Updated April 29, 2016
Duchenne Muscular Dystrophy
I have written previously about Duchenne muscular dystrophy, a rare and fatal, genetic muscle disease that affects children (CLICK HERE TO VIEW PREVIOUS POSTS).
What Is Duchenne Muscular Dystrophy?
DMD is a degenerative neuromuscular disorder causing severe progressive muscle loss and even premature death. It is one of the nine types of muscular dystrophy and it is mainly caused by the absence of dystrophin, an important protein that helps keep the muscle cells intact.
Symptoms of this disease first appear during childhood, usually between ages 3 and 5. It primarily affects boys, but can also affect girls in rare cases.
Patients affected with DMD usually do not survive beyond their teen years, but thanks to advancement in medicine and cardiac care, the life expectancy of boys affected by the condition is increasing dramatically. Some of the patients have reached young adulthood, with some having families of their own and others living into their 40s and 50s.
Four potentially Important developments have taken place in the research to treat victims of this horrible disease, since I last wrote about it on December 6, 2015:
1) NICE Recommends Translarna™ (ataluren) for the Treatment of Patients with Nonsense Mutation Duchenne Muscular Dystrophy in England
Positive Recommendation Enables Reimbursed Patient Access to First Approved Therapy to Treat Underlying Cause of Devastating Rare Disease
The provision of patient access is subject to the finalization of the NICE draft guidance, which the agency expects in May of 2016.
"This is an important day for the Duchenne community, which has been working hard to make this ground-breaking drug available to boys with nonsense mutation Duchenne muscular dystrophy," said Paul Lenihan , Chief Executive of Action Duchenne. "We are delighted by this positive recommendation and NICE's recognition that Translarna is an important new medicine for patients. This decision is a hugely encouraging sign that both NICE and NHS England have listened to the patient community, bringing hope to each and every parent and patient fighting DMD."
Primarily affecting males, Duchenne muscular dystrophy (DMD) is a progressive muscle disorder caused by the lack of functional dystrophin protein. Dystrophin is critical to the structural stability of skeletal, diaphragm, and heart muscles. Patients with DMD lose the ability to walk from as early as 10 years of age and experience life-threatening lung and heart complications in their late teens and early twenties.
"We are extremely pleased by the NICE recommendation, which recognizes Translarna as an innovative medicine with the potential to change the course of this devastating disease," said Stuart W. Peltz , Ph.D., Chief Executive Officer, PTC Therapeutics, Inc. "This is a crucial step for the boys and young men in England with nonsense mutation DMD. We are grateful to the patients, families, advocacy groups and physicians who have supported PTC Therapeutics through this important access process and look forward to working with NHS England to conclude the managed access agreement."
PTC and NHS England are in the process of finalizing an MAA outlining financial and clinical details surrounding the use of Translarna, including a confidential financial arrangement. The MAA is expected to allow PTC to collect further data on the efficacy of Translarna for the treatment of nmDMD over a five-year period with NICE guidance to be reviewed again at the end of that period.
Translarna was approved by the European Commission in August 2014 to treat nmDMD and is currently available to patients in 23 countries through either expanded access programs or commercial sales.
About Translarna™ (ataluren)
Translarna, discovered and developed byPTC Therapeutics, Inc. , is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as dystrophin in Duchenne muscular dystrophy. Translarna is licensed in the European Economic Area for the treatment of nonsense mutation Duchenne muscular dystrophy in ambulatory patients aged five years and older. Translarna is an investigational new drug in the United States . The development of Translarna has been supported by grants from the Cystic Fibrosis Foundation Therapeutics Inc. (the nonprofit affiliate of the Cystic Fibrosis Foundation ); Muscular Dystrophy Association ; FDA's Office of Orphan Products Development ; National Center for Research Resources ; National Heart, Lung, and Blood Institute ; and Parent Project Muscular Dystrophy.
Translarna, discovered and developed by
Further information about Translarna, including the European Public Assessment Report, Summary of Product Characteristics and Patient Information Leaflet, is available on the European Medicines Association website.
This medicinal product is subject to additional monitoring. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system or to PTC at medinfo@ptcbio.com.
For more information on the company, please visit their website www.ptcbio.com.
For More Information:
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2) Capricor Therapeutics Announces DSMB Recommends Continuation of HOPE-Duchenne Clinical Trial
Enrollment to Continue Following Pre-Specified Safety Analysis
3) Catabasis Pharmaceuticals Initiates Part B of the MoveDMDSM Trial of CAT-1004 for the
Treatment of Duchenne Muscular Dystrophy
- Positive NF-kB Biomarker Data from Part A of the MoveDMD Trial in Patients -
CAMBRIDGE, MA, April 12, 2016 – Catabasis Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company, today announced that dosing of the first patient has been initiated in Part B of the MoveDMD trial, a 12-week trial to assess the efficacy of CAT-1004 in Duchenne muscular dystrophy (DMD). Catabasis also announced positive biomarker results from Part A of the MoveDMD trial, demonstrating successful NF-kB target engagement.
The biomarker assay piloted in boys affected by DMD showed a statistically significant decrease in NF-kB gene expression markers compared to baseline at the 67 mg/kg and 100 mg/kg per day doses as well as a statistically significant dose response in the gene expression data measured from whole blood samples. Catabasis has previously reported positive safety, tolerability and pharmacokinetics results from Part A of the trial.
“We are very glad to advance CAT-1004 into Phase 2 with the initiation of Part B of the MoveDMD trial in boys affected by DMD,” said Jill C. Milne, Ph.D., Chief Executive Officer of Catabasis. “We are pleased with the positive NF-kB biomarker results in Part A of the trial demonstrating target engagement as well as the 5 - 10 fold higher CAT-1004 concentration that we have seen in muscle compared to plasma in pre-clinical models.” “I am glad to see the advancement of this novel potential therapy in boys affected by Duchenne,” said H. Lee Sweeney, Ph.D., Professor, Director, Myology Institute at the University of Florida. “Therapies that have the potential to make a meaningful difference are needed to address the profound unmet medical need in DMD.” CAT-1004 is an oral small-molecule that the Company believes has the potential to be a diseasemodifying therapy for the treatment of DMD, regardless of the underlying dystrophin mutation. CAT-1004 is an inhibitor of NF-kB, a protein that is chronically activated in DMD as well as multiple other skeletal muscle disorders and rare diseases.
In animal models of DMD, CAT-1004 inhibited NF-kB, reduced muscle degeneration and increased muscle regeneration. The MoveDMD trial is being conducted in two sequential parts, Part A and Part B. In Part A of the MoveDMD trial, 17 ambulatory boys between ages 4 and 7 with a genetically confirmed diagnosis of DMD across a range of dystrophin mutations received CAT-1004.
The boys were steroid naive or had not used steroids for at least six months prior to the trial. Part A of the trial was conducted at three sites in the U.S., and assessed the safety, tolerability and pharmacokinetics of CAT-1004 in patients at three dosing levels (33 mg/kg/day, 67 mg/kg/day and 100 mg/kg/day) during seven days of dosing.
Part B is a randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of CAT-1004 in DMD over a 12-week period at 5 clinical trial sites in the U.S. at two dosing levels, 67 mg/kg/day and 100 mg/kg/day. The boys that participated in Part A of the MoveDMD trial are asked to participate in Part B and additional participants are expected to be enrolled for a total of approximately 30 boys. We are currently identifying additional patients who are interested in participating in Part B of the trial. Entry criteria are similar to those in Part
More information about the MoveDMD trial can be found on the clinical trials page of the Catabasis website and on ClinicalTrials.gov under trial identifier NCT02439216.
About CAT-1004
CAT-1004 is an oral small molecule that has the potential to be a disease-modifying therapy for all patients affected by Duchenne muscular dystrophy (DMD or Duchenne), regardless of the underlying mutation. CAT-1004 inhibits NF-kB, a protein that is activated in Duchenne and drives inflammation and fibrosis, muscle degeneration and suppresses muscle regeneration. In animal models of DMD, CAT-1004 inhibited NF-kB, reduced muscle degeneration and improved muscle regeneration and function, and beneficial effects were observed in skeletal, diaphragm and cardiac muscle. The FDA has granted orphan drug, fast track and rare pediatric disease designations and the European Commission has granted orphan medicinal product designation to CAT-1004 for the treatment of DMD. We have previously reported safety, tolerability and reduction in NF-kB activity in Phase 1 trials in adults. We are currently conducting the MoveDMDSM trial of CAT-1004 in 4-7 year-old boys affected by Duchenne. From Part A of the MoveDMD trial, we have reported that CAT-1004 was generally well tolerated with no safety signals observed and successful NF-kB target engagement. Pharmacokinetic results demonstrated CAT-1004 average plasma exposure levels consistent with those previously observed in adults at which inhibition of NF-kB was observed.
About MoveDMDSM
MoveDMD is a Phase 1 / 2 clinical trial of CAT-1004 in boys ages 4-7 affected with DMD (any confirmed mutation). The MoveDMD trial is a two-part clinical trial investigating the safety and efficacy of CAT-1004 in DMD. Part A of the MoveDMD trial evaluated the safety, tolerability and pharmacokinetics of CAT-1004 with positive results. The boys in Part A of the trial will be asked to participate, if eligible, in Part B of the trial. Part B of the trial will be planned to evaluate the safety and efficacy of CAT-1004 in DMD over a 12-week treatment period and will enroll approximately 30 boys. The primary end point is changes in MRI of the leg muscles, and the secondary end point is age-appropriate timed function tests. Additional assessments include muscle strength, the North Star Ambulatory Assessment and the pediatric outcomes data collection tool (PODCI).
About MRI
Magnetic resonance imaging (MRI) is a non-invasive imaging technique that can visualize muscle structure and composition and measure disease status in children with DMD. Two MRI measures used in Duchenne to indicate muscle degeneration are T2 and fat fraction. MRI is sensitive to changes in muscle structure and composition induced by disease processes such as the inflammation, edema, muscle damage and fat infiltration that occur in Duchenne. Changes in T2 may be seen in less than 12 weeks while changes in fat fraction may take longer. Changes in these MRI measures have been correlated with longer-term changes in clinically meaningful measures of functional activity. Changes in MRI can show the effects of an investigational therapy on disease progression in Duchenne in an objective and quantifiable manner.
Corporate and Media Contact
Catabasis Pharmaceuticals, Inc.
Andrea Matthews, 617-349-1971
amatthews@catabasis.com
Catabasis Pharmaceuticals, Inc.
Andrea Matthews, 617-349-1971
amatthews@catabasis.com
4) FDA Panel Gives Thumbs Down To Sarepta Duchenne Muscular Dystrophy Drug Eteplirsen
April 27, 2016
Sarepta, a pharmaceutical company, lost a major battle in its quest to gain approval for eteplirsen, its drug for Duchenne muscular dystrophy (DMD).
A U.S. Food and Drug Administration (FDA) panel of outside experts voted 6 to 7, saying that the company was not able to provide significant evidence that the drug boosts the production of dystrophin to a level that provides a clinical benefit.
The committee also voted 3 to 7 against finding substantial evidence that eteplirsen is effective in treating people with the degenerative disease. Three panelists abstained from voting.
"We would like to thank the hundreds of patients and families who participated in the discussion today, underscoring the critical unmet need of people living with Duchenne," Dr. Edward Kaye, chief medical officer and interim CEO of Sarepta, said.
"We appreciated the opportunity to present our data to the advisory committee panel and will continue to work with FDA as they complete their review of the eteplirsen NDA. Today more than ever, we remain committed to our mission of bringing a treatment to the Duchenne community," he added.
The vote came after a gruelling 11-hour session, during which patients and drug advocates aired an emotional voice asking the regulatory agency to accelerate the approval of the drug's marketing in the U.S.
Sarepta, however, has fallen short on important questions regarding eteplirsen's ability to treat DMD, which the advisory committee considered.
"I was not convinced the data was there to prove something based on one, poorly controlled study," said Professor Richard Kryscio of the University of Kentucky, who voted against the drug.
Scientific Data Fell Short On Proving Efficacy
The patients suffering from the disease and their families attended the FDA meeting. They applauded the study's scientists and rebuked FDA regulators.
With more than 50 speakers who talked to the FDA during a public comment, they were all hopeful that the drug would be approved. Much to their dismay, the panelists acknowledged the anecdotes, but believe that the results claimed by the patients themselves were not reflected in the data presented by Sarepta.
"Unfortunately, what I would consider meaningful evidence from the testimony of the families is not properly measured in the study," said Dr. Chiadi Onyike of Johns Hopkins University.
It is my hope that those looking for information on Duchenne Muscular Dystrophy to save the lives of their children will find these research updates helpful & that one day a cure for this terrible disease will be found.
