from baseline (mean=394.5 meters), for a statistically significant treatment benefit of 69.4 meters over 36 weeks (p≤0.019).

"The magnitude of this clinical benefit is an unprecedented treatment effect in DMD. This result represents a major advance in the pursuit of a disease modifying treatment for this severe, progressive and life-threatening disease," said Jerry Mendell, M.D., Director of the Centers for Gene Therapy and Muscular Dystrophy at Nationwide Children's Hospital and principal investigator of the Phase IIb study. Dr. Mendell added, "The 6-minute walk test results with eteplirsen, combined with its safety profile to date, make eteplirsen the most promising advance to treat the underlying cause of muscular dystrophy I've seen in my more than 30 years in the field."

The clinical benefit observed in the 50mg/kg treatment cohort compared to placebo was also significant at week 32 with a benefit of 59.9 meters (p≤0.045). The safety profile of eteplirsen was evaluated across all subjects through 36 weeks and there were no treatment-related adverse events, no serious adverse events and no discontinuations. Furthermore, no treatment related changes were detected on any safety laboratory parameters, including several biomarkers for renal function.

"These data suggest that the previously reported levels of dystrophin we observed in muscle biopsies after 24 weeks of treatment are translating to a clinical benefit on the standard measure of ambulation in DMD patients," said Chris Garabedian, President and CEO of Sarepta Therapeutics. "The magnitude of this 69.4-meter difference after 36 weeks of treatment and the robustness of the statistical analysis is encouraging, especially given the average benefit in the 6-minute walk test for several approved drugs in other diseases has been 30 to 40 meters." 

There was no statistically significant difference between the cohort of patients who received 30mg/kg weekly of eteplirsen and the placebo/delayed treatment cohort.

Modified Intent-to-Treat and Subgroup Analyses

A modified intent-to-treat (mITT) population was evaluated that excluded two patients who were randomized to the 30mg/kg weekly eteplirsen cohort who showed signs of rapid disease progression within weeks after enrollment and were unable to perform measures of ambulation beyond 24 weeks. This mITT population consisting of 10 patients (4 eteplirsen-treated patients receiving 50mg/kg weekly, 2 eteplirsen-treated patients receiving 30mg/kg weekly, and 4 placebo/delayed-treatment patients) was further analyzed.

Summary of 6MWT: Eteplirsen versus Placebo/Delayed-treatment through Week 36*

Treatment Arm   Mean 6MWT Change from Baseline (meters)   Estimated Treatment Effect (Eteplirsen minus Placebo/Delayed-Tx)   p-value
Placebo/Delayed-Tx (n=4)   -70.9        
Eteplirsen 50 mg/kg (n=4)   -5.2   65.8 meters   0.0002
Eteplirsen Both Doses (n=6)   -14.6   56.2 meters   0.0004
Eteplirsen 30 mg/kg (n=2)   -33.3   37.6 meters   ns

*Note: Analysis based on Mixed Model Repeated Measures test

Summary of Additional Sub-Group Analyses at Week 36**

Subset   Mean 6MWT Change from Baseline (meters)   Estimated Treatment Benefit (Eteplirsen minus Placebo/delayed-Tx)   p-value
             
Placebo/delayed Tx:
 < 9.5 yrs at baseline
(n=2; mean=7.6 yrs)
  -60.6   63.6 meters   0.0040
Eteplirsen: 
 < 9.5 yrs at baseline
(n=3; mean=8.4 yrs)
  +3.1        
Placebo/delayed Tx:
≥9.5 yrs at baseline
(n=2; mean=10.1 yrs)
  -73.4    36.0  meters   ns
Eteplirsen: 
≥9.5 yrs at baseline
(n=3; mean=10.4 yrs)
  -37.4        
Placebo/delayed Tx:
Higher 6MWT baseline
(n=2; mean=422m)
  -75.5   82.5  meters   0.0001
Eteplirsen:
Higher 6MWT baseline
(n=3; mean=424m)
  +7.0        
Placebo/delayed Tx: Lower 6MWT baseline
(n=2; mean=367m)
  -72.1   39.9 meters   ns
Eteplirsen:
Lower 6MWT baseline
(n=3; mean=375m)
  -32.3        
Placebo/delayed Tx:
Genotype 49-50 deletion (n=3; age mean=9.2 yrs, 6MWT BL mean=397m)
  -67.6   68.5 meters   0.0001
Eteplirsen:
Genotype 49-50 deletion
(n=2; age mean=9.1 yrs, 6MWT BL mean=383m)
  +0.9        

 ** Note: Analysis based on Mixed Model Repeated Measures test

About Study 201 and Study 202 (Phase IIb Eteplirsen Study)

Study 4658-US-201 was conducted at Nationwide Children's Hospital in Columbus, Ohio. Twelve boys meeting the inclusion criteria being between 7 and 13 years of age with appropriate deletions of the dystrophin gene that confirm eligibility for treatment with an exon-51 skipping drug, received double-blind IV infusions of placebo (n=4), 30 mg/kg of eteplirsen (n=4), or 50 mg/kg of eteplirsen once weekly for 24 weeks (n=4). Muscle biopsies for evaluation of dystrophin were obtained at baseline for all subjects, and after 12 weeks for patients in the 50 mg/kg cohort and after 24 weeks for patients in the 30 mg/kg cohort. Two placebo patients were randomized to the 30 mg/kg cohort and two placebo patients were randomized to the 50 mg/kg cohort. This study design allowed Sarepta to investigate the relationship of dose and duration of eteplirsen treatment on the production of dystrophin over the course of the 24-week study.

Study 4658-US-202 is the extension study to 201 and continues to assess the long-term safety and efficacy of open-label eteplirsen. The four placebo patients were rolled over to open-label eteplirsen at week 24, with six patients on 30 mgs/kg, and six patients on 50 mgs/kg. Third biopsies will occur at 48 weeks in the original study 201 treated patients, and at 24 weeks, the same time point, in the original placebo patients. 6MWT was performed at 32 weeks and 36 weeks, and will continue to be performed every 12 weeks going forward.



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Research

Ataluren Update July 2012

by Admin 7/24/2012 10:39:00 AM

Summary of trial results

The pivotal Phase 2b trial of ataluren, an investigational new drug being studied in nonsense mutation Duchenne/Becker muscular dystrophy (DBMD), was completed in late 2009. It had enrolled 174 patients at 37 trial sites in 11 countries on four continents. As PTC and statistics experts have analyzed the complex data from this trial using various statistical methods, the company has come to understand that the results are very promising.

Efficacy

  • The trial had low-dose ataluren and high-dose ataluren arms as well as a placebo arm. The main criterion, or endpoint, used to determine differences in performance among the three arms was the Six Minute Walk Test, which measured, every six weeks, the distance that participants could walk in 6 minutes (6MWD).

  • Participants receiving low-dose ataluren (10, 10, 20 mg/kg) showed a clinically meaningful difference (approximately 30 meters) in the change in their 6MWD results when compared to the placebo arm.

  • The FDA requires that trial sponsors specify in advance which statistical models will be used to analyze data at the end of a study. The data was first analyzed using the pre-specified statistical method. The unexpected complexity of the ataluren data could not be fully addressed using this method, so it was necessary to use a different (ie, post hoc) statistical model to fully understand the results.

o A post hoc statistical analysis, using a model suggested by independent statistics experts, showed an average difference between low-dose ataluren and placebo of 31.3 meters (103 feet) in the 6MWD. The p-value for this result is 0.0561. A p-value is a test of statistical significance that measures how likely it is that a result is due to an actual effect rather than to chance. In this case, the post hoc corrected p value of 0.0561 indicates that there is only about a 5% possibility that the results could have been obtained if ataluren was no different than placebo.

o A second measure used to compare the effects of ataluren at the two different doses and against placebo was the time it took for the 6MWD to worsen by 10% and remain so. This was defined as “time to persistent 10% worsening.” This analysis indicated that patients receiving low-dose ataluren experienced slower disease progression than patients receiving placebo. By the end of the trial, 26% of the low-dose patients were persistently 10% worse in 6MWD than when they started, compared to 48% in the high-dose arm and 44% in the placebo arm (post hoc p=0.0652 for low-dose ataluren vs placebo).

The 6MWD results from the high-dose (20, 20, 40 mg/kg) arm were similar to the placebo arm. At the completion of the preliminary data analysis, all patients in three ongoing DBMD clinical trials (Phase 2a and 2b extension studies and a non-ambulatory study) were receiving the high dose. Although an independent data monitoring committee agreed that ataluren was well tolerated by patients, the committee recommended that the trials be suspended because all patients in ongoing trials were on the high dose.

Safety

Safety results showed that ataluren was generally well tolerated:
o Adverse events were similar across all three arms of the study: high-dose, low-dose and

placebo.
o No patients discontinued treatment due to an adverse event.
o Serious adverse events were infrequent and none was considered to be related to ataluren.

Current status

Extension Studies

  • In the US, PTC is providing access to ataluren to 106 previous trial participants through an open- label study in which all patients receive ataluren (10, 10, 20 mg/kg). Safety data is being collected. Enrollment in this trial is complete and patients have been receiving ataluren for at least six months.

  • In Canada and nine other countries that had Phase 2b trial sites, PTC has initiated an open-label study, collecting safety and efficacy data. Several patients have already been enrolled and are now receiving drug. Many sites are in various stages of obtaining national and local regulatory permission and completing paperwork to enroll patients over the next several months.

    Regulatory Path

    • PTC remains committed to the development and commercialization of ataluren and is engaged in discussions with regulatory authorities in the US and Europe regarding the path forward for ataluren in nonsense mutation Duchenne/Becker muscular dystrophy.

    • The FDA feedback is that the efficacy data from the single Phase 2b trial is not adequate to support approval at this time.

o When the FDA is presented with data from a single pivotal trial, even for a rare disease, the

data has to meet a particularly high standard. Discussions with the FDA regarding ataluren and

the path forward are still ongoing.
o The FDA considers a p-value of 0.05 to be the standard criterion for statistical significance.

This means that there is no more than a 5% chance that the trial results were due to chance and not to an actual drug effect. The corrected post-hoc analysis showed a p-value of 0.0561 for the comparison of low-dose ataluren vs. placebo in the 6MWD.

o The ataluren Phase 2b study was the first registration-directed trial ever conducted in DBMD and it was not known what the clinical endpoints, some of which had never been used before, would show when measuring the impact of a disease-modifying therapy.

o Several other factors contributed to the difficulty of obtaining more robust evidence of efficacy in this trial, including the variability in the natural history of DBMD, the requirement to pre- specify the statistical analysis in the absence of a previous trial that could act as a model, and the limitations of doing trials in rare diseases.

o The most likely outcome of our FDA discussions is that a pre-approval confirmatory study will be necessary.

The company is simultaneously in discussions with the European Medicines Agency (EMA) concerning the path forward in Europe. It is possible that we will be able to file in the European Union under the mechanism of conditional approval, in which approval is granted with the requirement to conduct a confirmatory study.

o PTC is engaged in the formal scientific advice process of presenting data from the trial to selected regulatory officials for their input. The precise timing of the filing, however, will depend on the outcome of our upcoming meetings. We are encouraged by discussions with the EMA thus far.

Confirmatory study

Whether in the context of conditional approval in Europe, or to meet additional requirements in the US, PTC is currently planning to conduct an additional confirmatory study of low dose ataluren (10, 10, 20 mg/kg) vs. placebo.

  • This study design will be based on the Phase 2b trial results and the goal is to confirm the previous findings in the low-dose patient group.

  • PTC is in discussions with clinical investigators and regulatory agencies about the specific design and endpoints for this trial and will update the community when a protocol is finalized.

  • It is important to realize that a confirmatory study is often more restrictive in its inclusion/exclusion criteria than the original trial, as it is intended to confirm specific results. The goal of the clinical trial is to secure approval of ataluren so all patients who might benefit from ataluren may have access. 



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Duchenne Ireland works with Irish Politicians to establish further UK/Ireland care for Irish Duchenne patients at the British-Irish Parliamentary Assembly

by Admin 5/18/2012 9:57:00 AM
Irish politicians pushed for closer collaboration between UK and Ireland with respect to Duchenne Muscular Dystrophy patient care this week at the British-Irish Parliamentary Assembly. Deputy Joe McHugh TD reitterated the words of the minister for health stating that for rare diseases such as Duchenne, that it was not feasibile to expect Ireland to manage the full extent of the care requirements on it's own and that international co-operation expecially with our closest neighbour, the UK was essential.
 
"I acknowledge the contributions by many members on health synergies across Britain and Ireland. There is the success of the partnership approach between the Irish Government and the Northern Ireland Executive to develop radiotherapy facilities at Altnagelvin Hospital, and we should expand that to other potential areas of cross-Border and east-west co-operation. Deputy Patrick O’Donovan referred to the process where Irish boys with Duchenne muscular dystrophy go to Newcastle to avail of services to treat the disease. The Minister for Health was present on Monday, and he indicated it is not feasible to expect all rare diseases to be managed on a stand-alone basis by individual jurisdictions. There are significant advantages from a quality and economies of scale perspective to widening these matters beyond borders. Although we are focused primarily on the site of the new children’s hospital in Ireland, we should also examine how to work together on sharing services. There will be co-operation behind the scenes but if we are to have a state of the art children’s hospital providing a range of services, we should consider shared services and synergies on an east-west basis."

Deputy Joe McHugh
 
http://debates.oireachtas.ie/dail/2012/05/17/00009.asp


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Duchenne Connect Registry releases treatment options analysis based on registry information

by Admin 4/29/2012 12:34:00 AM

"Have you ever wondered if anyone is examining all the data entered into DuchenneConnect? Would you like to hear the results from a study focusing on the registry data? If so, you must listen to this webinar with Dr. Stanley Nelson, Professor of Human Genetics at the David Geffen School of Medicine at the University of California, Los Angeles, as he discusses his study of the DuchenneConnect data. His research focused on analyzing the registry data from the start of the registry in 2007 through June, 2011. His research team investigated several associations, including associations between corticosteroid use, supplement use, and ambulation, and they have some very interesting results to share."

Full Credit to Parent Project Muscular Dystrophy and the Duchenne Connect Registry for bringing this information to the Duchenne Community.



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