One Scientist’s Marathon Quest for the Exercise Pill
Ronald Evans realized the word was out when scores of strangers, some fit and some fat, started showing up at his biology lectures around the country. Soon, via email and voicemail, they were hounding him at all hours. Was it true, some wanted to know, that he had pills that could vaporize fat? Could the pills really, others asked, increase athletic endurance by 70 percent? Would he be interested in coming over and doping a racehorse?
During a lecture for a crowd of 200 in Montreal, a pair of college athletes took the mic and peppered Evans with questions about the pills’ potential impact on the effectiveness of human growth hormone and erythropoietin. They ignored his interjections that those two performance-enhancing drugs were banned by most athletic rule-making bodies.
That was 2007. Evans was finishing up a study showing that mice taking the drug, an experimental GlaxoSmithKline Plc compound called GW501516, vastly increased their fat burn and athletic performance, even with minimal exercise. Some mice demonstrated the kind of endurance that would normally require intense training. Evans, a researcher at the Howard Hughes Medical Institute and the Salk Institute for Biological Studies, warned repeatedly that the pills weren’t ready for human consumption when he published the study in 2008. They were just a proof of concept, he said, using some potentially dangerous substances. There were no studies showing they’d work on humans, no data on possible side effects.
His caveats didn’t make it into the headlines. By 2009 enough athletes had been caught using GW501516 (aka Endurobol) that the World Anti-Doping Agency banned it. By 2013 so many had been caught that WADA took the rare step of issuing a health notice. Human trials with the drug had been abandoned because of “serious toxicities,” the oversight body noted. Among the side effects in mice: cancerous tumors. “For a lot of athletes, winning is more important than their intrinsic health or the risk they are taking,” says Evans, who at 67 has a lean runner’s build, tight black curls, and a thin goatee that’s peppered with a lot more gray than it was in ’08. “So I guess I’m not surprised they were taking it. They want to win.”
His story is an object lesson in what happens when the world can’t wait for the science to catch up with the hype. “The drug companies got way ahead of our understanding of the biology,” says Daniel Kelly, director of the Cardiovascular Institute at the University of Pennsylvania. “That kind of soured the field. The biology now has caught up.”
Just about, Evans says. In July, almost a decade after that first study, his company, Mitobridge Inc., in partnership with Astellas Pharma Inc., began testing MA0211, a new drug that he’s betting can safely upgrade human cellular metabolism. The six-year-old company has received $45 million in venture funding to make it happen, much of it earmarked for development and trials targeting those in the greatest need. The first treatment is aimed at Duchenne muscular dystrophy, a genetic protein mutation that affects 1 in 5,000 men, causing a progressive loss of muscle and killing most by the age of 26. Given the severity of the disease, Mitobridge and Astellas can expect speedy approval from the U.S. Food and Drug Administration if their study, the first phase of which will be finished within a year, shows even some promise of building muscle in Duchenne sufferers.
Seated in his third-floor office at Salk on the bluffs of La Jolla, Calif., where he’s had a stunning view of the Pacific for 38 years, Evans is already thinking about what comes next. “A drug that promotes the benefits of fitness could have widespread applications,” he says with more than a little understatement. Beyond tackling obesity, a pill that replicates the benefits of exercise could help reduce the risk for chronic inflammation, diabetes, even cancer. From behind a desk buried in a pile of awards, DNA models, and photos of his twentysomething daughter, Lena, Evans insists the previous efforts failed only because they were based on incomplete pictures of the human body. “When you’re gaming a genetic system, if you overgame it, you activate genes outside your target, causing side effects,” he says, rising from his chair. He walks past the two acoustic guitars in his office and picks up a recent scientific paper. “Our molecule is completely different.”
Evans’s record sets him apart from the hucksters who’ve been peddling get-fit-quick schemes and weight-loss pills since the dawn of footwear. A pioneer in molecular biology, he was the first, three decades ago, to discover nuclear receptors. These microscopic proteins, sticking out from the surface of a cell’s nucleus like antennae, can be triggered to switch cellular processes on and off. These switches became the principal means by which scientists learned to manipulate genes. Ten years later, in 1995, Evans found the receptor that appeared to control the storage and metabolization of fat, known as a peroxisome proliferator-activated receptor, or PPAR-alpha. A few years after that, he identified PPAR-gamma and PPAR-delta, related receptors that appear to activate fat-burning.
The study published in 2008 started there. In 2003, Evans and his team tweaked mouse genes to turn the fat-burning switches on permanently in fat tissue, and their mice slimmed down dramatically. A year later he flipped the fat burners on in muscle tissue, and the mice developed Type 1 muscle, the kind found in marathon runners and endurance cyclists. These mice lasted an hour longer on the treadmill than normal ones and ran twice as far. The downside was burnout, says Michael Downes, a senior scientist who’s been working with Evans since the 1990s. Permanently flipping all of the cellular switches on made the mice’s muscles grow faster than any known medication had.
Big Pharma had seen all it needed to charge ahead. “Drugs were built pretty quickly, because there was enthusiasm for new targets,” says Evans, meaning such targets as obesity and heart disease. For the 2008 study he principally used GlaxoSmithKline’s GW501516, along with a less potent drug that worked in a similar way. GW501516 allowed the mice to run 75 percent farther than normal mice before collapsing from exhaustion. But by the time Evans published the study, bringing a stream of obsessive athletes to his door, Glaxo had abandoned efforts to test GW501516 on humans. Only later did published papers link its testing in mice to development of tumors in the liver, bladder, stomach, and skin.
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.”
Athletes are probably already conducting their own off-the-books studies, says Catlin of the Banned Substances Control Group. “As soon as it is gets into clinical trials,” he says, “it will be in the hands of some doper.” But if an exercise pill is safe enough for everyone to use—safe enough that everyone should use it—is that still cheating?