Type 2 Diabetes
Dutogliptin for the Treatment of Type 2 Diabetes
Dutogliptin Tartrate & DPP-4 Inhibitors:
Dutogliptin tartrate is currently in Phase 3 clinical development. Dutogliptin is a dipeptidyl peptidase-4, or DPP-4, inhibitor that we are advancing as a once daily, oral treatment for Type 2 diabetes.
DPP-4 inhibitors have a favorable tolerability profile and represent the most recently approved class of agents for the treatment of Type 2 diabetes. They prevent the DPP-4 enzyme from breaking down GLP-1, thereby increasing the levels of this hormone in the digestive tract and the blood. The increased levels of intact GLP-1 stimulate insulin production by the pancreatic beta cells and reduce glucagon production by the pancreas, both of which result in reduced blood glucose levels. In clinical trials to date, DPP-4 inhibitors have been well tolerated and have provided clinically meaningful reductions in HbA1c when used as the sole medical treatment, as well as important incremental decreases in HbA1c when used in combinations with other anti-diabetic medications. DPP-4 inhibitors also offer several advantages over other types of diabetes therapies, including: absence of weight gain and edema, low risk of hypoglycemia, and potential for improved beta cell function.
Collaboration:
On November 24, 2009, Phenomix concluded a collaborative agreement with Chiesi Farmaceutici, S.A., based in Parma, Italy for commercialization of dutogliptin in Europe and other large markets including Russia and other member of the Commonwealth of Independent States, Brazil, Turkey and Northern Africa. Chiesi will be responsible for additional development and regulatory approval in its territory. Phenomix is eligible to receive royalties from sales in these countries.
Clinical Development:
Phenomix’ Phase 2a clinical trial of dutogliptin in patients with Type 2 diabetes demonstrated that dutogliptin was well tolerated and met its primary endpoint of reducing post-meal blood glucose levels. In a Phase 2b clinical trial in 422 patients completed in the first quarter of 2008, dutogliptin demonstrated statistically significant reductions in HbA1c when administered in combination with existing drugs for the treatment of Type 2 diabetes. Dutogliptin also demonstrated statistically significant effects on secondary efficacy endpoints, including change in fasting blood glucose levels, change in postprandial blood glucose levels and achievement of a target HbA1c level of less than 7%. In addition, the study demonstrated that dutogliptin was well-tolerated.
Phenomix initiated the dutogliptin Phase 3 clinical development in the third quarter of 2008. The six-month study compared dutogliptin 400mg and 200mg once daily as monotherapy versus placebo and was completed in the first quarter of 2010. The trial was an international study and the patient population consisted of 542 patients randomized in a 2:1:1 ratio (273 to the 400mg dutogliptin group, 137 to the 200mg dutogliptin group, and 132 to the placebo group).
In this study, patients with moderately elevated baseline hemoglobin A1c (HbA1c) levels (mean: 8.19%) treated with dutogliptin showed statistically significant reductions of HbA1c versus placebo at week 24, the primary endpoint of the study. Reductions in HbA1c corrected for placebo effects were 0.59% for the 400mg dose (p < 0.0001) and 0.28% for the 200mg dose (p <0.0138). The results are similar to published data from trials evaluating other drugs from the DPP-4 inhibitor class and are consistent with the results received in the Phase 2b study.
Statistical significance was also observed at the 400mg dose for all secondary endpoints, which included change from baseline in fasting and peak postprandial plasma glucose, change from baseline in glucose AUC (0-2 hours) after a standard test meal, and percentage of subjects reaching treatment goal of HbA1c of less than 7.0%.
In this study, dutogliptin was well tolerated. The percentages of subjects reporting adverse events, discontinuing due to adverse events and reporting serious adverse events were similar in the dutogliptin and placebo groups. Adverse events reported with a frequency of greater than 5% were urinary tract infection (5.8% 200mg, 4.8% 400mg compared to 9.8% placebo) and dyslipidemia (2.2% 200mg, 5.5% 400mg, compared to 5.3% placebo). For further information regarding this study, please see our press release
Additional Phase 3 studies required for U.S. registration evaluating the safety and efficacy of dutogliptin utilizing the 400mg dose in combination with metformin, sulfonylurea and pioglitazone were commenced in 2009. For more information, please visit www.clinicaltrials.gov.
Type 2 Diabetes:
Type 2 diabetes is a chronic disease associated with abnormally high levels of glucose in the blood. High blood glucose over time can lead to serious long-term complications for the heart, kidney, eyes and limbs. Type 2 diabetes affects more than 160 million people worldwide, including approximately 21 million people in the United States. According to the American Diabetes Association, direct and indirect expenditures related to diabetes comprise one out of every five healthcare dollars, or 20% of all U.S. healthcare expenditures. In 2007, worldwide sales of diabetes medications totaled over $21 billion, with approximately $14 billion spent on oral anti-diabetic medications, or OADs.
Despite existing therapies and increasing awareness of the need for careful glucose control, nearly two-thirds of patients diagnosed with Type 2 diabetes do not achieve and maintain proper control of blood glucose. Furthermore, many existing therapies result in common side effects, including an increased risk of hypoglycemia, or abnormally low blood glucose levels, weight gain and gastrointestinal problems. There is a need for improved therapies for Type 2 diabetes.