When Boston-based Rhythm Pharmaceuticals started up in 2010 with a plan to develop drugs to address diabetes and obesity, the biotech world was littered with companies struggling to make a mark in those disease areas. San Diego based Arena Pharmaceuticals was fighting to produce data for the FDA showing its obesity drug was safe. Phenomix, also based in San Diego, could no longer afford the FDA-mandated trials for its Type 2 diabetes drug and had to shut down. But the folks at MPM Capital, which started Rhythm by leading a $40 million Series A that closed in September 2010, were undeterred. They licensed two compounds from French biotech company Ipsen that had been tested extensively in animals. “The clarity of the efficacy and safety from those studies—the strength and consistency of the data—led us to believe we could clearly be best-in-class,” says Bart Henderson, co-founder and president of Rhythm.
Rhythm, which is also backed by New Enterprise Associates and Third Rock Ventures, is now completing Phase 1 human trials of its lead compound, RM-131, in patients with Type 2 diabetes. The drug is derived from ghrelin, which is commonly called “the hunger hormone.” Ghrelin is produced in the gut and regulates functions such as food consumption, nutrient absorption, and gastrointestinal motility—the movement of food through the digestive tract.
Several drug companies have tried targeting ghrelin to treat diseases that range from growth-hormone deficiency to muscle degeneration, with limited success. Rhythm is instead going after a common but largely untreated complication of both Type 1 and Type 2 diabetes called gastroparesis, a digestive disorder marked by an abnormal emptying of the stomach. Normally, ghrelin receptors in the gut prompt a well-synchronized handoff of food from the stomach to the rest of the digestive tract. “In diabetes, that process seems to be attenuated, so many patients complain of abdominal pain and bloating,” says Elizabeth Stoner, co-founder and chief development officer of Rhythm. “It causes their glucose control to go amiss, because they’re not really emptying the stomach as expected.”
According to figures Rhythm has collected, about a third of the 25.8 million people with diabetes in the U.S. suffer from gastroparesis, costing the economy $3.5 billion a year. The primary treatment, a generic drug called metoclopramide, can only be taken for a short time because of the risk that it could touch off a potentially dangerous muscle disorder.
If all goes well, Rhythm will start a Phase 2 gastroparesis study in early 2012, Stoner says. Henderson adds that because ghrelin is such an essential hormone, RM-131 could someday prove useful in a range of other diseases, including anorexia and cachexia, or wasting syndrome.
Rhythm’s second compound, RM-493, could address an equally broad population: severely obese people who suffer from diabetes or are at risk of developing it. RM-493 targets melanocortin type 4 receptor (MC4R), which when mutated, is estimatedto cause as much as 6 percent of severe obesity. The drug is designed to curb food intake, thereby reducing body weight and insulin resistance.
In primate models, Rhythm’s weight-loss drug has produced results similar to gastric-bypass surgery, Henderson says. “Shortly after treatment, food intake was reduced 30 to 40 percent, but then it came back to baseline by week four of treatment,” he says. Still, the primates continued to lose weight, he says.
Drug development in the MC4R class came to a virtual halt in 2009, when a paper was published in the New England Journal of Medicine describing how an MC4 drug being developed by Eli Lilly (NYSE: LLY) triggered severe hypertension in some patients. The authors suggested it was a “class effect,” meaning they believed hypertension would be a risk with all drugs targeting MC4.
Lee Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital, says there’s “no extraordinary reason” to believe hypertension will be a problem with Rhythm’s drug. Kaplan signed on to chair Rhythm’s scientific advisory board after scrutinizing the animal data generated in studies of both of the company’s lead compounds. “The thought was high blood pressure was an effect that couldn’t be overcome, but we argue that’s not the case,” he says of RM-493.
Nevertheless, Kaplan acknowledges, The FDA will likely require Rhythm to design large studies involving thousands of patients. “The FDA is going to be extra cautious about cardiovascular and central nervous system effects,” he predicts. But he doesn’t expect regulators to shut out Rhythm completely. “Obesity is such a devastating problem. We can’t offer gastric-bypass surgery to every obese patient. We need drug therapies that will be effective in millions of people who have this problem.”
Rhythm plans to file an application with the FDA by the end of the year to start human trials of RM-493.
Rhythm will likely face competition in obesity, where—despite setbacks suffered by companies such as Arena and Lilly—there is still plenty of interest. AstraZeneca (NYSE: AZN), for example, is currently in early-stage testing of an MC4R drug it is developing with Cranbury, NJ-based Palatin Technologies (AMEX: PTN).
A scientific advisory board stocked with world-renowned experts in diabetes and obesity is guiding Rhythm. In addition to Kaplan, the board includes John Amatruda, who oversaw the development of Merck’s blockbuster diabetes treatments sitagliptin (Januvia) and sitagliptin/metformin (Janumet); Michael Camilleri, professor of medicine and physiology at the Mayo Clinic College of Medicine; and William Chin, an Eli Lilly veteran who is now executive dean for research at Harvard Medical School.
Henderson says Rhythm’s $40 million in funding should take the company through Phase 2 studies of both compounds. At that point, the startup will consider taking on a Big Pharma partner, Henderson says, especially for the obesity compound. “Clearly given the breadth of that program, we need a partner,” he says. “The place for that will be after we establish proof-of-concept.”
As for the challenges other startups have faced in diabetes and obesity, Henderson says, Rhythm sees only opportunity. “There is still a big, acute need for treatments for obese diabetics,” Henderson says. “Our opportunity is to show we have something that’s effective and safe for these higher-risk populations.”
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