NPS Pharmaceuticals, Inc. reported top-line results from the company's phase III study of its investigational drug Gattex (teduglutide, recombinant GLP-2) in which 83 patients with short bowel syndrome (SBS) received either a low dose of Gattex, (0.05 milligrams/kilogram/day), a higher dose (0.10 mg/kg/day) or placebo.
The clinical efficacy endpoint of the study was a reduction in parenteral nutrition (PN) of at least 20 per cent comparing baseline to weeks 16 to 24, measured as a graded response to capture reductions up to 100 per cent. In an intent-to-treat analysis, forty-six percent (46 per cent) of patients receiving the lower dose of Gattex (N=35) responded and achieved a highly statistically significant reduction in PN compared to placebo (p=0.007), with two patients gaining independence from and discontinuing PN by week 20 and a third patient discontinuing PN at the end of treatment. Twenty-five percent of patients receiving the higher dose of Gattex (N=32) responded and showed a trend in the difference between the treatment group and placebo, but this did not reach statistical significance (p=0.161).
The study's criteria for conducting the statistical analysis of the primary endpoint required that the results for the high-dose group show statistical significance before the results of the low-dose group could be considered. However, given the drug's orphan designation in SBS and the statistically strong (p=0.007) and clinically meaningful findings in the low-dose group, the company intends to meet with the FDA to discuss the path to regulatory approval for Gattex.
"Judging from these top-line results, teduglutide is an exciting new treatment option for our patients with intestinal failure due to massive intestinal loss. We eagerly await the peer review and publication of the full results of this international, multi-centre clinical trial to determine the specific indications for this new therapeutic advance," said, Dr. Stephen O'Keefe, professor of medicine and director of the Centre for Intestinal Health & Nutrition Support, University of Pittsburgh Medical Centre.
In this phase III study, there were no statistical differences in the incidence rates of adverse events or serious adverse events among the treatment groups when compared to placebo. The study's Data Safety Monitoring Board (DSMB) found that Gattex was generally well tolerated and demonstrated clinical benefits. Additionally, the DSMB supported the company's recommendation to continue the ongoing extension study. Ninety-two percent (92 per cent) of the 71 patients who completed the Phase 3 trial enrolled in the extension study.
There are several hypotheses that may explain the higher response in the low-dose group versus the higher-dose group. One theory is that, at higher doses, GLP-2 suppresses appetite and it is possible that patients on the higher dose consumed fewer calories from food and thus did not decrease their PN regimens. A second hypothesis is that GLP-2 exerts various dose-dependent effects and may act by increasing nutrient absorption at low-doses while higher doses of GLP-2 may have a greater effect on mucosal and epithelial regeneration.
Dr. Daniel Drucker, director, Banting and Best Diabetes Centre at the University of Toronto and the scientist who discovered the role of GLP-2, said, "Recently published animal studies demonstrate that lower doses of GLP-2 can enhance nutrient absorption through enhancement of mechanisms promoting nutrient transport across the gut epithelium and via improved intestinal cell survival, while higher doses of GLP-2 can result in mucosal regeneration. These observations suggest that lower doses of Gattex may have the greatest potential for effectively treating short bowel syndrome by improving nutrient absorption, while higher doses of Gattex may have the greatest potential for effectively treating other gastrointestinal disorders where mucosal regeneration may be more important."
This multicenter, double-blind, international phase III trial was designed to evaluate the efficacy, safety, tolerability and pharmacokinetics of Gattex compared with placebo in patients with parenteral nutrition (PN)-dependent short bowel syndrome. Eighty three patients who were enrolled in the trial were randomly assigned to receive daily subcutaneous injections of 0.05 milligrams or 0.10 milligrams of Gattex per kilogram of body weight or a placebo for six months after an evaluation period of three days to eight weeks and a period of stabilization of four to eight weeks. A total of 71 patients completed the study with a 14.5 per cent dropout rate.
The clinical efficacy endpoint of the study was a reduction in parenteral nutrition (PN) of at least 20 per cent comparing baseline to weeks 16 to 24, measured as a graded response to capture reductions up to 100 per cent.
The dose levels were selected based on the results of the Gattex phase II proof-of-concept study where doses of 0.03, 0.10 and 0.15 mg/kg/d were administered. Since this study had few subjects in the 0.03 mg/kg/d low dose group, it proved difficult to determine the effects of a low dose. Therefore a low dose of 0.05 mg/kg/d was selected for the phase III study. The highest dose (0.15mg/kg/d) did not seem to provide any additional benefit compared to the 0.10 mg/kg/d dose, therefore the 0.10 mg/kg/d dose was selected as the maximum dose for the phase III study.
SBS is a condition resulting from the surgical removal of significant portions of the bowel following injury or illness. There are 16,000 to 20,000 adult patients with SBS in the United States. Regulatory authorities in the U.S. and European Union have granted orphan drug status to teduglutide for its potential use, if approved, in treating SBS. Symptoms of SBS include diarrhea, dehydration, malnourishment, and weight loss caused by an inadequate absorption of nutrients and fluids from the diet. Long-term complications of the condition may include an increased risk of systemic infections due to the presence of an intravenous feeding line, degenerative changes in the bones and nerves due to vitamin and mineral deficiencies, and liver failure
A potential first-in-class drug, Gattex is a proprietary analog of naturally occurring human glucagon-like peptide 2 (GLP-2), a peptide secreted primarily in the distal intestine and involved in the regeneration and repair of the intestinal epithelium. A previous phase II proof-of-concept clinical study in patients with SBS showed that daily subcutaneous injections of Gattex resulted in significant regeneration of the intestinal lining and improved dietary absorption of nutrients and fluids. Once the company has completed its analysis of data from the phase III SBS study, it expects to pursue a pre-NDA meeting with the US Food and Drug Administration to discuss its potential plan for submitting a New Drug Application. NPS is also pursuing development of Gattex as a possible treatment for chemotherapy-induced gastrointestinal mucositis in cancer patients and necrotizing enterocolitis in preterm infants.