When we think of diabetic neuropathy, most of us think of our feet, not our stomachs. There is, however, a debilitating form of neuropathy, known as gastroparesis, that affects the gastrointestinal tract (GI). And while we don’t hear about this form of neuropathy all that often, it affects as many as 12% of people with diabetes.
Gastroparesis occurs when there is damage to the vagus nerve which controls stomach contractions. Normally, when a person eats the stomach contracts and within three hours those contractions cause the food to move down through the gastrointestinal tract. In individuals with gastroparesis, food moves slowly or stops moving through the digestive tract. Those suffering with gastroparesis experience symptoms such as nausea, vomiting, bloating, abdominal pain, abdominal discomfort, and they may experience these symptoms every time they eat. This, obviously, reduces overall quality of life.
Gastroparesis is a chronic condition which, in addition to affecting people with diabetes, affects approximately 4% of the general population in the U.S. There is currently no safe and effective treatment for it. However, Tranzyme Pharma, a late clinical stage biotechnology company focused on developing novel therapeutics for upper gastrointestinal motility disorders, is developing new drug candidates to treat conditions of the upper GI. Because most of the companies developing therapies for the GI tract are focused on the lower GI tract, there is a significant unmet medical need for upper GI therapeutics.
Tranzyme currently has a Phase 2b trial underway to evaluate a drug known as TZP-102, an orally-administered treatment for diabetic gastroparesis, as well as two Phase 3 pivotal trials evaluating ulimorelin, for the acceleration of GI recovery in patients undergoing partial bowel resection.
We had the opportunity to talk to Dr. Franck Rousseau, Tranzyme’s Chief Medical Officer, responsible for overseeing the development of drug programs.
What are the current available treatments for gastroparesis? Why aren’t they effective?
Currently, there are no safe and effective drugs on the market for treating gastroparesis. Reglan (metoclopramide) is the only FDA approved therapy for gastroparesis, yet it has a “black box” warning due to serious tardive CNS side effects. Another drug, Propulsid (cisapride) had been used to treat gastroparesis but it was removed from the market in 2000 due to safety issues. As a result, there is a large unmet medical need for the treatment of gastroparesis which we hope to fill with TZP-102.
Can you tell us more about this new approach to treatment? What is the drug? How was it discovered? How does it work?
TZP-102 mimics ghrelin, a hormone produced in the stomach that plays a direct role in stimulating GI motility. More specifically TZP-102 is a ghrelin agonist. TZP-102 has a completely different and novel mechanism of action as compared to prior promotility agents that were removed from the market because of toxicities and as a result, we believe TZP 102 will not have the safety issues that plagued the older generation of prokinetic drugs. TZP-102 was discovered by Tranzyme utilizing our proprietary drug discovery technology, Macrocyclic Template Chemistry (MATCH™).
What were the results of your Phase 2 study? What was the structure of the study?
We achieved positive results in our Phase 2 study of TZP-102. Ninety-two patients with type 1 or type 2 diabetes with gastroparesis were enrolled in the study. The study was a double-blind, placebo-controlled multinational study and evaluated the safety and efficacy of TZP-102. Patients were randomly assigned to receive one of three daily oral doses of TZP-102 or placebo, for a treatment period of 28 days, and then were followed for an additional 30-day post-dosing period.
Patients given TZP-102 experienced significant improvement in critical gastroparesis-related symptoms as compared to those on placebo. When asked the severity of symptoms before the trial began, both the placebo group and the test group reported moderate to severe symptoms. At the end of the treatment period, the TZP-102 group rated their symptoms as very mild to mild while the placebo groups remained at a moderate level. Throughout the study, all doses of TZP-102 were well tolerated by patients without significant metabolic or cardiac changes.
You have just started a Phase 2b study. What are you hoping to show in this study? How long will it follow the patients?
The Phase 2b trial is a double-blind, multinational evaluation of two dose levels of TZP-102 (10 and 20mg) and placebo administered orally, once daily, for 12 weeks in diabetic patients with a history of moderate to severe symptoms of gastroparesis. Along with safety, we are evaluating the changes in the severity of symptoms associated with diabetic gastroparesis over a 12 week period. Initial data are expected by year-end 2012.
The Food and Drug Administration (FDA) has granted TZP-102 Fast Track designation. What does this mean?
The FDA Fast Track Development program was designed to expedite the development and review process and “Fast Track” products must meet two criteria. First, the product must concern a serious or life-threatening condition; second, it has to have the potential to address an unmet medical need. Once granted, the benefit is close communication with FDA and the ability to submit sections of the NDA (new drug application) as they become available (a rolling submission). Typically, products designated as fast track will also receive a priority review (6 months) but that is not determined by FDA until after the NDA is submitted. The FDA has granted TZP-102 Fast Track designation because they recognize the lack of currently safe and effective options for treating diabetic gastroparesis.
Are there other hormones that are being targeted to increase intestinal motility?
Yes. Motilin is a hormone target for drug development for modulation of GI motility but there are no drugs in that class that are in late stage development.
If all goes well, when do you expect TZP-102 to be available to patients?
Assuming the results of the Phase 2b and Phase 3 trial are favorable, TZP-102 could be available to patients as early as 2015.
Tranzyme is actively enrolling patients in our Phase 2b trial. Anyone interested in participating should review the eligibility requirements at http://clinicaltrials.gov/ct2/show/NCT01452815?term=tzp-102&rank=2. If you think you meet the inclusion criteria, and live near one of the clinical trial sites, please contact Kelly E. Webb at 512-852-6954 or via email at firstname.lastname@example.org.