Study results show that an alternative to currently-marketed injectable agents retains the efficacy of GLP-1 mimetics, while reducing gastrointestinal adverse events and providing the convenience of oral dosing.
Although 29 million Americans are currently diagnosed with diabetes, that number is expected to significantly increase as the population ages and millions of Americans with prediabetes develop full diabetes. With so many patients requiring treatment, there is a great need for new clinically effective treatments that offer convenient dosing and fewer side effects than current options.
Glucagon-like peptide-1 (GLP-1) agonists, a relatively new class of injectable diabetes therapies, have shown great promise. However, only a couple of products have shown significant uptake, with several factors (including patient and provider aversion to injectable vs. oral therapies) limiting more widespread use.
Against this backdrop, the diabetes community is watching with great interest the progress of several investigational orally available GLP-1 agonists.
Speaking at a session Sunday at the American Diabetes Association’s 74th Scientific Sessions, held June 13-17, 2014, in San Francisco, CA, Stephanie Gustavson, PhD, Director of Clinical Research at TransTech Pharma in High Point, NC, delivered a presentation on a GLP-1 agonist that the company is developing for the treatment of type 2 diabetes.
In her introduction, Gustavson said, “Multiple injections and gastrointestinal side effects have limited the use of currently marketed GLP-1 agents. This study examined the safety and efficacy of 12 weeks’ dosing with our flagship compound, TTP054, the first novel, orally-available GLP-1 agonist.”
Following FDA guidance, TransTech enrolled a broad population of patients to better understand safety issues associated with this class of medications, and then used an enrichment strategy to evaluate the magnitude of the drug effect based on the intention-to-treatment concept, with primary efficacy analysis focusing on a protocol target population.
Patients with type 2 diabetes on stable metformin treatment were enrolled in this multi-center, randomized, placebo-controlled, double-blind clinical trial. Mean age of the participants was 55 years with a standard deviation (SD) of ±10 years. Mean HbA1c level of participants was 9.0% (SD±0.8%) at the beginning of the study with mean body mass index of 28kg/m2(SD±6). Participants received placebo (n=31) or TTP054 once daily for 12 weeks. There were 3 possible doses of the test drug delivered, either 200 mg (n=19), 400 mg (n=28), or 800 mg (n=35).
In discussing the results, Gustavson said, “Proof-of-concept for oral GLP-1R agonist TTP054 was demonstrated by significant lowering of HbA1c at all doses tested. The same conclusions were reached from using either the target population as a basis or the full protocol population; the magnitude was just slightly different. Efficacy of TTP054 was consistent with that seen for injectable GLP-1 agonists, delivering decreases in HbA1c at p values below 0.05 in each dose group. Additionally, we had a trend for body weight reduction which was significant in the metformin monotherapy patients.”
Gustavson said that TTP054 was safe and well-tolerated with no adverse events (AEs) for hypoglycemia. As TTP054 is an orally administered medication, treatment-emergent adverse events of a gastrointestinal nature were of special interest to investigators. Gastrointestinal AEs, including nausea and vomiting, were minimal and similar in incidence and severity (ie, mild) in both active and placebo groups.
“SAEs involved 2 patients with elevated liver function test results in the 800 mg cohort. Both patients had other potential contributing factors and both resolved. There were no major concerns on other liver function tests, no increase in median liver function test values over time in any dose group, and no liver function test signal seen in any other clinical or toxicology study,” Gustavson said.
In summarizing the results, Gustavson told the audience, “TTP054, an orally available, small-molecule GLP-1 agonist currently in development, is an attractive alternative to currently-marketed injectable agents, in that it retains the efficacy of GLP-1 mimetics, while reducing gastrointestinal adverse events and providing the convenience of oral dosing. TTP054 demonstrated proof-of-concept, with HbA1c lowering at all doses tested. We reach the same conclusions whether we use the target population or the full protocol population, the magnitude was just slightly different. What we found interesting is that the magnitude of HbA1c reduction was very similar to what we had predicted from our 4-week study. We predicted a 1% placebo-adjusted decrease based on those results which was exactly what we achieved in this study.”