In A First, an Experimental Drug May Help Boys with Muscular Dystrophy

Barron's (America's premier financial magazine) Oct 8 2012

Forbes  ( leading source for reliable business news and financial information)10.03.2012

A new experimental drug appears to improve the muscle function of boys with muscular dystrophy, increasing the distance the boys can walk in six minutes compared to when they began taking it a year before.

Those results are “incredibly promising,” says Lee Sweeney, chairman of physiology at the University Perelman School of Medicine, who studies muscular dystrophy and was not involved in the study. “They don’t ever improve once they start going down. The fact you can improve them is not something that happens normally. That’s not random.”

The most common form of the disease, Duchenne muscular dystrophy, affects only 13,000 American boys; girls almost never get it because is caused by a defect of a gene on the X chromosome, of which girls have a second copy. The new medicine, eteplirsen, is targeted at the 13% of those boys whose muscular dystrophy is caused by a certain type of mutation. Without treatment, patients’ muscles continually weaken, leaving them wheelchair.

Eteplirsen, if successful, will be a huge victory for muscular dystrophy patients and researchers, who have never had a treatment that might make any of these kids get any better.

The results are also a big win for Sarepta Therapeutics, the  cambridge, Mass.-based biotechnology company that developed the drug. Sarepta’s shares have more than quadrupled since it first released data from the 12-patient study in July, showing that eteplirsen increased the amount of a key muscle protein, dystrophin. Thirty-six-week results released in August showed that the 4 patients who got the top dose of the drug could walk 69 meters further in six minutes than those who started on placebo.

Now 48-week data show those four boys who got the drug actually walking 21 meters further than they could when the study began. The patients who began the study on placebo were switched to getting eteplirsen at 24 weeks. Those “delayed treatment” patients appear to be stabilizing too, with their six-minute walk test scores increasing 10 meters since the 36 week result, although they are still down 68 meters from the beginning of the study. The patients who got the top dose of eteplirsen were able to walk 89 meters further than those who started placebo, and the difference was statistically significant.

The number of muscle fibers that tested positive for dystrophin increased 47% in patients who had been receiving eteplirsen since the beginning of the study and 38% in the patients who started on placebo and switched to eteplirsen after 24 weeks.

“This is the best-case scenario that anybody could have scripted out,” says Chris Garabedian, Sarepta’s chief executive, of the new data.

But there are still some reasons for caution. In the study, eteplirsen, which is given intravenuously for sixty minutes once a week, was given at a dose of 50 milligrams per kilogram to four patients and 30 mg/kg to another four. Another four patients got placebo. Two of the patients in the 30 mg/kg group got dramatically worse early in the study, apparently because their disease had progressed before the drug could begin to work. That complicates the reading of the results.

Another problem may be the size of the study: just twelve patients. For comparison, another Duchenne drug targeting a small slice of patients with a particular genetic mutation, atalauren from PTC Therapeutics, was studied in a trial of 174 patients. (It failed to show a dramatic benefit.)

Sweeney, who worked on the PTC drug, says that he knows some patients are hoping the FDA will approve eteplirsen just based on this data. He says that while the results are very convincing, it’s possible that more patients will need to be studied. A super-fast regulatory approval may be “too much to hope for.”

Garabedian says that it’s impossible to know what the food and drug administration (FDA) will say until Sarepta meets with the agency later this year. He does point to some drug approvals that reflected data from similarly small numbers of patients. Cerezyme, from sanofi's genzyme division, was approved after a study in 12 patients, and Genzyme’s Myozyme was approved after a study in just 18 patients; both drugs were for incredibly rare diseases.novartis  Afinitor and Alexion’s Soliris were also approved for tuberous sclerosis and atypical hemolytic uremic syndrome, respectively, after similarly small studies, but both of those drugs were already approved for other uses that had required much larger studies. (Update, 10/4/2012: On Twitter, jq points out that although Myozyme had an 18-person pivotal trial, there was a second, 21-patient study, too. See the original drug label, here.) 

Even if another study is required, it might be done relatively quickly. And Sarepta is developing other drugs to treat muscular dystrophy in a way that may lay the groundwork for the medicines in the future. Eteplirsen is an oligonucleotide (roughly speaking, its chemistry resembles that of DNA). It works because many cases of muscular dystrophy are caused by mutations in the dystrophin gene (incidentally, one of the longest genes in the body) that make the entire genetic code for the protein shift by one letter. By skipping a single missing letter, the drug makes a shorter but effective version of dystrophin.

Eteplirson works by causing the body’s gene-reading sofware to skip a part of the dystrophin gene called exon 51. But Sarepta is working on other exon-skipping drugs that skip exon 45 and exon 50, which could help 9% and 5% of Duchenne patients, respectively. In the long run, it’s possible that Sarepta could develop a framework for approving drugs that use its chemistry in all Duchenne patients that might be helped. Eighty-five percent of Duchenne patients have the exon-skipping gene. This might pave the way for the way regulators will have to think about drugs in the future, when many medicines might target small, genetic differences that only a small number of people have.

But before it can forge that path, Sarepta has to get eteplirsen approved. And there is competition. Another exon 51-skipping drug, developed by Prosensa, a Dutch biotech, and partner GlaxoSmithKline, is expected to have results from a large study later this year. In results from a 12-patient study of that drug published in the New England Journal of Medicine last year, there was a small improvement in six-minute walk time.