Rhythm Eyes Pivotal Study as GI Drug for Diabetics Hits Phase 2 Mark

Xconomy Boston — 

Along with all the well-known and frightening effects of diabetes, people with the disease also suffer debilitating gastrointenstinal problems that often send them to the emergency room. Rhythm Pharmaceuticals wants to replace a decades-old drug for diabetic gastroparesis with one of its own, and data released today bring the Boston-based biotech an important step closer.

Diabetic gastroparesis is a complication of diabetes in which the stomach doesn’t empty food into the intestine quickly enough, leading to abdominal pain, bloating, and vomiting. In Phase 2 results released today, Rhythm’s relamorelin (also called RM-131) reduced patients’ gastric emptying time—how long it takes for the stomach to flush out food—in a statistically significant way.

That was the main goal of the study, and a biomarker for the drug’s effects on the digestion rate of diabetic gastroparesis patients. Rhythm now plans to move the drug into what CEO Keith Gottesdiener says “certainly should be” a pivotal study, though he wouldn’t comment further given the company is currently planning and designing the trial with the FDA.

Still, while the biomarker data are evidence the drug might be working, what’s just as important, if not more, is how these digestion effects translate into making people with diabetic gastroparesis feel better. Will it cut down on patients’ nausea and vomiting, keeping them from potential costly hospital stays? Alleviate pain or bloating? While those things weren’t the main goals of Rhythm’s study, they are the types of things Gottesdiener says the company would likely have to show the FDA that the drug can do in a further study. Rhythm still believes relamorelin is proving itself there too, because the drug helped reduce vomiting episodes by 60 percent compared to a placebo—even if it didn’t have the same luck halting some of the other side effects. The company is citing a high placebo effect, for instance, for confounding its numbers measuring the drug’s impact on all side effects, such as nausea, and bloating.

“Vomiting is really the cardinal symptom of these people,” says Rhythm co-founder and president Bart Henderson. “It’s what’s drives them to the emergency room, it’s what really drives people to doctors, and it really messes up diabetic control. Of all the symptoms that we wanted to hit, that was the one that was really the most critical to hit and I think we nailed it.”

Rhythm, of course, will have to reproduce that kind of the result in a future study powered to gauge side effects before it really knows if it has a potential drug on its hands. That study is expected to get underway by the end of the year, and will look at both side effects, and gastric emptying, according to Gottesdiener.

Rhythm was formed four years ago by licensing two peptide drug candidates from Paris-based Ipsen. One of them was relamorelin, an injectable peptide drug derived from ghrelin, a hormone in the stomach that helps food move through the digestive tract. The idea is that the drug might help spur gastrointestinal movement (typically called GI motility), stop the stomach from getting clogged up, and alleviate the pain and vomiting that patients experience.

If Rhythm succeeds, there’s a sizeable opportunity awaiting. About 2.3 million of the 24 million or so Americans with type 1 and type 2 diabetes in the U.S. have “moderate to severe” symptoms of gastroparesis and are seeking care, which can lead to costly hospital stays. The last drug specifically approved for the disorder in the past 40 years is the now-generic drug metoclopramide, but Henderson says the drug isn’t commonly used because of safety issues that limit the drug to short courses. Henderson also says metoclopramide isn’t very potent.

Solana Beach, CA-based Evoke Pharma (NASDAQ: EVOK) would likely disagree. Evoke is developing a nasal spray version of metoclopramide for gastroparesis, and just began enrolling patients in a Phase 3 trial of the drug a few weeks ago.

Rhythm has raised about $73 million from the likes of MPM Capital, Third Rock Ventures, New Enterprise Associates, Pfizer Ventures, and Ipsen to bankroll the development of relamorelin and a second drug candidate, RM-493. Its first clinical data were released in 2012, with a small, 10-person Phase 1 study that showed relamorelin helped reduce gastric emptying rates by about 66 percent. That trial gave Rhythm the confidence to run the drug through the larger Phase 2 trial it’s revealing today.

This time around, Rhythm enrolled 204 patients with moderate to severe symptoms of diabetic gastroparesis and slow gastric emptying, according to Gottesdiener.

All of those patients were given a placebo treatment for a week, and then broken up into three groups of 67 to 69 patients apiece, randomized, and dosed with either a placebo, a once-daily 10-milligram injection of relamorelin, or a 10 mg injection twice per day, for 28 days. The main goal of the study was to reduce gastric emptying. Rhythm says that the drug succeeded in doing so in a statistically significant way, though the company didn’t provide the full details from the study.

Rhythm also put in additional measures to judge a potential change in a combination of various side effects like pain, nausea, and vomiting. Rhythm didn’t hit statistical significance here—meaning had this been a study goal, the drug would’ve failed it. Gottesdiener says this was because an unexpected, strong placebo effect “obscured” the results, so the company added in figures after the study filtering the data.

Rhythm looked at a subgroup of people who vomited during that first one-week period when everyone got a placebo, and saw that its drug hit statistical significance. Post-study subgroup analyses like these come off as data spin, of course. But Rhythm executives say that this group of people represented a majority—60 percent—of the folks in its study, and could serve as a way to identify the sicker patients who might better respond to its drug going forward.

“That’s a very easy clinical marker for really more severity in these patients,” Gottesdiener says.

Now it’s likely on to the deep end of the pool for Rhythm, a make-or-break pivotal trial. Gottesdiener and Henderson were tight-lipped about Rhythm’s strategy in preparation for the study. They wouldn’t comment on whether the company might look to a further round, IPO, or partnership to help bankroll the study, for instance. But Rhythm could get past a Phase 3 study before having those discussions, because that trial will likely be a three-month study that isn’t too pricey for a small company like Rhythm to run, according to Gottesdiener.

That being said, assuming the data hold up, a strategic move is coming sooner or later.

“Ultimately, we’ll need partners in some form,” Henderson says.