In this second of two fall reports on treatment development for Duchenne muscular dystrophy, news about ARM210, CAP-1002, PDE5 inhibitors, drisapersen and CAT-1004 is presented
Update (Feb. 6, 2015): This article has been amended to show that Catabasis' compound CAT-1004 is expected to move into clinical testing in boys with DMD during the first half of 2015.
Several experimental drugs are in development to treat Duchenne muscular dystrophy (DMD), a genetic disorder that results in a lack of the dystrophin protein in cardiac and skeletal muscle cells.
While many investigational therapies aim to raise levels of dystrophin or a related protein, others are designed to perform other functions that may be therapeutic in this disorder and possibly other muscle diseases. These include combatting inflammation, repairing calcium leaks in cells, replacing damaged cells, and improving blood flow to muscles.
Drug targeting calcium leaks passes mouse tests, will likely move to human trials
The experimental compound ARM210, whose development is being supported in part by MDA, has shown promise in treating mice lacking the dystrophin protein and showing a disease resembling DMD,and it will likely be tested in DMD patients in the near future.
ARMGO Pharma, a Tarrytown, N.Y.-based biotechnology company, and its partner, the multinational pharmaceutical company Servier, are developing ARM210 and announced the encouraging mouse results in a Dec. 4, 2014, press release. MDA began funding development of this compound in 2013.
ARM210, also known as S48168, is an oral medication designed to repair "leaky" calcium channels inside the cells of the heart and skeletal muscles. Such internal calcium leaks are thought to contribute to muscle weakness and degeneration in DMD and possibly other muscle disorders. ARM210, which belongs to a class of drugs known as Rycals, acts on these leaks without regard to the underlying genetic mutation causing DMD.
Dystrophin-deficient mice treated with ARM210 showed "significant and robust" positive differences in exercise capacity, muscle force, grip strength and the microscopic appearance of muscle tissue compared to mice treated with an inert substance, the companies said. In addition, a set of animal safety studies for ARM210 that is required for beginning human trials was successfully completed.
"Based on the collective strength of the completed preclinical efficacy and safety studies, ARM210/S48168 has been formally selected for advancement for clinical development," the companies said, noting that clinical trials are scheduled to begin in 2015, following finalization of development plans, manufacturing and formulation work and input from regulatory agencies.
The initial trials will be in healthy volunteers followed by studies in DMD patients, but ARM210 could also be found to have applications in other muscle diseases, such as Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy (LGMD)and central core disease (CCD).
Cardiac stem cells show promise in DMD mice
Los Angeles-based Capricor Therapeutics recently announced that encouraging results seen in dystrophin-deficient mice after treatment with its CAP-1002 cardiac stem cells will form the basis for taking these cells into a clinical development plan to treat DMD-related heart disease. CAP-1002 cells are derived from donor heart tissue.
At a November 2014 meeting of the American Heart Association and in a Nov. 18, 2014, press release, Capricor described how mice with a DMD-like disorder, including heart muscle degeneration, showed markedly better cardiac pumping function and better exercise capacity after treatment with CAP-1002 cells than similar mice showed after treatment with an inert substance.
"The findings raise the possibility [these] cells may be useful therapeutically to treat heart failure in patients with Duchenne muscular dystrophy," the company said.
At the same meeting, Capricor announced that CAP-1002 cells were safe and possibly therapeutic in a trial of 14 patients who had experienced a myocardial infarction ("heart attack"). No major cardiac adverse events occurred in association with infusion of these cells into the heart, Capricor said. Some participants in the phase 1 trial also showed improvements in cardiac pumping ability and reduction in the size of the injury-related scar tissue. A phase 2 trial is now underway in post-heart attack patients.
Listen to a Nov. 18 conference call from Capricor that focuses on development of cardiac stem cells for DMD.
Two new studies sound cautionary note for PDE5 inhibitors
The PDE5 inhibitors sildenafil and tadalafil – on the market to treat erectile dysfunction as Viagra and Cialis, respectively – are being studied to see whether they can improve blood flow to exercising muscles in DMD and BMD, as pilot studies have suggested.
However, two new studies, both small, have cast doubt on the benefits of sildenafil. Doris Leung and colleagues, writing in the October 2014 issue of Annals of Neurology, reported that sildenafil did not improve cardiomyopathy (cardiac muscle degeneration) in adults with DMD or BMD. And in the same issue of that journal, Nanna Witting and colleagues reported that sildenafil did not improve blood flow, work capacity or heart function in adults with BMD. Both these sildenafil studies were in boys who were at least in their teens and had compromised heart function at study entry.
A large-scale, multicenter, Eli Lilly-funded trial of tadalafil in DMD remains open. (See A Study of Tadalafil for DMD or enter NCT01865084 in the search box at ClinicalTrials.gov.) This tadalafil study is much larger than the sildenafil studies, and it is being conducted in boys who are ages 7 to 14 with normal or nearly normal heart function. Cardiac function will be carefully monitored during the trial. Tadalafil has a different chemical formulation from sildenafil, which could be advantageous.
BioMarin acquires Prosensa, aims to take exon-skipping drugs through approval process
Multinational biopharmaceutical company BioMarin will acquire Dutch biotechnology firm Prosensa, developer of drisapersen and other experimental compounds designed to treat DMD by changing the way cells interpret genetic instructions (RNA) for the dystrophin protein. The announcement was made in a Nov. 24, 2014, press release.
Prosensa announced in October that it had begun its submission of a new drug aplication for drisapersen to the U.S. Food and Drug Administration (FDA) and was on track to submitting a marketing authorization application for conditional approval of drisapersen in Europe in early 2015. The company is also developing several additional DMD compounds.
"BioMarin is dedicated to the rare disease community, and the acquisitino of Prosensa fits strategically with our mission of delivering therapies that address serious unmet medical needs," said Jean-Jacques Bienaimé, the company's CEO, in the Nov. 24 announcement. "We are committed to working closely with regulatory authories worldwide in bringing a potentially breakthrough therapy to patients with this devastating condition," he added, referring to DMD.
Giles Campion, Prosensa's chief medical officer, expressed his enthusiasm for the acquisition in a letter to patient advocacy groups on Nov. 24. "As you know," he wrote, "getting a product approved and commercializing it is an incredible undertaking. Since 1997, BioMarin has successfully developed and brought five products to people with rare diseases. BioMarin has the resources, bandwidth and experience to get our RNA drugs to market – but it wouldn't be possible without the tremendous amount of work that Prosensa has done and [that] we will continue to do. BioMarin's extensive experience and infrastructure will enhance our mission to bring much-needed therapies to patients on a global basis quickly and more efficiently."
MDA has supported research in exon skipping for DMD since the 1990s. A current MDA grant to Terence Partridge at Children's National Medical Center in Washington, D.C., is focused on directing exon-skipping drugs to the heart in this disease.
CAT-1004 receives orphan drug designation
CAT-1004, an experimental DMD drug in development by Catabasis Pharmaceuticals with support from MDA, has received orphan drug designation from the U.S. Food and Drug Administration (FDA). Orphan drug designation is a mechanism the FDA uses to provide financial incentives to companies developing drugs for rare disorders.
MDA awarded $120,000 to Catabasis in 2012 to develop and test CAT-1004 and a related compound, both designed to reduce inflammation in DMD-affected muscle fibers. A clinical trial to test the drug in DMD patients is expected to begin during the first half of 2015.
"We look forward to progressing CAT-1004 into phase 2 clinical development in 2015," said Catabasis' chief scientific officer Michael Jirousek in a Nov. 24, 2014, press release
For more information
To learn more, see Drug Development for DMD: Fall 2014 Update, published in November.