Omarigliptin

Drug notes

Omarigliptin

Iona Galloway1 Date Event MBChB, MRCP, Specialty Trainee in Diabetes and Endocrinology 2010 Phase I studies with MK-3102 (omarigliptin) commence

Gerry McKay1 2012 First patients recruited into phase III studies including a cardiovascular BSc (Hons), FRCP, Consultant Physician outcome trial: MK-3102-018

Miles Fisher1 2014 First phase III results with omarigliptin presented MD, FRCP, Consultant Physician 2015 Omarigliptin approved and launched in Japan 1 Glasgow Royal Infirmary, Glasgow, UK 2016 Merck announces that it will no longer be filing for a licence in the United States and Europe; the cardiovascular outcome trial is terminated Correspondence to: Dr Iona Galloway, Department of Diabetes, Table 1. Timelines relating to the development of omarigliptin Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK; email: [email protected] Introduction Trials of safety and efficacy Dipeptidyl peptidase-4 (DPP-4) in diabetes inhibitors have been available for To date, there are two published use in the management of diabetes trials which give useful informa- mellitus since 2006. These drugs tion on the possible clinical use are normally administered once of omarigliptin. daily. Recent drug developments In a 12-week, dose-ranging have been focused on creating phase II clinical trial, 685 subjects longer-acting inhibitors. were randomised to placebo or five Omarigliptin is one example of different doses of omarigliptin.3 a long-acting DPP-4 inhibitor which Eligible participants were aged is administered once weekly as 18–70 years old with type 2 diabetes either monotherapy or as add-on mellitus and a BMI of 20–43kg/m2. therapy for optimisation of glycae- Exclusion criteria included renal mic control.1 It has been licensed impairment, significant cardiovas- for use in Japan since 2015 but its cular or liver disease and prior phase III development programme treatment with a DPP-4 inhibitor or in Europe and the United States GLP-1 analogue. A follow-on study has been halted for undisclosed over 66 weeks was commenced on commercial reasons. completion of the base study to assess long-term safety and tolera- Pharmacology bility. The primary endpoint was Omarigliptin is a competitive, change in HbA1c with secondary reversible inhibitor of DPP-4 which endpoints of 2-hour post meal is cleared by excretion into the glucose and fasting blood glucose. urine. It is structurally different Participants were randomised from currently available once-daily into receiving placebo or omari- dosing DPP-4 inhibitors. gliptin at 0.25mg, 1mg, 3mg, 10mg It is rapidly absorbed after or 25mg once weekly. Participants administration, with time to maxi- could receive additional treatment mum concentration ranging from during the base study with met- 0.5–4 hours.2 The terminal half-life formin if glycaemic targets were of omarigliptin was greater than not met. All groups who received 100 hours which allows for once- omarigliptin demonstrated a reduc- weekly administration.2 Steady state tion in HbA1c at 12 weeks from of the drug is achieved after two to baseline in a dose-dependent way three doses. Both pre-clinical and (HbA1c changes: +0.14%, -0.14%, clinical studies have demonstrated -0.36%, -0.35%, -0.53% and -0.57% significant inhibition of DPP-4 for 0.25mg, placebo, 1mg, 3mg, activity with an associated increase 10mg and 25mg weekly, respec- in active GLP-1 levels.2 tively).3 There was a -0.72% (-0.93%

to -0.5%, p<0.001) change in HbA1c pooled omarigliptin group); none for the 25mg dose compared with were deemed related to the drug. Key points placebo. Overall, the percentage of The phase III development pro- participants requiring additional gramme for omarigliptin was set to ● Omarigliptin has a prolonged half-life therapy with metformin during the include 10 clinical trials recruiting allowing for once-weekly dosing first 12 weeks reduced as the dose approximately 8000 patients with ● Omarigliptin has been shown to of omarigliptin increased (8% pla- type 2 diabetes, including a cardio- be non-inferior in glycaemic cebo vs 1% 25mg omarigliptin). vascular outcomes trial. The control when compared to currently During the follow-on study, O-QWEST (Omarigliptin Q Weekly used DPP-4 inhibitors. It is well those participants randomised to Efficacy and Safety in Type 2 tolerated with no increased incidence omarigliptin had a dose increase Diabetes) trial compared the effi- of side effects when compared with to 25mg once weekly. The placebo cacy of omarigliptin 25mg once sitagliptin group was switched to blinded weekly vs sitagliptin 100mg once ● Although available for clinical use in pioglitazone initially, which was daily in patients inadequately Japan, MSD has decided for then converted to blinded met- controlled on metformin therapy. commercial reasons not to pursue formin based on the safety con- Inclusion criteria included patients marketing authorisation in Europe and cerns of pioglitazone.3 with type 2 diabetes mellitus aged the United States Rescue therapy during the over 18 with an HbA1c between extension study was with glime- 6.5–9% (48–75mmol/mol). This piride. In all, 485 patients were double-blinded, randomised con- licensed DPP-4 inhibitor.3 It has entered into the extension study trolled trial lasted 24 weeks. In been demonstrated to be well toler- with 374 patients completing the total, 642 subjects were recruited: ated during clinical trials with, 66-week follow up. HbA1c measure- 322 randomised to omarigliptin importantly, a weight neutral effect ments in the 25mg weekly omari- 25mg once weekly and 320 ran- and a low incidence of hypoglycae- gliptin group had deteriorated domised to sitagliptin 100mg once mia. However, despite being avail slightly compared to week 12 meas- daily. Data were collected regard- able in Japan for clinical use and urements (-0.34% at week 78 vs ing HbA1c, fasting plasma glucose, well on in terms of development, -0.57% at week 12).3 This trend was blood, weight and adverse events. the pharmaceutical company has seen across all groups receiving At week 24 there was no sign decided not to pursue a licensing omarigliptin. The group receiving ificant difference between the authorisation in Europe and the placebo and add-on therapy with changes in HbA1c measurement United States, citing commercial pioglitazone then metformin were (percentage omarigliptin -0.47 vs reasons. No other information noted to have a marked improve- sitagliptin -0.43).4 On completion regarding this decision has been ment in HbA1c at week 78 (-0.73% of the study, no statistically signifi- made public. (Table 1.) at week 78 vs +0.14% at week 12). cant differences were noted in the There was no statistical differ- percentage of subjects attaining Declaration of interests ence in body weight observed optimal glycaemic control in both Dr Galloway has no conflicts of between the placebo group and groups (54.4% omarigliptin vs interest to declare. the omarigliptin groups. The inci- 52.4% sitagliptin).4 The incidence Professor Fisher has received dence of adverse events recorded of adverse events was 36.3% in the payment for lectures and advisory during the initial 12-week study was omarigliptin cohort and 40.6% for boards from MSD. similar across all study cohorts. the sitagliptin cohort. There was Professor McKay has received There were no cases of pancreatitis one episode of severe hypoglycae- payment for lectures and advisory in the initial 12-week study and mia recorded in a patient receiving boards from MSD. there was one case in the extension omarigliptin. There were no cases study in a patient taking omariglip- of pancreatitis recorded during References tin which was deemed to be sec- the study period. No changes were 1. Biftu T, et al. Omarigliptin (MK-3102): A novel long- ondary to gallstones. With respect observed in blood pressure or acting DPP-4 inhibitor for once-weekly treatment of to hypoglycaemic episodes, there ECG monitoring. type 2 diabetes. J Med Chem 2014;57(8):3205–12. 2. Tsuchiya S, et al. Single and multiple dose were three cases in the placebo pharmacokinetics and pharmacodynamics of group and five recorded episodes Discussion omarigliptin, a novel, once‐weekly dipeptidyl in the groups randomised to omari Compliance with medication in peptidase‐4 inhibitor, in healthy Japanese men. gliptin. None of these episodes chronic disease has been shown to J Diabetes Investig 2017;8(1):84–92. 3. Sheu WHH, et al. Safety and efficacy of omari- were severe. In the extension study, be related to the number of medi- gliptin (MK-3102), a novel once-weekly DPP-4 no episodes of hypoglycaemia were cations and dosing frequency. A inhibitor for the treatment of patients with type recorded in the placebo/met- once-weekly preparation may be 2 diabetes. Diabetes Care 2015;38(11):2106–14. 4. Goldenberg R, et al. Randomized clinical trial com- formin group, while 14 occurred in more appealing to patients with paring the efficacy and safety of treatment with the pooled omarigliptin group improvement in adherence and the once‐weekly dipeptidyl peptidase‐4 (DPP‐4) (two severe episodes). overall improved disease control. inhibitor omarigliptin or the once‐daily DPP‐4 During the extension study, Omarigliptin has been shown to inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin mono- there were five deaths (one in the be non-inferior in glycaemic con- therapy. Diabetes Obes Metab 2017 Jan 17. doi: placebo group and four in the trol in comparison to a currently 10.1111/dom.12832. [Epub ahead of print.]