putting his stamp on things. Right away, he killed the lead clinical trial AVI had been running for its Duchenne Muscular Dystrophy drug. This trial was designed to ask whether the drug worked differently in a large single shot, or in an intravenous infusion, at a low 50 milligram per kilogram of body weight dose, and then see over 12 weeks whether it could help the boys produce more dystrophin—the key protein that patients would need to produce in order to keep their muscles functioning. If that didn’t work, the study was designed to double the dose, and see what happened next.
Garabedian looked at the study and thought it was a waste of the company’s precious resources. He had spent time talking to about a dozen “thought leaders” in Duchenne Muscular Dystrophy. One researcher, Francesco Muntoni of University College London, convinced Garabedian that the duration of dosing, rather than the size or manner of the dose, was more important to get patients to start producing dystrophin again.
But this wasn’t an obvious call to make.
“I talked to a dozen experts who live and breathe DMD, and guess what, 12 experts all have 12 different opinions,” Garabedian says. “But what happens when you talk to all 12 experts, and have all their wisdom and experience? You start to understand the trade-offs. They’re not all right, they’re not all wrong. You have to come up with the best strategy based on talking to the true experts in the field.”
Garabedian found Muntoni’s argument compelling, and went with it. Based on that input, he advocated for an unusual design that tested a 50 milligram/kilogram of body weight dose over 12 weeks, and a lower dose—30 milligrams/kilogram— over 24 weeks.
Sounds like a simple test, but in the real world, it wasn’t. The company needed to manufacture more of the drug to carry out this test. Resources, at a small company, were limited. Here’s how Garabedian recalls the situation:
“I called up my head of manufacturing, and said, ‘how much drug do we have?’
“We don’t have much.”
“How much is not much?” Garabedian replied.
“We have enough to treat eight patients for about 24 weeks.”
“How long will it take to get more drug?
“Nine months to a year.”
This put Garabedian in a squeeze. He was adamant that he wanted to run a study that asked not just a scientific question, but one that spoke to the scientific community, the medical community, and the financial folks. That would be the only way to build value, and get the resources needed to take the drug to a higher level. He needed to get really valuable data on a small budget.
So he pushed for a study that would enroll eight patients on the new drug, and gambled by adding four more patients to a placebo group, to provide a valid comparison that medical and financial analysts would want to see. The main goal would be to show Duchenne boys were producing more dystrophin proteins that could be seen in muscle biopsies at 24 weeks, but the boys would also be evaluated with a standardized clinical test that measured how far they could walk in six minutes. If the company could somehow show that dystrophin levels were increasing for boys in inexorable decline, then it would at least have a good chance to raise the money it needed to carry out the next steps to prove it had an important drug. If it showed improvement in 6-minute walk distance, that would be a home run.
There were still a couple big barriers in the way. The company hadn’t yet finished its long-term toxicity studies in animals, which are normally required by the FDA before companies are allowed to do long-term dosing on humans. The company pleaded with the FDA to do long-term dosing in its clinical trial, even beyond 24 weeks, while it finished up the long-term animal tox studies in parallel. The FDA said yes. And Sarepta followed through on its promise.
“That could also have killed this program if we weren’t able to continue dosing beyond 24 weeks,” Garabedian says.
Knowing that it would be important for the company to show a benefit at 24 weeks, Sarepta also knew it would even more compelling to sustain the benefit all the way out to 48 weeks. That meant the company needed to start manufacturing the drug to anticipate needs of longer-term dosing. That took some money, and Garabedian needed to cut from some other internal drug-development programs to do it.
All this time, Garabedian was courting shareholders with his long-term vision, including many blue-chip funds. They listened, but mostly didn’t bite. He was able to raise $30 million in April 2011, but it didn’t allow for much margin for error, at the company’s cash burn rate. Still, it was an exciting time for Garabedian, putting his stamp on the company, as he placed a stake in the ground that he hoped people would remember for years later.
“For the first time, we were telling a story about how we could create value, as opposed to just doing a deal with a heavy share discount and lots of warrants, just to get money in the door,” Garabedian says.
Data from the trial came a year later, and the numbers weren’t good enough to meet expectations.
The study randomly assigned 12 boys to a couple different doses of the drug or a placebo, showing boys on the drug produced about 22.5 percent of normal dystrophin levels after 24 weeks on the therapy, while there was no increase on the placebo. No serious adverse events were reported in patients on the experimental treatment, and no patients dropped out of the study. The study’s lead investigator hailed it as a “major advance” for Duchenne Muscular Dystrophy.
The big problem? Boys on the drug didn’t do any better than placebo on the 6-minute walk test at 24 weeks.
Investors ran for the exits, smelling another failure. Sarepta shares fell below $1. Garabedian pleaded for patience, noting that Sarepta had another thorough follow-up analysis built in at 48 weeks, which might
