2106 Diabetes Care Volume 38, November 2015 fi Wayne H.-H. Sheu,1 Ira Gantz,2 Safety and Ef cacy of Omarigliptin Menghui Chen,2 Shailaja Suryawanshi,2 Arpana Mirza,2 Barry J. Goldstein,2 (MK-3102), a Novel Once-Weekly Keith D. Kaufman,2 and Samuel S. Engel2 DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes Diabetes Care 2015;38:2106–2114 | DOI: 10.2337/dc15-0109 OBJECTIVE This study was conducted to determine the optimal dose of omarigliptin, a once- weekly (q.w.) dipeptidyl peptidase IV (DPP-4) inhibitor, for the treatment of patients with type 2 diabetes and evaluate the long-term safety of that dose. RESEARCH DESIGN AND METHODS In a multicenter, double-blind, 12-week, dose-range finding study, 685 oral antihy- perglycemic agent-na¨ıve or washed-out subjects with type 2 diabetes were random- ized to one of five once-weekly doses of omarigliptin (0.25 mg, 1 mg, 3 mg, 10 mg, or 25 mg) or placebo. The primary efficacy end point was change from baseline in HbA1c, and secondary end points were 2-h postmeal glucose (PMG) and fasting plasma glucose (FPG). Analysis included all patients who received at least one dose of the study medication. Subjects who completed the base study were eligible to enter a 66-week extension study. RESULTS Once-weekly treatment for 12 weeks with omarigliptin provided dose-related reduc- 1Division of Endocrinology and Metabolism, De- partment of Internal Medicine, Taichung Veterans EMERGING TECHNOLOGIES AND THERAPEUTICS tions in HbA , 2-h PMG, and FPG. At week 12, the omarigliptin 25-mg dose provided 1c General Hospital, Taichung, Taiwan; School of the greatest glycemic efficacy. The placebo-adjusted least-squares mean reductions Medicine, National Yang-Ming University, Taipei, from baseline in HbA1c, 2-h PMG, and FPG were 20.72% (27.8 mmol/mol), 22.5, Taiwan; and College of Medicine, National Defense and 21.3 mmol/L, respectively (all P < 0.001). The incidence of adverse events was Medical Center, Taipei, Taiwan 2 similar across dose groups, with a low incidence of symptomatic hypoglycemia and Merck & Co., Inc., Kenilworth, NJ no effect on body weight. Omarigliptin was generally well-tolerated throughout the Corresponding author: Ira Gantz, ira.gantz@ merck.com. base and extension studies. Received 16 January 2015 and accepted 25 July CONCLUSIONS 2015. fi Clinical trial reg. no. NCT01217073, clinicaltrials Omarigliptin 25 mg q.w., compared with placebo, provided signi cant glucose .gov. lowering and was generally well tolerated for up to 78 weeks in patients with This article contains Supplementary Data online type 2 diabetes. at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc15-0109/-/DC1. Dipeptidyl peptidase IV (DPP-4) inhibitors improve glycemic control in patients with A slide set summarizing this article is available online. type 2 diabetes by prolonging the half-life of incretin peptides, which stimulate insulin fi secretion and decrease glucagon release in a glucose-dependent manner (1). Studies B.J.G. is currently af liated with Covance, Inc., Princeton, NJ. with daily DPP-4 inhibitors have demonstrated a good efficacy, safety, and tolerability fi © 2015 by the American Diabetes Association. pro le as monotherapy and as an add-on to other antihyperglycemic agents (AHAs) Readers may use this article as long as the work is (2–6). Omarigliptin (MK-3102) is a potent, selective, oral DPP-4 inhibitor with a half-life properly cited, the use is educational and not for that supports once-weekly dosing (7). Availability of a once-weekly administered oral profit, and the work is not altered. care.diabetesjournals.org Sheu and Associates 2107 AHA could represent a paradigm shift in Study Design However, because of concerns raised by the treatment of type 2 diabetes. Data- The base study was a multicenter, double- various health agencies about the long- base analyses of prescription records and blind, randomized, placebo-controlled, term use of pioglitazone, a protocol patient preference surveys suggest that dose-range finding study, followed by an amendment substituted blinded metfor- the availability of an efficacious, safe, extension study to evaluate longer-term min for blinded pioglitazone. Blinded and well-tolerated weekly oral AHA may safety and tolerability. The base study metformin was started at 500 mg q.d. offer the potential to improve medication included a 1-week screening period, an and up-titrated to 1,000 mg b.i.d. At adherence for some patients with type 2 8-week washout period for subjects on each study site, as subjects were switched diabetes (8–10). Herein are reported the oral AHAs, a 2-week single-blind placebo from pioglitazone to metformin, subjects results of a 12-week dose-range finding run-in period, and a 12-week double-blind on omarigliptin were switched to placebo study (base study), which was conducted treatment period. The extension study matching metformin, initially once and to determine the optimal clinical dose of lasted 66 weeks. Subjects were random- then twice daily. Those who were res- omarigliptin, and a 66-week extension ized to one of five doses of omarigliptin cued with open-label metformin in the study that evaluated the long-term safety (0.25mg,1mg,3mg,10mg,or25mg base study did not receive blinded and tolerability of omarigliptin 25 mg, once weekly [q.w.]) or placebo in equal metformin. The placebo/pioglitazone/ administered once weekly. ratio. During the base study, omarigliptin metformin subjects are henceforth re- and matching placebo were administered ferred to as the placebo/metformin group. RESEARCH DESIGN AND METHODS in a blinded manner as two capsules once No comparison of omarigliptin with met- Subjects weeklytoresultinomarigliptindoses formin was intended in the extension Eligible trial participants were male or ranging from 0 to 25 mg as specified by study because treatments were not con- female patients with type 2 diabetes, treatment group assignment. At random- currently initiated and the placebo group 18 to 70 years of age (20 to 70 years ization, subjects were stratified according switched to metformin at extension entry of age for Japanese patients), with a to their use of oral AHAs at screening and was no longer the intact group randomized BMI .20 kg/m2 and ,43 kg/m2 (BMI region location (Japan or not Japan). Dur- at the beginning of the base period. Res- .18 kg/m2 and ,43 kg/m2 for Japanese ing the base study, subjects who did not cue therapy during the extension study patients) who were not on an oral AHA meet prespecified glycemic control crite- was open-label glimepiride; if additional (off AHA medication for $14 weeks) and ria after randomization were to be res- rescue was required, subjects were discon- had an HbA1c $7.0% (53 mmol/mol) and cued with open-label metformin (for tinued from the study. #10.0% (86 mmol/mol). Patients on oral details see Supplementary Table 1). A meal tolerance test (MTT) was con- AHA medication monotherapy or low- Subjects who completed the base ducted at randomization (day 1), at dose (i.e., #50% maximum labeled dose study (with or without initiation of glyce- week 12, and at weeks 46 and 78 for of each agent) dual oral combination mic rescue medication) and who pro- those subjects who participated in the therapy (except thiazolidinediones) who vided written informed consent were extension study. MTTs were performed met the HbA1c inclusion criteria described eligible to participate in the extension at trough, 7 days after the last dose of above after an 8-week washout period study. A double-blind design was main- omarigliptin. The standard meal for the were also eligible to participate in the tained in the extension study. On the ba- MTT consisted of ;460 kcal, with 75 g study. sis of unpublished phase I study data, the carbohydrate, 9 g fat, and 18 g protein. Patients were excluded from the study if 25-mg dose of omarigliptin used in the The patient was expected to finish the they had type 1 diabetes, a history of base study was predicted to yield maxi- meal within 15 min of beginning to eat. ketoacidosis, active liver disease, significant mum glycemic efficacy. Therefore, in the A blood sample for glucose was col- cardiovascular disease, a history of malig- extension study, subjects randomized to lected just before ingestion of the meal nancy, hematological disorders, hyperthy- doses of omarigliptin other than 25 mg q.w. and at 60 and 120 min from the start of roidism, had been previously treated were switched to omarigliptin 25 mg q.w. the meal. with a DPP-4 inhibitor or a glucagon-like at entry into the extension study, and The study (Omarigliptin Protocol 006) peptide 1 receptor agonist, or required in- subjects randomized to omarigliptin was conducted in accordance with the sulin therapy within 14 weeks before sign- 25 mg q.w. continued on 25 mg q.w. principles of Good Clinical Practice and ing informed consent. Omarigliptin 25 mg or matching placebo was approved by the appropriate insti- Laboratory exclusion criteria included a was administered to each study subject tutional review boards and regulatory serum creatinine $1.4 mg/dL (males) or in a blinded manner once weekly. Down- agencies. $1.3 mg/dL (females), estimated glomer- dosing of omarigliptin was planned in 2 ular filtration rate ,60 mL/min/1.73 m the event that evaluation of the base Study Evaluations (calculated by the MDRD formula [11]), study data indicated a lower dose The primary objective of this study was alanine aminotransferase or aspartate achieved maximum efficacy. assessment of the safety, tolerability, aminotransferase more than two times Subjects randomized to placebo in and efficacy of omarigliptin.