Compounds designed to alter genetic instructions for dystrophin, increase production of utrophin, or prevent scar tissue formation in muscle are moving through the development pipeline
Drug development for Duchenne muscular dystrophy (DMD) is progressing on several fronts. Here are some updates as of early November 2014.
In August 2014, ataluren, also known as Translarna, received conditional approval in Europe for ambulatory patients ages 5 and older with DMD caused by specific genetic mutations known as premature stop codons (also known as nonsense mutations). Ataluren is being developed by PTC Therapeutics of South Plainfield, N.J., a biotech company to which MDA gave a $1.5 million grant in 2005. It's known as a "stop codon read-through" drug.
In September, PTC announced it had completed enrollment for its phase 3 trial of ataluren and that initial results are expected in the second half of 2015. This large-scale, 48-week, multinational trial will be necessary before full approval can be considered for ataluren in either the United States or the European Union. For details about the large-scale trial, see Phase 3 Study of Ataluren, or enter NCT01826487 in the search box at ClinicalTrials.gov.
In addition, full results for an earlier, phase 2b trial of ataluren, originally announced in 2010, were published in the October 2014 issue of the journal Muscle & Nerve. In this trial, all participants showed a decline in the distance they could walk in six minutes, but those treated with a particular dose of ataluren declined more slowly than those treated with a different dose or with a placebo.
In October 2014, British biotechnology company Summit PLC announced that SMT C1100, its experimental, orally administered drug in development with support from MDA, was found in a phase 1b trial in boys with DMD to be safe and to reduce blood levels of enzymes associated with muscle damage.
SMT C1100 — known as a "utrophin modulator" — is designed to increase the levels of and distribution of a muscle protein called utrophin, which is similar to the dystrophin protein that is missing in DMD-affected muscles. Evidence from rodent studies suggests that raising utrophin levels and distribution in muscle fibers can at least partially compensate for the loss of dystrophin. Utrophin modulators are designed to be effective regardless of the specific DMD-causing genetic mutation.
At a meeting in October of the World Muscle Society, Summit presented the phase 1b results as well as positive laboratory data about additional utrophin-altering compounds in its pipeline and said it is developing new ways to measure utrophin and various aspects of muscle health. Presentations from the conference are available on the Summit site.
In July 2014, the MDA-supported company ReveraGen BioPharma, based in Silver Spring, Md., announced it will move its experimental DMD compound VBP15 into testing in healthy people and plans to follow up with testing in DMD patients if all goes as planned. The compound is designed to provide the benefits to DMD-affected muscle of corticosteroid medications like prednisone but without the harsh side effects (weight gain, growth slowing and mood changes, to name a few) caused by these drugs.
Recently, compelling evidence for the proposed mechanism by which VBP15 could reduce the formation of scar tissue in the muscles of DMD patients was offered in an MDA-supported paper published in the Oct. 13, 2014, issue of the Journal of Cell Biology.
The paper, authored by MDA grantee Eric Hoffman and colleagues, found an interesting phenomenon: When neighboring fibers in mouse muscles are injured 10 days apart, the tissue between the two injury sites gets conflicting signals, becomes "confused," and scars over instead of regenerating. Treatment with prednisone or VBP15 appeared to resynchronize the healing program.
Hoffman's group reasoned that, since muscle tissue in DMD is constantly sustaining damage (because it lacks the dystrophin protein) in different muscle sections at various time points, the ability of the muscle to heal itself is probably improved by the resynching effects of prednisone and could perhaps be improved with fewer side effects by VBP15.
Read a summary of the paper, or listen to an approximately seven-minute podcast about the findings on the Journal of Cell Biology website.
Update (Nov. 10, 2014): The trial to test eteplirsen in patients with DMD who can no longer walk a minimum distance is now open. See Safety Study of Eteplirsen to Treat Advanced Stage Duchenne Muscular Dystrophy, or enter NCT02286947 in the search box at ClinicalTrials.gov.
In fall 2014, Cambridge, Mass.-based Sarepta Therapeutics opened a large-scale, phase 3 trial of its experimental DMD drug eteplirsen. For details and contact information, see Confirmatory Study of Eteplirsen in DMD Patients, or enter NCT02255552 in the search box at ClinicalTrials.gov.
This drug is designed to target and block a section of genetic instructions for the dystrophin protein known as exon 51, thereby causing muscle cells to make a short, but functional, version of the dystrophin protein, which is missing in DMD-affected cells. Known as an exon-skipping compound, eteplirsen may help those with DMD who have dystrophin gene mutations near (but not in) exon 51.
The company had hoped to submit a new drug application for eteplirsen to the U.S. Food and Drug Administration (FDA) by the end of 2014, based largely on encouraging results from a small (12-participant), phase 2b study of the drug. However, on Oct. 27, Sarepta revised its estimate of the timing of the new drug application submission from late 2014 to mid-2015, following requests from the FDA for additional information.
Specifically, the agency asked to see data from more patients treated with eteplirsen, more information about the natural history of DMD from untreated patients, and more convincing evidence that dystrophin protein levels have increased in the muscle biopsy samples of treated trial participants.
On Oct. 30, the FDA released a statement to the DMD community in which it explains its desire for more data, assures patients and families of its commitment to DMD drug development, and says it understands the urgency of the situation.
"We understand that this news is disappointing to the DMD community, and we feel the same sense of urgency that our families do when it comes to finding effective treatments,” said neurologist Valerie Cwik, M.D., MDA's chief medical and scientific officer. "We hope this development will not significantly delay the process as the FDA ensures eteplirsen is safe and effective before it is brought into the clinic.”
Sarepta plans to submit its Sarepta application via the FDA's accelerated approval pathway, one of several mechanisms the agency offers to speed up development of new drugs.
Whether or not the company receives an accelerated approval for eteplirsen, it will need to conduct a confirmatory, phase 3 trial before full approval can be granted by the FDA. In addition to the confirmatory trial, which is being conducted in boys with DMD who are ages 7 to 16 and walking, Sarepta plans to conduct a trial of eteplirsen in boys who are younger than 7 years old and another in patients up to age 20 who are no longer able to walk a minimum distance.
The company is developing additional exon-skipping compounds that target exons 53, 45, 50, 44, 52 and 8 of the dystrophin gene. These compounds, which are designed to treat DMD patients with dystrophin mutations near but not in the targeted exons, are not yet in clinical trials.
MDA has supported the development of exon skipping for DMD since the 1990s and provided supplemental support for a phase 2 eteplirsen trial.
For much more on the FDA's mechanisms to speed up drug approvals see The FDA Approval Process: Can We Have This Drug Now?. For more about Sarepta's exon-skipping drug development program, see Sarepta's Let's Skip Ahead website.To receive updates from Sarepta, see Join Us.
In October 2014, Prosensa, a Dutch biotechnology company, announced it had begun its new drug application submission to the U.S. Food and Drug Administration (FDA) for its DMD drug drisapersen, making use of the FDA's accelerated approval mechanism. At the same time, the company said it was on track to submit a marketing authorization application for conditional approval by the European Medicines Agency (EMA) in early 2015.
In September, Prosensa announced it had begun readministering drisapersen to participants in ongoing studies in North America and in Europe. Administration of the drug had been temporarily halted in 2013, after a phase 3 trial of drisapersen failed to show it was better than a placebo on tests of walking distance or motor function at 48 weeks.
In contrast to the phase 3 results, a U.S.-based phase 2 trial showed encouraging results in March 2014, as did a non-U.S. phase 2 trial in April 2013.
Like eteplirsen (see above), drisapersen targets exon 51 of the dystrophin gene and is designed to treat patients with DMD who have mutations near (but not in) this part of the gene. The goal is to cause muscle cells to produce a short, but still functional, dystrophin protein. MDA has supported exon skipping as a strategy for DMD treatment since the 1990s.
Prosensa is also developing compounds that target exons 44, 45, 53, 52 and 55 of the dystrophin gene. A European phase 1-2 trial of PRO044, which targets dystrophin exon 44 and is designed for patients with dystrophin mutations near that section, has been completed. A phase 2 trial of PRO045, targeting exon 45 of the dystrophin gene, is underway in Europe and the United Kingdom and is open to participants. Enter NCT01826474 in the search box at ClinicalTrials.gov for details. Also in Europe and the United Kingdom, a phase 1-2 trial of PRO053, which targets exon 53, is underway, with some sites recruiting new participants. Enter NCT01957059 in the search box at ClinicalTrials.gov for details.