BOSTON, May 6, 2014 /PRNewswire/ -- Rhythm announced today the presentation of pharmacodynamic results from a Phase 2 clinical trial with relamorelin (RM-131) for the treatment of chronic constipation at the Digestive Disease Week 2014 conference in Chicago. Analysis of the data indicates that relamorelin administered once daily for two weeks in patients with chronic constipation significantly accelerates lower gastrointestinal (GI) transit with a magnitude of effect associated with clinically important improvement on the Bristol Stool scale. This study also demonstrated improvement in gastric emptying and small bowel transit, confirming relamorelin's prokinetic effect on both upper and lower GI function.
Separately, investigators at Mayo Clinic presented results from a preclinical study assessing the mechanism of relamorelin's prokinetic effect on colonic smooth muscle. Analysis of the data suggests that relamorelin increases lower GI transit by relaxing colonic smooth muscle cells through hyperpolarization. Relamorelin's effects in increasing upper GI contractility together with a relaxation of colonic smooth muscle are a possible explanation for the coordinated acceleration of full GI transit demonstrated in human clinical trials of relamorelin.
"There is a critical need for safe and effective treatments for chronic constipation caused by impaired GI motility," said Michael Camilleri, M.D., a gastroenterologist at Mayo Clinic and the principal investigator for the study.* "We are now assessing the effects of the drug on the symptoms of chronic constipation and expect these data to be complete later this year."
Study Results – Phase 2 Chronic Constipation Substudy
In a poster presentation entitled, "A Phase II, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, Parallel-Group Study to Evaluate the Efficacy, Safety, and Pharmacodynamics of RM 131 in Patients with Chronic Constipation," investigators from Mayo Clinic presented initial data from an ongoing Phase 2 study assessing relamorelin in the treatment of chronic constipation. As part of a larger trial of 48 patients, relamorelin 100 mcg subcutaneous injection once daily was evaluated in a pre-specified double-blind pharmacodynamic (GI transit) substudy in 24 patients. This methodology has been used previously in the evaluation of other clinical candidates for chronic constipation and can provide a benchmark for potential efficacy in the treatment of symptoms. Highlights of the results from the pharmacodynamic substudy:
- Relamorelin significantly accelerated colonic transit at 32 and 48 hours after ingestion of a radiolabeled study meal (p=0.040 and p=0.017, respectively). The magnitude of effect on colonic transit ( GC48 )is associated with a 1 point difference in stool consistency on the Bristol Stool Form scale, suggesting that the PD effect is clinically relevant.
- Relamorelin also significantly accelerated gastric emptying (p=0.027) and small bowel transit (p=0.051).
Study Results – Preclinical Colonic Mechanism of Action
In a poster presentation, "Effect of RM-131 on Circular Smooth Muscle Cells in Human and Mouse Colon and on Colonic Intraluminal Pressure In Conscious Mice," investigators from Mayo Clinic presented results from a preclinical study assessing the mechanism of relamorelin's prokinetic effect on both human and mouse colonic smooth muscle. Analysis of the data suggests that relamorelin increases lower GI transit by decreasing colonic tone of the resting membrane potential of circular smooth muscle cells via hyperpolarization, and decreasing the excitability of colonic circular smooth muscle cells. Highlights of the study:
- Relamorelin (0.25 μM) significantly hyperpolarized the resting membrane potential for human colonic circular smooth muscle cells by 2.8±0.7 mV (P<0.01, n=9) and in mouse preparations by 3.4±0.4 mV (P<0.01, n=6).
- In the relamorelin-treated group, intraluminal pressure was 0.57±0.05 (n=8), which was significantly less compared to the control group (0.82±0.08, n=8), suggesting that relamorelin significantly reduced colonic tone.
- These data suggest that relamorelin decreases colonic tone by hyperpolarizing the resting membrane potential of circular smooth muscle cells and decreases the excitability of colonic circular smooth muscle cells.
"The results from both these studies with relamorelin are encouraging for chronic constipation and confirm the impressive prokinetic effects on both upper and lower GI function that we have measured in Phase 1 clinical trials," said Keith Gottesdiener, MD, CEO of Rhythm. "There is a high incidence of patients with lower GI conditions who also have overlapping upper GI motility disorders, such as Parkinson's disease patients. For this reason, we are assessing relamorelin in an ongoing Phase 2 study of refractory constipation in Parkinson's patients."
About Relamorelin (RM-131)
Relamorelin is a small-peptide analog of ghrelin, a hormone produced in the stomach that stimulates gastrointestinal activity. Derived from the natural ghrelin sequence, relamorelin has been optimized to stimulate gastrointestinal (GI) motility, with greater potency and enhanced stability and pharmacokinetics. In Phase 1 clinical trials, RM-131 was effective in accelerating both gastric emptying and colonic transit and was shown to be safe and well-tolerated. Relamorelin has completed a Phase 2 study in diabetic gastroparesis, and additional Phase 2 trials are under way in lower GI functional disorders. The U.S. Food and Drug Administration (FDA) has granted Fast Track review status to relamorelin for the treatment of diabetic gastroparesis.
Gastroparesis affects a significant number of the 24 million diabetics in the U.S; an estimated 2.3 million type 1 and type 2 diabetic patients with moderate or severe gastroparesis symptoms are seeking treatment. Gastroparesis symptoms include nausea, vomiting, abdominal pain, and malnutrition and results in a significant rate of hospitalization. This condition also often undermines measures to manage hyperglycemia.
About Rhythm (www.rhythmtx.com)
Rhythm is a biotechnology company developing peptide therapeutics that address unmet needs in metabolic diseases. Rhythm is developing the ghrelin peptide agonist, RM-131, for the treatment of diabetic gastroparesis and other GI functional disorders; and the MC4R peptide agonist, RM-493, for obesity and diabetes. Rhythm investors include MPM Capital, New Enterprise Associates, Third Rock Ventures, Ipsen, and Pfizer Ventures. The company is based in Boston, Massachusetts.
* Dr. Camilleri has research funded by Rhythm to study RM-131. He also serves on the company's Scientific Advisory Board. He receives no personal financial compensation from Rhythm.