“As soon as a drug gets into clinical development, China does the reverse development and gets some powder out there”
By then, however, the drug was already available from shady overseas suppliers, and a number of websites were hawking the active ingredient in a wide array of powders, pills, and other products. And athletes kept taking it. (You can still find sellers on Amazon.com.) WADA began catching cheaters almost as soon as it employed a detection test Evans designed; it suspended five pro cyclists for using the drug during one week in 2013. “Most of the time, as soon as a drug gets into clinical development, China does the reverse development and gets some powder out there,” says Oliver Catlin, president of the Banned Substances Control Group, a nonprofit that certifies health supplements as dope-free. During his years at the UCLA Olympic Analytical Laboratory, where he helped oversee drug-testing programs for the U.S. Olympic Committee, the NFL, MLB, and the U.S. military, Catlin regularly saw drugs become more popular among athletes after they were banned.
PPAR drugs in general have fallen out of favor because of side effects or related questions about their effectiveness, says Penn’s Kelly. There have been no publicly documented cases of athletes developing cancer linked to GW501516 and no systemic studies of their effectiveness or side effects in humans. But after approved PPAR drugs used to treat Type 2 diabetes were linked to possible side effects in heart tissue, many pharma companies abandoned development programs involving them. Evans, however, maintained that the right drugs could be created once the biological pathways they targeted were better understood.
“They were too potent,” he says of the 2008 study’s pills. “The natural physiologic way in which drugs work should be similar to what happens in your body. If you don’t manipulate the system exactly right, then it gets messy.” He says his new PPAR drug, the first he’s involved in making and commercializing himself, will be different. It won’t just flip all the switches to the on position; he’s spent the past decade learning how to fine-tune his controls.
As he strolls through his 4,000-square-foot La Jolla lab, Evans passes rows of gloved assistants hunched over microscopes and test tubes, holding liquid-filled droppers and scribbling furiously. On one counter a series of machines topped with rows of sealed test tubes is vibrating at high speed, separating the proteins inside so gene expression patterns can be analyzed. Inside a rectangular glass enclosure nearby, robotic arms are moving compounds among machines 24 hours a day, testing how rodent and human cells respond to various compounds.
By 2011 these tools and others had taught Evans enough to start creating a drug without the carcinogenic side effects. He’d also identified an ideal business partner: Kazumi Shiosaki, a founder of several successful biotech startups and a managing director at venture firm MPM Capital. Evans first met Shiosaki in 2008, when she recruited him to serve on the scientific advisory board of Epizyme Inc., a Cambridge, Mass., company developing anticancer drugs. After one board meeting, the two began discussing the potential for Evans’s design. Shiosaki had already been thinking about the need for drugs that more discretely target similar pathways. “I thought, Wow, why isn’t anyone starting a company in this?” she recalls. She co-founded Mitobridge in 2011 and became its chief executive officer.
The Mitobridge team, including a handful of researchers, works out of a lab a few blocks from Harvard Yard, while Evans and his team consult from La Jolla. Together they’ve built a drug to activate the genes involved in burning fat while leaving most dangerous, unrelated genes safely off. Their testing process was much easier than the one that yielded GW501516, Shiosaki says, because contemporary diagnostic tools gave the scientists a much better sense of which genes had been turned on or off, and in a post-Human Genome Project world, they had a much better sense of what each one did. “We know what negative or adverse signals that could lead to the negative results—like cancer—look like,” she says. The drug appears to increase endurance in mice with Duchenne muscular dystrophy, without the markers associated with higher risk of cancer.
After the Phase I safety trial is done, likely by July 2018, the next phase will involve people with Duchenne. “Our current intent here is to focus on rare diseases where there is unmet need,” Shiosaki says. Keeping the drug’s initial target narrow also makes it far more likely to win FDA approval. The FDA declined to comment because the study is pending.
Like Shiosaki, Evans stresses that his first priority for MA0211 is treating Duchenne sufferers, and it’s too early to say when the pill could be approved for other uses. In his office, though, he’s less measured about his endgame. Everyone should experience the health, cognitive, and other benefits of consistent minimum exercise, he says, clad in mesh shorts and a tight-fitting Under Armour shirt after a trip to the gym.
Evans isn’t quite ready to say he believes everyone, even the healthy, should be prescribed the exercise pill. But it’s clear he doesn’t think it’s a bad idea. “The challenge for this kind of drug is deciding who should get it,” he says. “I’m mindful that the FDA can only approve drugs that can actually treat a disease. This is a new concept.”