Sitagliptin汤姆森路透报告

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SUMMARY .Drug Name

sitagliptin Company

Merck & Co Inc Highest Dev

Status

Launched Therapy Areas

Glucose intolerance; Non-insulin dependent diabetes Actions Glucagon-like peptide 1 metabolism modulator; DPP IV inhibitor antidiabetic product;

Hypoglycemic agent; Dipeptidyl peptidase IV inhibitor

Technologies Oral formulation; Tablet formulation; Small molecule therapeutic

Target Dipeptidyl peptidase IV

Update date 13-MAR-2013

Reason for

update

Sales and market share updated OVERVIEW

Merck & Co and Ono Pharmaceutical have developed and launched sitagliptin (Januvia; Xelevia; Glactiv;

Ristaben; MK-0431; ONO-5435), an oral dipeptidyl peptidase IV (DPP IV) inhibitor that enhances endogenous GLP-1 levels [1050130]. It is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes, either as a monotherapy or in combination with metformin or a PPAR-gamma agonist when the single agent does not provide adequate glycemic control [822258], or as an initial therapy in combination with metformin, add-on therapy with a sulfonylurea, and add-on therapy to dual treatment with metformin and a sulfonylurea [840612]. It is also indicated for use as an add-on to insulin, and additionally, for restricted first-line use in the EU [1051442], [1096057], [1140068]. In Japan, sitagliptin is indicated as an adjunct to diet and exercise, sulfonylureas, thiazolidines, biguanides, alpha-glucosidase inhibitors or insulin [1193789],

[1223189].

Sitagliptin was launched in the US in October 2006 [785672]. In March 2007, Sitagliptin as Januvia tablets was approved in Spain and was subsequently launched by Merck Sharp & Dohme [1362979]. In December 2007,the drug was launched by Merck Sharp Dohme in Portugal [1387967]; by that time, the drug had been launched in Germany by Merck Sharp Dohme [1342278]. In March 2008, the drug was launched in France [1350453].The drug had been launched in several European territories by April 2008 [908763]. In October 2007, the FDA approved an updated label for use as initial therapy in combination with metformin, and as an add-on therapy to a sulfonylurea or dual treatment with metformin and a sulfonylurea when adequate glycemic control is not achieved [840612]. By February 2010, the drug was approved in the US for use as an add-on to insulin

[1096057], [1140068]. In August 2009, the drug was approved in the EU for first-line use in the treatment of type 2 diabetes [1051442]. In October 2009, the drug was launched in the UK [1356033]. In December 2009, Ono launched sitagliptin for the treatment of type 2 diabetes in Japan [1063689]; in May 2011, the use of sitagliptin in combination with alpha-glucosidase inhibitors was approved in Japan [1193789]. In September 2011, the

drug was approved in Japan for use in combination with insulin [1223189]; it is presumed that the product was launched for this indication shortly after approval.

Development for other indications is ongoing. In July 2011, a phase II efficacy trial was planned in patients with impaired glucose tolerance [1216026].

Merck has also developed and launched Janumet (sitagliptin/metformin) and Juvisync (sitagliptin/simvastatin). Additionally, the company is developing combinations of sitagliptin and pioglitazone (MK-0431C) and atorvastatin (MK-0431E) [1267460].

The FDA updated prescribing information in September 2009, to include information on reported cases of acute pancreatitis in patients using sitagliptin; 88 cases had been reported since first launch [1051372].

PATENT AND GENERICS INFORMATION

The US patents which cover the sitagliptin compound and salt are scheduled to expire in July 2022 and 2026, respectively [1267460].

In October 2012, Mylan received tentative FDA approval for its generic sitagliptin tablets (25 mg) [1349933].

In January 2013, Sandoz was granted tentative FDA approval for its generic sitagliptin tablets (25, 50 and 100 mg) [1365760].

REGULATORY INFORMATION

The US

By February 2006, Merck had filed an NDA, which was accepted for review by the FDA [650549]. In October 2006, was approved in the US as a monotherapy or with metformin or thiazolidinediones (TZDs) [732059], [732234]; it was launched there later that month [785672]. In February 2007, sNDAs were accepted for as add-on therapy to a sulfonylurea when the single agent is insufficient and as add-on therapy to the combination of sulfonylurea plus metformin when dual therapy is insufficient [766451]. In October 2007, the FDA approved an updated label for use as initial therapy in combination with metformin, and add-on therapy to a sulfonylurea or to dual treatment with metformin and a sulfonylurea when adequate glycemic control was not achieved [840612]. By February 2010, sNDAs had also been filed with the FDA for sitagliptin as add-on therapy with a PPAR agonist and metformin, and for initial use with pioglitazone [1075633]; at that time, the drug was approved in the US for use as an add-on to insulin. As part of the approval, the FDA requested that a 3-month pancreatic safety study in a diabetic rodent model treated with sitagliptin be completed and submitted to the FDA by June 2011 [1096057], [1140068], [1267599]. By February 2012, Merck had submitted data from a 12-month mouse study conducted by an independent researcher. However, at that time, the FDA's Office of Scientific Investigations issued a warning letter stating that the request for a postmarketing study had not been fulfilled. In response, Merck planned to initiate the study within 6 months, following FDA approval of the study protocol [1267599]. Europe

In March 2006, the EMEA began reviewing and in January 2007, the CHMP recommended approval of the drug for type 2 diabetes in combination with metformin or PPAR gamma agonists [760580]; the drug was approved in March 2007 [777921], [779239]. At that time, Sitagliptin as Januvia tablets was approved in Spain and was subsequently launched by Merck Sharp Dohme [1362979]. In December 2007, the drug was launched by Merck Sharp Dohme in Portugal [1387967]; by that time, the drug had been launched in Germany by Merck Sharp Dohme [1342278]. In March 2008, the drug was launched in France [1350453]. By April 2008, it had been launched in Spain and Italy [908763]. In April 2009, the EMEA's CHMP recommended extension of the drug's indication to include use in combination with a PPAR gamma agonist, where diet, exercise and sitagliptin therapy did not provide adequate glycemic control [1002924]. In June 2009, the EMEA's CHMP recommended an extension to the drug's indication to include use of the drug as a monotherapy when metformin use is inappropriate due to contraindications or intolerance [1021484]. In August 2009, the drug received EU approval for first-line use in the treatment of type 2 diabetes [1051442]. In September 2009, the CHMP recommended an 2013 THOMSON REUTERS. For more information go to 4717d33831126edb6f1a102c/copyright/

extension to the drug's indication to include use of the drug as an add-on to insulin for the treatment of type 2 diabetes [1045239], [1045237], [1045387]. In October 2009, the drug was launched in the UK [1356033].

In March 2010, the EMEA approved sitagliptin (as Ristaben) as a monotherapy and in combination with metformin, a sulphonylurea, or a PPARg agonist to improve glycemic control in type 2 diabetes, and as an add-on to insulin [1086479].

Japan

Sitagliptin was filed for approval in Japan in December 2007 [860644]; approval was granted in October 2009 [1050130]. In December 2009, the drug was launched [1063689].

By June 2010, an application for approval of sitagliptin in combination with alpha-glucosidase inhibitors had been filed [1110416]; the expanded indication was approved in May 2011 [1193789].

In October 2010, an application for sitagliptin in combination with insulin was filed in Japan [1142822]. In September 2011, the indication was approved [1223189]; it is presumed that launch for this indication occurred shortly after approval.

China

By August 2009, the drug had been approved in China [1051442]; launch took place in March 2010 [1191394] Rest of the world

In August 2006, was approved in Mexico [682954]. By March 2007, had been approved for use in the Philippines [777921]. Sitagliptin had been launched in Canada by April 2008, following approval in January 2008 [864647], [908763].

In February 2008, it was reported to have been approved for first-line and second line treatment in Korea in September 2007 and was expected to be launched in 2H08 [881325]; in October 2008, it was disclosed that the drug first failed in being listed on the reimbursed list, but the decision was later changed [974052]. The drug was launched in December 2008 [990351].

By May 2010, it had also been launched in India [1098641].

In December 2012, the product was approved in Australia, as monotherapy, for the treatment of diabetes mellitus type 2 in individuals 18 years of age and older who failed dietary measures and exercise; approval was as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus, when metformin cannot be used and as dual combination therapy, with metformin, or with a sulfonylurea, or with a thiazolidinedione where the use of a thiazolidinedione is considered appropriate [1354305]. POSTMARKETING STUDIES

In June 2012, data from a post-hoc pooled analysis of three double-blind studies comparing sitagliptin treatment as a monotherapy and in combination with metformin to sulfonylureas (glipizide or glimepiride) in patients

aged 65 years and above with type 2 diabetes were presented at the American Diabetes Association (ADA)'s 72nd Annual Scientific Sessions in Philadelphia, PA. Sitagliptin treatment achieved similar sugar reductions to sulfonylureas with less hypoglycemia during a 30-week treatment period. Patients treated with sitagliptin (n = 178) achieved a 0.73% LS mean A1c reduction from baseline compared with 0.78% for those on sulfonylurea (n = 195). The proportion of patients experiencing one or more episodes of symptomatic hypoglycemia was 6.2 and 28.2% for the sitagliptin and sulfonylurea groups, respectively [1299256]. In October 2012, these data were presented at the 48th Annual EASD meeting in Berlin, Germany [1328735].

In September 2011, clinical data were presented at the 47th EASD Annual Meeting in Lisbon, Portugal. In

a double-blind study investigating the metabolic response to chronic sitagliptin treatment, patients received sitagliptin (100 mg/day; n = 25) or placebo (n = 22) for 6 weeks. It was found that changes in fasting glucose levels and glucose AUC values were greater for drug-treated patients, compared with placebo. Insulin sensitivity was increased and overall, chronic sitagliptin treatment improved glycemic control [1220195].

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In June 2011, data from a 16-week study in Japanese type 2 diabetics were presented at the ADA 71st Scientific Sessions in San Diego, CA. In the 127 patients studied, sitagliptin significantly reduced HbA1c, FPG and PMG compared to placebo. There were not notable differences in AEs. Though hypoglycemia was higher than placebo, this was not seen in long-term studies [1201945].

In December 2010, an open-label, randomized, parallel-group, multicenter study (COAST-J) was planned to compare the efficacy and tolerability of sitagliptin, metformin and pioglitazone in diabetic patients (expected

n=1600) in Japan. At that time, results were expected in 2013 [1161259].

In June 2010, a post-hoc analysis was presented at the ADA's 70th Scientific Sessions in Orlando, FL. In patients with a mean baseline A1C of 7.5%, the analysis demonstrated that over one year 38.1% of sitagliptin patients experienced the composite endpoint of A1C reduction without weight gain or hypoglycemia compared 11.8% of glipizide patients [1111129].

In June 2009, data were presented from a post-hoc pooled analysis of HbA1c over time in two sitagliptin monotherapy clinical trials at the American Diabetes Association 69th Annual Scientific Sessions in New Orleans, LA. Mean HbA1c in patients (n = 32) completing two years of sitagliptin monotherapy decreased from a baseline of 8.3 to 6.9%. In another presentation of a similar post-hoc pooled analysis of data from two clinical trials (n = 347), this time evaluating the addition of sitagliptin to metformin therapy, the mean HbA1c decreased from a baseline of 7.7 to 6.9% [1016771]. In September 2009, similar data from these studies were presented at the 45th Annual Meeting of the European Association for the Study of Diabetes in Vienna, Austria [1045581].

In September 2008, a randomized, double blind, active controlled phase III trial (; MK0431-102) was initiated

in patients (expected n = 1295) with type 2 diabetes in the US. The patients were to receive a combination of sitagliptin (100 mg) tablets plus pioglitazone (15, 30 or 45 mg), or pioglitazone alone, taken once daily for 54 weeks. The primary endpoint was to compare the coadministrative efficacy of sitagliptin and pioglitazone versus pioglitazone monotherapy. In February 2010, the study was expected to complete in March 2011 [949373]. In June 2012, data were presented at the ADA 72nd Scientific Sessions in Philadelphia, PA. Sitagliptin + low-dose pioglitazone demonstrated greater glycemic improvements, when compared with higher doses of pioglitazone. The changes in A1C in 15/100-mg and 30/100-mg groups were -1.5 and -1.6, when compared with the change (-1.2) in pioglitazone monotherapy groups. The combination is well tolerated [1301013].

In May 2008, a randomized, double-blind, phase III trial (; MK0431-803) was initiated in type 2 diabetics (expected n = 1050) with inadequate glycemic control on metformin in 20 countries worldwide. The subjects were to receive sitagliptin (100 mg qd) or glimepiride (1 to 6 mg qd) in addition to metformin for 34 weeks. The primary endpoint was change in HbA1c from baseline to 30 weeks. The study was completed in October 2009 [950644].

In June 2009, interim 4 month data from a study of sitagliptin compared with rosiglitazone as a third-line oral therapy for type 2 diabetes in inner city ethnic minority patients were presented at the 69th ADA scientific sessions in New Orleans, LA. There was no significant difference between sitagliptin (100 mg qd) compared with rosiglitazone (8 mg qd) in terms of reducing HbA1c (reduction from a baseline of 7.7% to less than 7%

in 55% of sitagliptin-treated subjects and 63% of rosiglitazone-treated patients). Sitagliptin was well tolerated [1013540].

By December 2007, Merck was planning to initiate a large cardiovascular outcomes trial in patients with type 2 diabetes during 2008 [861096].

In October 2007, a randomized, double blind, active control, parallel assignment, safety and efficacy phase III trial () was initiated in subjects (expected n = 150) with type 2 diabetes mellitus and end-stage renal disease in the US , Germany, Hong Kong, Israel, Malaysia and Russia. The subjects were to receive sitagliptin or glipizide. The primary endpoint was to establish blood sugar levels at 52 weeks. The study was expected to be completed in August 2009 and was still recruiting in October 2008 [922070].

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In August 2007, a worldwide randomized, double blind, active control, parallel group, safety and efficacy

phase III trial () was initiated in subjects (expected n = 500) with type 2 diabetes mellitus and moderate and severe renal insufficiency. The subjects were to receive sitagliptin (25 mg for 54 weeks) or glipizide (2.5 mg qd, titrating up to 10 mg bid, based on glycemic control). The primary endpoint was to compare change in

HbA1c levels. By May 2010, enrollment had been completed and the study was expected to complete in March 2011 [922021]. In June 2012, data were presented at the ADA 72nd Scientific Sessions in Philadelphia, PA. Patients (n = 277; per-protocol population) stratified based on chronic kidney disease were randomized (1:1) to receive sitagliptin (50 or 25 mg/day) or glipizide. The least-square mean changes from baseline in HbA1c in the sitagliptin and glipizide groups were -0.76 and -0.64%, respectively. Irrespective of baseline HbA1c, age, BMI, diabetes duration, gender, race or severity of chronic kidney disease, the patients treated with sitagliptin showed reductions in HbA1c levels similar to those observed with glipizide [1301015]. In October 2012, these data were presented at the 48th Annual EASD meeting in Berlin, Germany [1328724].

In March 2007, Merck began a worldwide randomized, double blind, active controlled phase III study () of sitagliptin versus metformin in patients (n = 1000) with type 2 diabetes. The primary outcome was HbA1c after 24 weeks of treatment. This study was completed in August 2008 [796947].

PREMARKETING STUDIES

Non-insulin dependent diabetes

Phase III

In late 2011, a phase III study was initiated in Japan in type 2 diabetes patients of sitagliptin together with a rapid-acting insulin secretagogue [1235535].

In June 2009, pooled long-term efficacy data from four studies of sitagliptin as a monotherapy or as an add-

on therapy to metformin over 2 years, were presented at the 69th ADA scientific sessions in New Orleans,

LA. Sitagliptin as a monotherapy (data from study 021 and study 036) decreased mean HbA1c from 8.3% at baseline to 6.9% at 2 years. As an add-on to metformin therapy (data from study 020 and study 024), HbA1c was decreased from a baseline of 7.7 to 6.9% at 2 years. In each trial sitagliptin treatment was well tolerated [1013531].

In September 2008, clinical data were presented at the 44th Annual Meeting of the European Association for the Study of Diabetes in Rome, Italy. A twice-daily combination of sitagliptin (50 mg) and metformin (1000 mg) reduced HbA1c by 1.8% from baseline after one year (n = 153) and by 1.7% after two years (n = 105) compared with 1% after one year and 1.1% after two years for subjects receiving metformin only. In another trial, 262 subjects taking metformin (at least 1500 mg/day) and rosiglitazone (at least 4 mg /day) were randomized 2:1

to the addition of or placebo. After 18 weeks, the addition of reduced mean HbA1c by 0.7% relative to placebo, this figure was 0.8% at 54 weeks. Measures related to beta-cell function were also significantly improved for compared with placebo [941879].

In September 2007, data were presented at the 43rd Annual Meeting of the European Association for the Study of Diabetes (EASD) in Amsterdam, the Netherlands, showing that 50 mg sitagliptin twice-daily in combination with metformin provided sustained improvement in blood sugar control compared to metformin alone and was well tolerated over a one-year period [831201].

In December 2006, a randomized, double blinded, phase III trial () began in patients (n = 641) with type 2 diabetes who had inadequate glycemic control on insulin or insulin in combination with metformin. The primary outcome was a measure of HbA1c levels after 12 weeks of treatment. The study was completed in October 2008 [814584].

In December 2006, Merck commenced a multicenter, randomized, double blind clinical trial () to evaluate the safety and efficacy of sitagliptin coadministered with pioglitazone, in 520 patients with type 2 diabetes. The primary outcome was to establish safety, tolerability and HbA1c after 24 weeks. The study was completed in June 2008 [746788].

In August 2006, Merck began a non-randomized, open label, uncontrolled phase III trial (, ONO-5435-10)

of sitagliptin in patients (n = 209) with type 2 diabetes [814565]. At that time, two further phase III trials of

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sitagliptin in addition to glimepiride monotherapy (, ONO-5435-09) and in addition to metformin monotherapy (NCT00363948, ONO-5435-08), were also initiated in patients (n = 130 for each trial), with type 2 diabetes [814566], [814568]. By February 2008, these studies had been completed [814565], [814566], [814568].

In June 2006, clinical data from multiple studies were presented on at the 66th ADA scientific sessions in Washington DC. A total of 701 patients received metformin plus placebo or 100 mg qd for 24 weeks in Study 020. The drug reduced HbA1c and post meal glucose, and increased fasting insulin and C-peptide. Measures of beta cell function (HOMA-beta and proinsulin/insulin ratio) were also improved and the drug was well tolerated [672127], [672963]. In a 12-week, randomized, double-blind, parallel-group, Japanese study (Study 201),

151 patients were treated with sitagliptin 100 mg qd or placebo. HbA1c decreased by 0.65% in the sitagliptin group compared with a 0.41% increase for placebo. The HbA1c goal was met by 58% of patients and 14.5% of placebo patients. The drug was well tolerated [672128], [673617], [672963]. A subgroup analysis from Studies 021, 023 and 201 showed that sitagliptin increased the beta-cell response to glucose and improved markers of beta-cell function (proinsulin/insulin ratio and HOMA-B levels) [673617]. In a randomized, double blind, parallel group, incremental-dose, Japanese study, 10 volunteers were treated with 25 to 400 mg qd and 50 mg bid of sitagliptin, or placebo, for 10 days. The drug was well tolerated with no hypoglycemia. The half-life of the drug was 10.8 to 12.4 h and the inhibition of DPP-IV over 24 h was 80% on day 10. The drug increased active GLP-1 levels after meals, compared with placebo [672600]. In a randomized, open label, two-period crossover study, 200 mg of daily sitagliptin for 6 days did not affect the pharmacokinetics of a single 1.25 mg dose of glyburide on day 5 [672621]. In a 12-week, randomized trial, 91 patients with renal insufficiency were treated with 25 or 50 mg of qd sitagliptin or placebo. The drug (pooled data from both doses) reduced HbA1c and fasting plasma glucose by 0.59% and 25.5 mg/dl, compared with 0.18% and 3 mg/dl for placebo. The drug was generally well tolerated and appeared to be effective [674805]. In an open label, randomized, two-period crossover trial, 12 patients were treated with a single dose of 4 mg of rosiglitazone on day 5, with or without 200 mg qd sitagliptin for 5 days. Sitagliptin did not meaningfully affect rosiglitazone's pharmacokinetics [674811].

In September 2006, further clinical data were presented at the EASD in Copenhagen, Denmark. In the 24-week, randomized, double blind, placebo controlled study, 1056 patients were treated with 50 mg sitagliptin together with 1000 mg metformin twice daily, or metformin monotherapy. Patients treated with the combination showed a 2.1% mean placebo-subtracted reduction in HbA1c levels. Furthermore, two-thirds of patients achieved

HbA1c levels of less than 7% compared to 38% of patients on metformin alone. As an open label cohort, an additional 117 patients with severely elevated baseline HbA1c were also recruited. In this group, there was

a 2.9% mean reduction of HbA1c from baseline. With a lower 500 mg dose of metformin, significant HbA1c placebo-subtracted reductions were also seen. The drug was well tolerated and the most common side effects included diarrhea, nausea and vomiting. The second arm of the study treated patients with 100 mg sitagliptin once daily or 500/1000 mg metformin twice daily and as a monotherapy [690529], [690533]. In June 2008, further clinical data were presented at the 68th ADA scientific sessions in San Francisco, CA. Combinations of sitagliptin and metformin significantly improved markers of beta cell function and reduced HbA1c levels at year one and year two of treatment [914591], [914563].

In August 2006, an 18-week, randomized, double blind, placebo controlled, phase III, sitagliptin add-on study (), in 190 patients with type 2 diabetes inadequately controlled by metformin therapy, was initiated. The primary endpoint was HbA1c after 18 weeks, safety and tolerability. The study was completed in August 2007 [675809]. In April 2006, a placebo controlled, randomized, double-blind, phase III trial () was initiated in subjects (n = 530) with type 2 diabetes in India, China and Korea. The primary endpoints were reduction in glycosylated hemoglobin, as well as safety and tolerability. The study was completed in March 2007 [819094]. Results

from the study were published in January 2009. Patients received received sitagliptin 100 mg qd or placebo. Data showed that sitagliptin significantly reduced mean HbA1c (by 1%), fasting plasma glucose (by 1.7 mmol/ l), and 2 h postprandial glucose (by 3.1 mmol/l) compared to placebo. Furthermore, a significantly greater proportion of sitagliptin-treated versus placebo-treated patients achieved HbA1c less than 7% (20.6 versus

5.3%, respectively) at study end. Overall, sitagliptin was generally well-tolerated; clinical adverse events (mainly gastrointestinal adverse events) were reported in 23.3 and 15.2% of sitagliptin- and placebo-treated patients, respectively [1102981].

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In March 2006, a randomized, double blind, placebo controlled, parallel group phase III trial (; MK0431-047) was initiated in 206 elderly patients. Patients received sitagliptin (50 or 100 mg/day depending on creatinine clearance), or placebo for up to 32 weeks. The primary endpoint was HbA1c at 24 weeks. The trial was completed in March 2008 [675810]. In November 2008, data were presented at the 61st Annual Scientific Meeting of the Gerontological Society of America in National Harbor, MD. Results showed that treatment with sitagliptin caused a significant reduction in blood sugar levels and was not associated with hypoplycemia

in elderly patients. The mean placebo-adjusted HbA1c reduction from baseline at 24 weeks was 0.7% in sitagliptin-treated patients. Compared with placebo-treated patients (15%), significantly more sitagliptin-

treated patients (35%) achieved an HbA1c which was less than that recommended by the American Diabetes Association. Similar responses to sitagliptin treatment were observed in patients aged greater than or equal

to 75 years (n = 30), compared with those aged less than or equal to 75 years (n = 71). The mean placebo-adjusted reductions from baseline in fasting plasma glucose and 2-h post-prandial glucose were 27 and 61 mg/ dl, respectively, in sitagliptin-treated patients. The incidence of pre-specified gastrointestinal events (nausea, vomiting, abdominal pain and diarrhea) was similar between the two groups. A 1.1 kg weight loss from baseline was observed in the sitagliptin group (p = 0.079), compared with a 1.7 kg reduction in weight observed in the placebo group (p = 0.010) [965659].

Phase III studies (including NCT00086502) were initiated in 2Q04 [550239], [817519]. In June 2006, clinical data on were presented at the 66th ADA scientific sessions in Washington DC. In a 24-week, randomized, double-blind, phase III study (Study 019), 353 patients were treated with pioglitazone plus sitagliptin (100 mg qd) or placebo. Sitagliptin reduced HbA1c compared with placebo and 45% of patients met the HbA1c goal as compared with 23% of placebo patients. Some measures of beta-cell function were also improved [672130], [673617], [672963]. In a 24-week, randomized, multinational, double-blind, phase III study (Study 021), 741 patients were treated with 100 or 200 mg qd sitagliptin or placebo. The two doses reduced HbA1c levels by

0.79 and 0.94%, and fasting plasma glucose by 17.1 and 21.3 mg/dl, both compared with placebo. Greater reductions in HbA1c were observed for higher baseline HbA1c [674795], [673617], [672963]. In an 18-week, randomized, multinational, double blind study (Study 023), 521 patients were treated with 100 or 200 mg qd sitagliptin or placebo. The two doses reduced HbA1c levels by 0.6 and 0.48%, and fasting plasma glucose

by 19.7 and 16.9 mg/dl, both compared with placebo. Greater reductions in HbA1c were observed for higher baseline HbA1c [674797], [673617], [672963]. A subgroup analysis from Studies 021, 023 and 201 showed that sitagliptin increased the beta-cell response to glucose and improved markers of beta-cell function (proinsulin/ insulin ratio and HOMA-B levels) [673617]. A further subgroup analysis from three phase III trials showed that the drug improved beta-cell function [674880].

In October 2004, an active-controlled, randomized, double-blind phase III trial () was initiated in subjects (expected n = 1000) with type 2 diabetes and inadequate glycemic control from metformin monotherapy in the US. The subjects were to receive , or glipizide, in addition to metformin. The primary endpoint was reduction

in HBA1c after 52 weeks, and safety and tolerability. The study was complete by May 2007 [819074]. In June 2006, results from the study were presented on at the 66th ADA scientific sessions in Washington DC. A total of 1172 patients received sitagliptin (100 mg qd) or glipizide (titrated from 5 mg qd to 10 mg bid). The target HbA1c level was achieved by 62.8% of the sitagliptin recipients, compared with 58.9% of those taking glipizide. The rate of hypoglycemia was 4.9% in the sitagliptin group, compared with 32% in the glipizide group. While glipizide increased weight by a mean of 1.2 kg, weight was reduced by a mean of 1.3 kg by sitagliptin. The adverse event profile for sitagliptin was the same or lower than for glipizide [673617], [673455]. Similar data were published in March 2007 [839406]. In January 2010, 2-year data from the study were published and showed that the mean change in HbA1c from baseline was -0.54% with sitagliptin (n = 248) and -0.51% with glipizide (n = 256). Furthermore, the beta-cell responsiveness to a meal challenge was maintained with sitagliptin and decreased with glipizide. A total of 5 and 34% of patients who received sitagliptin and glipizide, respectively reported hypoglycemia and sitagliptin was associated with weight loss (-1.6 kg) compared with weight gain (+0.7 kg) with glipizide [1103036].

In July 2004, a randomized, double blind phase III trial (; MK0431-021) was initiated in the US and Puerto Rico, to evaluate the safety and efficacy of sitagliptin monotherapy in subjects (expected n = 600) with type 2 diabetes and inadequate glycemic control. The primary endpoints were reduction in HBA1c after 24 weeks, and tolerability. Results from the study were published in December 2006. Patients (total n = 741) were randomized to sitagliptin 100 or 200 mg or placebo for 24 weeks. Data showed that both doses of sitagliptin produced statistically significant placebo-subtracted reductions in Hb1c (by -0.79 and -0.94% for the 100 and 200 mg

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doses, respectively) and fasting plasma glucose (by -1.0 mmol/l [-17.1 mg/dl] and -1.2 mmol/l [-21.3 mg/dl], respectively). Furthermore, patients with HbA1c greater than or equal to 9% at baseline had greater reductions in placebo-subtracted HbA1c with sitagliptin 100 and 200 mg (-1.52 and -1.50%, respectively) than those

with baseline HbA1c less than 8% (-0.57 and -0.65%) or greater than or equal 8% to less than 9.0% (-0.80

and -1.13%, respectively). Sitagliptin 100 and 200 mg also significantly reduced 2 h postprandial glucose; however, this parameter was not significantly different between sitagliptin doses. Safety data revealed that

the hypoglycemia incidences were similar across all groups, and overall gastrointestinal adverse events were slightly higher with sitagliptin. By October 2007, the study had been completed [819054], [839208].

Phase II

In June 2005, data from three phase II trials of were presented at the 65th ADA Scientific Sessions in San Diego, CA. The first trial was a 4-week, randomized, double blind, placebo controlled crossover study evaluating the combination of sitagliptin with metformin versus metformin plus placebo. After a 5-week diet

and exercise run-in period, 28 patients with baseline HbA1c values ranging from 6.9 to 9.6% (mean of 7.7%) were randomized to receive either metformin plus placebo or metformin plus sitagliptin (50 mg po bid). After

the first 4-week treatment period, patients given metformin plus placebo were then given sitagliptin (50 mg)

and vice versa. After the first 4-week treatment period, patients who received metformin plus sitagliptin had

a 24 h weighted mean blood-glucose concentration of 125 mg/dl compared with 158 mg/dl in the metformin plus placebo group. Sitagliptin was well tolerated in combination with metformin, with no clinically relevant differences in the incidence of adverse events compared with metformin alone [605640], [606955], [607244]. The second study presented was a randomized, double-blind, placebo-controlled trial evaluating the efficacy and tolerability of sitagliptin compared with glipizide in patients with HbA1c baselines ranging from 6.3 to 11.0% (mean HbA1c baselines were 7.8 to 7.9% with 20% of patients having a baseline </= 7.0%). After a diet/ exercise and/or drug wash-out period, a total of 743 patients were randomized to receive sitagliptin (5, 12.5,

25 or 50 mg bid), placebo or glipizide (titrated from 5 to 20 mg/day). After a 12-week period, sitagliptin reduced HbA1c values, with the largest reduction (0.77%) observed in the highest-dose group; in the glipizide-treated patients, the reduction in HbA1c was 1.0%. Placebo-subtracted HbA1c results did not appear to reach a plateau in the active treatment groups. An average weight gain of 1.1 kg was noted in the glipizide-treated patients, with no significant weight gain in the sitagliptin- or placebo-treated groups. Hypoglycemia was considered an adverse event in 17, 2 and 4% of patients in the glipizide, placebo and sitagliptin groups, respectively [605664], [606951], [607244].

A third, double blind, placebo-controlled, parallel group study was also presented at the 65th ADA Scientific Sessions. A total of 552 patients with type 2 diabetes were randomized to receive either placebo, qd oral sitagliptin (25, 50 or 100 mg) or bid oral sitagliptin (50 mg) after a period of diet and exercise and wash-out of any other antihyperglycemic drugs. The mean baseline HbA1c was 7.7 to 7.8%, with 28% of patients having

a baseline HbA1c of less than 7% and approximately 90% of patients classified as having mild-to-moderate hyperglycemia at baseline (</= 9%). After 12 weeks of treatment, all patients receiving sitagliptin had a significant reduction in HbA1c levels. An average reduction of 0.6% was observed in the 100 mg sitagliptin qd group. The mean reduction from baseline at week 12 for sitagliptin versus placebo was greater in patients with higher HbA1c levels. In patients with baseline HbA1c between 8.5 and 10%, a mean reduction of 0.8%, relative to placebo, was observed in patients in the 100 mg sitagliptin qd group, including those that did not complete the study; this figure was 1.1% when analyzing only those who completed the study. No significant weight gain was noted in any patients; one adverse event of hypoglycemia was reported in each sitagliptin treatment group, compared with none in the placebo [606627], [606955], [607086], [607244].

A study assessing the pharmacokinetic interaction of sitagliptin and metformin was presented in June 2005

at the 65th ADA meeting in San Diego, CA. This randomized, double blind, crossover study in type 2 diabetic patients consisted of three 7-day periods: sitagliptin (50 mg bid) plus metformin (1000 mg bid); sitagliptin (50 mg bid) plus placebo; and placebo plus metformin (1000 mg bid). Metformin plasma pharmacokinetics were not altered by coadministration of sitagliptin compared with administration of metformin alone and visa versa. Renal clearance of sitagliptin was also unaffected by metformin [608474].

In June 2004, data were presented at the 64th ADA scientific sessions in Orlando, FL. Sitagliptin was studied

in a randomized, placebo controlled, 3-period, crossover study in 56 patients with type 2 diabetes and on diet/ 2013 THOMSON REUTERS. For more information go to 4717d33831126edb6f1a102c/copyright/

exercise treatment. Patients were administered single, oral doses of sitagliptin (25 or 200 mg) or placebo after fasting overnight, separated by 7-day washout intervals. The 25 and 200 mg sitagliptin doses led to reductions in glucose AUC, increases in active GLP-1 levels, and increases in AUCs of plasma insulin and c-peptide, compared with placebo, was generally well tolerated [541525]. Similar data were presented in August 2004 at the 228th ACS meeting in Philadelphia, PA [556348], and in September 2004 at the 40th EASD Annual Meeting in Munich, Germany [560621].

In January 2004, Merck reported that sitagliptin was safe and well tolerated and lowered glucose levels effectively in phase IIb trials. Dosing was expected to be once-daily [520117].

Phase I

In August 2007, a randomized, double-blind, placebo-controlled, crossover, safety and efficacy phase I trial (; MK0431-077) was initiated in subjects (n = 90) with type 2 diabetes in the US, Mexico, Austria and Sweden. The subjects were to receive sitagliptin or placebo qd for 7 days. The primary endpoint was to evaluate the

24 h weighted mean glucose (WMG)-lowering efficacy. The study was completed in August 2008 [922081]. Results from the study were published in October 2009. Patients were randomized to one of six treatment sequences over three treatment periods (placebo, sitagliptin 100 or 200 mg qd; each of the treatment periods lasted for 7 days, with 28-day washout periods between treatments). The study failed to meet the primary endpoint and after an interim analysis, the study was stopped because the 24 h WMG values were not different between the sitagliptin doses. However, the 24 h WMG values were significantly lower with sitagliptin compared to placebo, but the difference between sitagliptin doses was not significant. Further data revealed that the corrected percentage plasma DPP-4 inhibition at trough was not significantly different with sitagliptin 200 mg compared to the 100 mg dose [1103245].

In July 2007, a randomized, double-blind, placebo-controlled, parallel group, safety and efficacy phase I trial (; MK0431-061) was initiated in subjects (n = 208) with type 2 diabetes in the US, Europe and Israel. The subjects were to receive sitagliptin (100 mg qd), sitagliptin plus pioglitazone (30 mg qd), pioglitazone monotherapy or placebo. The primary endpoints included changes from baseline in glucagon 3 h total AUC and percentage change from baseline in index of static beta cell sensitivity to glucose after 12 weeks of treatment. The study was completed in February 2009 [922077].

In February 2007, a randomized, double-blind, placebo-controlled, parallel group, safety and efficacy phase

I trial (; MK0431-059) was initiated in subjects (expected n = 57) with type 2 diabetes who had inadequate glycemic control in Italy. The subjects were to receive sitagliptin (100 mg qd) or placebo. The primary endpoint was a determination of incremental glucose AUC, safety, and tolerability. The study was expected to be completed in June 2010 [922089].

A study assessing single doses (1.5 to 600 mg) of sitagliptin in 34 healthy volunteers was presented in June 2005 at the 65th ADA Scientific Sessions in San Diego, CA. Single doses of sitagliptin 100 mg or higher

were associated with inhibition of plasma DPP-IV activity over 24 h of 80% or higher and an approximately

2-fold increase in active GLP-1 levels compared with placebo. Sitagliptin was well tolerated with no cases

of hypoglycemia reported. Plasma AUC increased approximately dose-proportionally over the range studied and the drug's primary elimination route was renal with an apparent t1/2 of 8 to 14 h. Food did not affect the pharmacokinetics and a once daily dosing was recommended [606610].

A study assessing multiple doses of sitagliptin over 28 days in middle-aged, obese, non-diabetic subjects was also presented at the 65th ADA Scientific Sessions. In the multicenter, randomized, double blind, placebo controlled study, obese subjects (BMI range 30 to 40 kg/m2) were randomized to sitagliptin (200 mg bid; n = 24) or placebo (n = 8) for 28 days. Sitagliptin plasma concentrations reached a steady-state within 2 days of dosing. Over 90% of sitagliptin was excreted in the urine. The 200 mg bid dose of sitagliptin produced DPP-

IV inhibition of 90% compared with placebo on day 28. Following an oral glucose tolerance test on day 28, sitagliptin increased active GLP-1 levels by 2.7-fold and decreased incremental glucose AUC by 35% compared with placebo [606611].

Another study presented at 65th ADA Scientific Sessions in June 2005 assessed multiple doses of sitagliptin

in healthy volunteers. In a double blind, placebo controlled, randomized trial, sitagliptin was administered daily 2013 THOMSON REUTERS. For more information go to 4717d33831126edb6f1a102c/copyright/

(25 to 600 mg) and twice daily (300 mg ) for 10 days. In the 600 mg cohort, the day one dose was 800 mg but this was lowered to 600 mg for 8 days. Steady-state plasma pharmacokinetics were achieved by day 3. Cmax increased in a slightly greater than dose-proportional manner. The major means of elimination was renal with

an apparent terminal t1/2 of 11.8 to 14.4 h over the dose range of 25 to 600 mg [608523]. A further study at the 65th ADA Scientific Sessions showed evidence that there was no clinically meaningful reason to adjust dose of between male, female, young or elderly patients [608524].

In January 2003, Merck began a non-randomized, open-label, active controlled phase I trial (; 2006_562), to investigate the pharmacokinetics, safety, and tolerability of sitagliptin in patients (n = 30) with renal insufficiency. By January 2007, the study had been completed [782187].

Impaired glucose tolerance

In July 2011, a randomized, double-blind, parallel-assignment phase II efficacy trial (; MK-0431-105) evaluating sitagliptin (25 or 50 mg once-daily) versus placebo was planned to begin in August 2011 in Japanese patients (expected n = 240) with impaired glucose tolerance who had inadequate glycemic control on diet/exercise therapy. The primary endpoint was change in glucose total area under the concentration curve (AUC) for meal tolerance test (MTT) from baseline to week 8. At that time, the trial was estimated to complete in November 2012 [1216026].

PRECLINICAL STUDIES

Sitagliptin

In June 2004, preclinical data on sitagliptin were presented at the 64th ADA meeting in Orlando, FL. In lean mice, single oral doses of sitagliptin (0.1 to 0.3 mg/kg) caused a dose-dependent reduction in blood glucose excursion. A 3 mg/kg dose markedly inhibited plasma DPP-IV activity, and concurrently increased circulating active GLP-1. Insulin-resistant mice with diet-induced obesity showed dose-dependent decreases in blood glucose excursion following oral doses of sitagliptin [542283]. Similar data were presented in August 2004 at the 228th ACS meeting in Philadelphia, PA [556348].

Other series

In August 2005, preclinical data on three series of DPP-IV inhibitors were presented at the 230th ACS meeting in Washington, DC. No compounds from a series of alpha-aminoacyl amides had a desirable combination of high selectivity and good rat pharmacokinetics. The most active compound had an hERG IC50 value of 0.54 microM and a bioavailability of 120% [619101]. A series of triazolopiperazine analogs of was less potent than but had a longer half-life and greater oral bioavailability. One compound had IC50 values against DPP-IV, DPP8 and DPP9 of 0.025, > 100 and > 100 microM, respectively, and an oral bioavailability of 74% when dosed to rats at 1 mg/kg iv and 2 mg/kg po. This compound also showed a dose-dependent inhibition of glucose excursion when dosed to lean mice at 0.1 to 3 mg/kg [618815]. One compound from a series of imidazopiperidine amide derivatives potently and selectively inhibited DPP-IV with an IC50 value of 0.0084 microM compared to 70 and greater than 100 microM against both DPP8 and DPP9, respectively. This compound demonstrated a low oral bioavailability of 16%, a clearance value of 64 ml/min/kg, a half-life of 1.5 h and a Cmax value of 0.072 microM (po) when dosed to rats at 1 mg/kg iv and 2 mg/kg po [619104].

In March 2005, preclinical data on analogs of were presented at the 229th ACS meeting in San Diego, CA. Modification of produced a compound that demonstrated better DPP-IV inhibition and pharmacokinetics

than . In rats, this compound had an IC50 value of 12 nM, a half-life of 5.5 h, clearance of 4.8 ml/min/kg, oral bioavailability of 67% and an IC50 value at hERG channels of 4600 nM. When administered to lean mice after a glucose challenge, compound 32 (0.1 to 3.0 mg/kg) had an IC50 value of 51 nM [585697], [590950].

By February 2005, a series of beta-aminoacylpiperidines had been investigated for the inhibition of DPP-IV.

In SAR studies, one compound exhibited the highest activity with an IC50 value of 1.4 nM. In in vivo tests

with Sprague-Dawley rats (typical dosing of 1 mg/kg iv and 2 mg/kg po), this compound displayed an oral bioavailability of 20%, clearance of 60 ml/min/kg, and a half life of 1.5 h [643923].

By February 2005, anti-substituted beta-methylphenylalanine derived amides which displayed selectivity

over DPP8 and DPP9 had also been investigated for the inhibition of DPP-IV. In SAR studies, a 5-oxo-1,2,4-oxadiazole analog was found to be the most potent compound that had an IC50 value of 3 nM [613664].

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In August 2004, preclinical data were presented at the 29th National Medicinal Chemistry meeting in Madison, WI. Sitagliptin was selected as a lead compound from a series of bicyclic derivatives of beta-amino 4-phenylbutanoyl piperazines that were more potent than their predecessors, the 2,5-difluoro and 2,4,5-trifluoro analogs of the beta-amino 4-phenylbutanolyproline amide and beta-amino 3-phenylpropylpiperazine derivatives [557243].

In August 2004, preclinical data on a series of beta-aminoacyl amides were presented at the 228th ACS meeting in Philadelphia, PA. Compounds with IC50 values ranging from 1.4 to 780 nM against DPP-IV were obtained, one of which had > 400-fold selectivity for DPP-IV over other peptidases and 55% bioavailability in the rat [555315]. Data were also presented at this meeting on a series of fused tricyclic piperazine-derived amides [555323].

By May 2004, a series of beta-homophenylalanine and substituted piperazines had been tested and shown

to be potent and selective inhibitors of DPP- IV. The most potent beta-homophenylalanine derivatives had

IC50 values of 270 and 119 nM against DPP-IV and half-lives of 0.5 and 1.1 h respectively. The substituted piperazines showing high potency displayed IC50 values of 14 nM and 19 nM against DPP-IV with selectivities of over 1000-fold and over 4000-fold respectively over quiescent cell proline peptidase, QPP [605128], [605132].

In March 2004, SAR data on a series of proline amide, piperazine and beta-homophenylalanine derivatives were presented at the 227th ACS meeting in Anaheim, CA. The proline amide compounds showed potent inhibitory activity and selectivity, with one compound exhibiting an IC50 value of 0.41 nM, but demonstrated poor pharmacokinetics. Again, the beta-homophenylalanine derivatives showed activity, with one compound displaying an IC50 value of 119 nM, but the pharmacokinetic data from rats revealed that they were not orally bioavailable (F ~ 2.5%) [529442], [529443], [529444].

In September 2003, preclinical data on the series were presented at the 226th ACS meeting in New York,

NY. A cyclopentylglycine S,R,R derivative gave an IC50 value of 0.013 microM against DPP-IV and exhibited selectivity, with IC50 values of 1.6, and greater than 100 microM, against quiescent cell proline dipeptidase (QPP) and prolyl endopeptidase, respectively [504444], [502269]. Further data presented at the same meeting described a series of fluoropyrrolidine amides. The most potent member of the series had an IC50 value of 21 nM; however, this lacked the selectivity of a compound with IC50 values of 48 and 12,000 for DPP-IV and QPP, respectively, and a Ki value of 49,000 nM for the potassium channel hERG [502271], [506489]. By August 2003, 4-amino cyclohexylglycine analogs had been synthesized. One of the compounds exhibited IC50 values of 88 nM and 88000 nM for DPP-IV and QPP, respectively. It also had an oral bioavailability equal to 100% in dog and was orally efficacious in a glucose tolerance test in lean mice at 3 mg/kg [540268].

In March 2003, preclinical data on a series of DPP-IV inhibitors were presented at the 225th ACS

meeting in New Orleans, LA. SAR on a cyclohexylpyrrolidyl lead compound led to a series of 2,4-difluorobenzenesulfonamides. The most active compound had an IC50 value of 0.088 microM, 36% bioavailability in rats and 100% bioavailability in dogs. These compounds were reported to have good in vivo efficacy in murine models but no confirmational data were presented [482039].

ADDITIONAL INFORMATION

In March 2009, the EMEA Pediatric Committee adopted a positive opinion on a pediatric investigation plan for sitagliptin in the area of endocrinology, gynaecology, fertility and metabolism [991941].

The recommended dose of sitagliptin is 100 mg qd, with or without food, for all approved indications [777921]. DRUG NAME

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Names associated with this drug

Name Type sitagliptin INN

sitagliptin phosphate USAN

486460-32-6CAS RN 654671-77-9CAS RN 654671-78-0CAS RN 667899-14-1CAS RN 677782-27-3CAS RN

MK-0431Research Code MK-431Research Code ONO-5345Research Code ONO-5435Research Code Glactive Trade Name Januvia Trade Name Ristaben Trade Name Xelevia Trade Name dipeptidyl peptidase IV inhibitors, Merck & Co

DPP-IV inhibitors, Merck & Co

IDDBCP158538

IDDBCP163384

IDDBCP170912

sitagliptin phosphate monohydrate

Tesavel

.

NEWS

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Date Title

15-FEB-2013Japanese term extensions granted to MSD Corp for Januvia.

01-FEB-2013Merck Announces Full-Year and Fourth-Quarter 2012 Financial Results

04-JAN-2013AusPAR: Sitagliptin (as phosphate monohydrate)

15-NOV-2012Q3 in line, Eklira now available to European patients

26-OCT-2012Merck Announces Third-Quarter 2012 Financial Results

.

Deals

.

Summary

Primary company Merck & Co Inc

Partnering company Simcere Pharmaceutical Group

Deal Type Drug - Commercialization License

Start date21-JUL-2011

Overview

In July 2011, Merck & Co and Simcere Pharmaceutical entered a framework agreement to form a joint venture that would initially improve access to branded therapeutics for cardiovascular and metabolic diseases in China. Products would include Merck's simvastatin, losartan, enalapril and sitagliptin, and Simcere's XINTA (levamlodipine) and SHUFUTAN (rosuvastatin). The agreement was subject to closing conditions [1209352]. By September 2012, the JV was established [1323283].

.

.

Summary

Primary company Merck & Co Inc

Partnering company Almirall Prodesfarma SA

Deal Type Drug - Commercialization License

Start date04-NOV-2008

.

Overview

In November 2008, Almirall obtained the Spanish marketing rights to sitagliptin from Merck; at that time Almirall also expected to launch and market a sitagliptin and metformin combination tablet in 2009 [961229]. .

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Summary

Primary company Merck & Co Inc

Partnering company Daewoong Pharmaceutical Co Ltd

Deal Type Drug - Commercialization License

Start date01-JUN-2008

.

Overview

By June 2008, Daewoong had signed an agreement to copromote Merck's Fosamax in Korea [915148]. In July 2008, Merck's sitagliptin (as Januvia) and Fosamax Plus were included for copromotion [972748].

.

.

Summary

Primary company Codexis Inc

Partnering company Merck & Co Inc

Deal Type Technology - Other Proprietary

Start date03-APR-2007

.

Overview

In April 2007, Merck & Co was granted non-exclusive access to Codexis' Codex Biocatalyst Panels in a 3-year agreement [780233]. By 2010, the companies had codeveloped a new process for the manufacture of sitagliptin active pharmaceutical ingredient (API), used in Merck's Januvia [1283322]. In May 2012, a three-year extension of the companies' catalyst and process development collaboration for the development of pharmaceutical manufacturing enzymes was announced [1293246].

.

.

Summary

Primary company Merck & Co Inc

Partnering company Ono Pharmaceutical Co Ltd

Deal Type Drug - Development/Commercialization License

Start date10-NOV-2004

.

Overview

In November 2004, the exclusive Japanese development and marketing rights to Merck & Co's aprepitant and Japanese comarketing rights for sitagliptin were obtained by Ono Pharmaceutical [570404]. By March 2013 THOMSON REUTERS. For more information go to 4717d33831126edb6f1a102c/copyright/

2012, the co-development agreement in Japan had included Glactiv and biguanide metformin combination tablets (ONO-5435A / MK-0431A) for [1288912].

.

DEVELOPMENT STATUS

.

Detailed status for Almirall Prodesfarma SA

Therapy Area Country Status Reference Date

Non-insulin dependent diabetes Spain Launched96122904-NOV-2008 Detailed status for Merck & Co Inc

Therapy Area Country Status Reference Date

Non-insulin dependent diabetes Australia Registered135430520-DEC-2012 Non-insulin dependent diabetes Brazil Launched76171230-JAN-2007 Non-insulin dependent diabetes Canada Launched90876321-APR-2008 Non-insulin dependent diabetes China Launched119139422-MAR-2010 Non-insulin dependent diabetes EU Launched90876321-APR-2008 Non-insulin dependent diabetes India Launched109864111-MAY-2010 Non-insulin dependent diabetes Mexico Launched73344220-OCT-2006 Non-insulin dependent diabetes South Korea Launched99035131-DEC-2008 Non-insulin dependent diabetes UK Launched135603301-OCT-2009 Non-insulin dependent diabetes US Launched78567220-OCT-2006 Detailed status for Merck Sharp & Dohme Ltd

Therapy Area Country Status Reference Date

Non-insulin dependent diabetes France Launched135045318-MAR-2008 Non-insulin dependent diabetes Germany Launched134227831-DEC-2007 Non-insulin dependent diabetes Portugal Launched138796701-DEC-2007 Non-insulin dependent diabetes Spain Launched1362979null

Detailed status for MSD Japan

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Therapy Area Country Status Reference Date Glucose intolerance

Japan Discovery 121602628-JUL-2011Non-insulin dependent diabetes

Japan

Launched

1063689

11-DEC-2009

Detailed status for Ono Pharmaceutical Co Ltd Therapy Area Country Status Reference Date Glucose intolerance

Japan Discovery 121602628-JUL-2011Non-insulin dependent diabetes

Japan

Launched

1063689

11-DEC-2009

.

DEVELOPMENT STATUS : HISTORY .

Detailed status for Merck & Co Inc Therapy Area Country Status Reference Date Non-insulin dependent diabetes

Canada

Registered

864647

03-JAN-2008

Non-insulin dependent diabetes

China Registered 105144222-OCT-2009

Non-insulin dependent diabetes

Mexico Registered 68295408-AUG-2006

Non-insulin dependent diabetes

South Korea Registered 88132530-SEP-2007

Non-insulin dependent diabetes

US Registered 73205917-OCT-2006

Non-insulin dependent diabetes

US Pre-registration 65068915-FEB-2006

Non-insulin dependent diabetes

US Phase 3 Clinical 55023930-JUN-2004

Non-insulin dependent diabetes

US Phase 2 Clinical 51424520-NOV-2003

Non-insulin dependent diabetes

US Discovery 48203903-APR-2003

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Non-insulin dependent diabetes

Western Europe Registered 77792129-MAR-2007

Non-insulin dependent diabetes

Western Europe Pre-registration 76058029-MAR-2006

Detailed status for Merck Sharp & Dohme Ltd Therapy Area Country Status Reference Date

Non-insulin dependent diabetes

France

Registered

1350453

21-MAR-2007

Non-insulin dependent diabetes

Spain Registered 136297927-MAR-2007

Detailed status for MSD Japan Therapy Area Country Status Reference Date Non-insulin dependent diabetes

Japan

Registered

1050130

16-OCT-2009

Non-insulin dependent diabetes

Japan Pre-registration 86064412-DEC-2007

Non-insulin dependent diabetes

Japan Phase 3 Clinical 68261204-AUG-2006

Non-insulin dependent diabetes

Japan Phase 2 Clinical 59729628-FEB-2005

Detailed status for Ono Pharmaceutical Co Ltd Therapy Area Country Status Reference Date Non-insulin dependent diabetes

Japan

Registered

1050130

16-OCT-2009

Non-insulin dependent diabetes

Japan Pre-registration 86064412-DEC-2007

Non-insulin dependent diabetes

Japan Phase 3 Clinical 68261204-AUG-2006

Non-insulin dependent diabetes

Japan Discovery 59729628-FEB-2005

.

LITERATURE EVALUATION

Carolyn F Deacon, Department of Medical Physiology, Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark

Submission date: 17 January 2005Publication date: 18 February 2005

Introduction

Type 2 diabetes is one component of a cluster of diseases collectively known as the metabolic syndrome, and is characterized by fasting and postprandial hyperglycemia, and insulin resistance. Current treatment consists of lifestyle changes, for example in exercise and diet, and pharmacological intervention with oral antihyperglycemic agents such as insulin sensitizers (eg thiazolidinediones), insulin secretagogues (eg sulfonylureas), biguanides or insulin. However, many patients still suffer from debilitating complications, such as cardiovascular problems, retinopathy, nephropathy and neuropathy [581998]. Furthermore, some of these complications, such as macrovascular complications, are arguably only marginally prevented by existing drug therapies [315243]. There is, therefore, a continued demand for new and more effective agents to target this unmet clinical need. The incretin hormone, glucagon-like peptide-1 (GLP-1), is released from intestinal L-cells in response to meal ingestion, and possesses a number of actions that make it a highly attractive target for drug design [580621].

It glucose-dependently reduces hyperglycemia by simultaneously enhancing insulin, and reducing glucagon, secretion. Additionally, it delays gastric emptying, and acts as a satiety agent, suppressing appetite and leading to weight loss. Therefore, it has the ability to reduce elevated blood glucose levels via several different physiological mechanisms, which, because of the glucose-dependency of its action, is associated with minimal risk of severe hypoglycemia. In animal studies, GLP-1 has been shown to exhibit trophic effects on beta-cells, hence raising the possibility that it may have the potential to modify the disease process by increasing beta-cell mass and function [580621]. More recently, GLP-1 has also been shown to exhibit beneficial cardiovascular effects [580623], [580626]; this is significant because cardiovascular complications are a major cause of mortality in the diabetic population. Taken together, therefore, GLP-1 has a unique spectrum of beneficial effects, which distinguish it from the currently available therapies [580621]. In its native form, however, GLP-1 is not clinically useful due to its rapid degradation and inactivation in vivo by the widely distributed serine protease dipeptidyl peptidase IV (DPP IV) [580628], giving it an unacceptable pharmacodynamic profile.

Over the past decade, following the initial suggestion that pharmacological 'harnessing' of the in vivo stability

of GLP-1 may be a novel approach to the management of type 2 diabetes [356321], two separate strategies

to overcome the inherent drawbacks in using native GLP-1 have been investigated by academic laboratories and the pharmaceutical industry alike [559655], [580621]. The outcome of this research has been the design of long-acting, DPP IV-resistant analogs, and/or derivatives of GLP-1, suitable for exogenous administration, and the development of inhibitors of DPP IV to enhance the endogenously released hormone. Compounds of both classes are now in advanced stages of clinical development.

MK-431 (Merck & Co Inc) is one of several DPP IV inhibitors in late-stage clinical development. These compounds include vildagliptin (LAF-237; Novartis AG), which has reached phase III development, and

BMS-477118 (Bristol-Myers Squibb Co), PSN-9301 (Prosidion Ltd) and 823093 (GlaxoSmithKline plc), which are currently in phase II clinical trials. MK-431 is a potent and selective DPP IV inhibitor, which entered phase III clinical trials in the first half of 2004 [550239]; filing with the FDA is anticipated in 2006 [576111].

Synthesis and SAR

The original discovery of substituted piperazines as novel DPP IV inhibitors was achieved through SAR studies leading to the incorporation of multiple fluorine atoms and modification of the piperazine ring to yield potent

and selective compounds related to MK-431 [482039], [529442], [529443], [555315], [555323]. MK-431 is a beta-amino acid-based compound, which is the monophosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine [580635].

A synthetic route for MK-431 has been described by Kim et al [580635]. Briefly, MK-431 is the peptide-coupling product of the beta-amino acid (3R)-amino-4-(2,4,5-trifluoro-phenyl)-butyric acid, and the heterocyclic amine 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine. The amino acid component is made

in six steps from 2,4,5-trifluorobenzyl bromide via Schollkopf's bis-lactam methodology to give (R)-2,4,5-

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trifluorophenylalanine, which is converted to the corresponding beta-amino acid via the Arndt-Eistert homologation procedure. The heterocyclic amine component is made in four steps from 2-chloropyrazine, which is reacted with hydrazine, acylated with trifluoroacetic anhydride, and condensed in polyphosphoric acid to give the trifluoromethylated triazolopyrazine system, which is then hydrogenated [580635].

Key factors in optimizing the affinity and pharmacokinetic properties of the structurally novel piperazine

family were realized in SAR studies, starting with lead compounds consisting of fluorobenzyl beta-amino

acid amides with simple piperazines. These key factors included the proper location of two or more fluorine atoms onto the phenyl ring of the compounds, and substitution of the metabolically labile piperazine moiety

with more metabolically robust heterocylic analogs [502269], [502270], [580635]. The triazolopiperazine system was selected among a variety of heterocyclic systems. Introduction of a 2-ethyl substituent to the triazolopiperazine core improved the affinity 2-fold, and importantly, also prolonged the t1/2 in rat hepatocytes. Replacing the 2-ethyl with a 2-trifluoromethyl substituent again improved the affinity, but more significantly,

also improved the bioavailability in the rat (from 2 to 44%) [580635]. Optimization of the fluorine substitution pattern of the phenyl ring of the beta-amino group, from 3,4-di-F to 2,5-di-F and 2,4,5-tri-F, led to further affinity improvements and the discovery of MK-431, which was selected for development [580635]. Attempted deletion of the trifluoromethyl group of the MK-431 structure led to a drastic loss of bioavailability in the rat (from 76

to 3%), and a 4-fold decrease in DPP IV inhibitory potency, demonstrating the importance of this group for

the pharmacokinetic profile and potency of the compound. Furthermore, replacement of the trifluoromethyl group with pentafluoroethyl restored the bioavailability (61%), but affinity remained compromised [580635].

On the basis of studies on an earlier series of (R)-beta-homophenylalanine-based DPP IV inhibitors, (R)-stereochemistry of the beta-amino amide was selected as the preferable form of the structure [575970]. Intriguingly, the 2-fluorophenyl analog was also more selective for DPP IV versus a related enzyme, QPP (quiescent cell proline peptidase, also called DPP II). This is of importance because QPP is thought to be

of significance in the physiology of immune function and selectivity against this enzyme is, therefore, an appropriate goal for compound optimization.

Preclinical Development

MK-431 is a potent, competitive, reversible inhibitor of DPP IV (IC50 value = 18 nM; Ki value = 9 nM) [542282], [554378], [580635], although not as potent as vildagliptin (IC50 value = 3.5 nM) [580798]. The (S)-enantiomer of MK-431 was considerably less potent than the (R)-enantiomer, exhibiting an IC50 value of 440 nM.

MK-431 is also highly selective for DPP IV versus other proteases, including aminopeptidase P, prolidase, prolylendopeptidase (also called prolyloligopeptidase or post-proline cleaving enzyme) and QPP, (IC50 values > 10 microM), and the more closely related enzymes, FAPalpha (fibroblast activation protein-alpha, also called seprase; IC50 value > 100 microM), DPP 8 (IC50 value = 48 microM) and DPP 9 (IC50 value > 100 microM) [542282], [580635]. This was an important finding as inhibition of the closely related DPP 8 and DPP 9 enzymes has been associated with severe toxicity in animal studies [580635], [580658]. Additionally, MK-431 did not show any significant activity against a wide range of other proteins, including numerous ion channels and receptors, or in enzyme-inhibition assays [580635].

The molecular binding of MK-431 to the active site of the DPP IV enzyme has also been characterized. The bound MK-431 is orientated with the opposite amide moiety to that of alpha-amide-based substrates, and the trifluoromethyl moiety fully occupies the S1 hydrophobic pocket. The beta-amino group of MK-431 is bound to one tyrosine and two glutamate DPP IV residues via hydrogen bonding [580635].

In lean mice, a single oral dose of MK-431, given 1 h before an oral dextrose (5 g/kg) challenge, dose-dependently reduced the glucose excursion (23, 35, 46 and 55% reduction at 0.1, 0.3, 1 and 3 mg/kg doses, respectively) in an oral glucose tolerance test [542282], [580635]. The 3-mg/kg dose raised intact, active GLP-1 plasma concentrations by 2- to 3-fold to reach similar levels seen after oral glucose administration in DPP

IV-deficient mice. The 0.1, 0.3, 1 and 3 mg/kg doses corresponded with approximate plasma concentrations

of 200, 380, 400 and 600 nM, and approximate plasma DPP IV activity inhibition of 20, 40, 68 and 85%, respectively, at 20 min following the dextrose challenge. A similar dose-dependent effect of orally delivered

MK-431 (68, 90 and 82% inhibition at 0.3, 3 and 30 mg/kg doses, respectively) was also observed in insulin-resistant mice with diet-induced obesity (DIO), with the maximal effect achieved following the 3-mg/kg dose [580635].

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A close structural analog of MK-431 was administered to low-dose streptozotocin-treated mice on a high-fat diet [580646], [580654]. The administration of ~ 60, 290 and 800 mg/kg/day (corresponding to 80 to 100% inhibition of plasma DPP IV activity) for 3 months resulted in dose-dependent decreases in postprandial and fasting hyperglycemia, and reductions in glycosylated hemoglobin (HbA1c), circulating triglyceride and free fatty acids. Histological examination of islets collected at the end of the study was performed. This showed that compared with non-treated diabetic mice, in which the insulin/glucagon ratio was reduced by > 6-fold, relative to normal control animals, inhibitor treatment resulted in near normalization of the insulin/glucagon ratio. This treatment also caused a dose-dependent increase in the staining of insulin-positive beta-cells. Islet size or number was not altered by treatment with the inhibitor [580646], [580654].

Metabolism and Pharmacokinetics

There is little information available concerning the metabolism and pharmacokinetics of MK-431. Bioavailability following the oral administration of MK-431 (2 mg/kg) is reported to be good (61% in mice, 76% in rats, 100% in dogs and 68% in monkeys), with the compound exhibiting AUC(norm) values of 0.52, 8.3 and 1.0 microM h.mg/ kg and Cmax values of 0.33, 2.2 and 0.33 microM in rat, dog and monkey, respectively. Tmax data for MK-431 are not available, but the compound exhibited plasma t1/2 values of 1.7, 4.9 and 3.7 h, and Cl values of 60, 6 and 28 ml/min/kg in rat, dog and monkey, respectively [542282], [580635]. Interestingly, the t1/2 of MK-431 in monkeys was > 2-fold longer than that of vildagliptin (1.5 h) [580798].

In lean mice, an oral dose of 1 mg/kg gives rise to a plasma drug concentration of 190 nM at 80 min post-dose, and is associated with a 69% inhibition of plasma DPP IV. The corresponding values following a 3-mg/kg dose were 600 nM and 84% inhibition, although it was noted that the extent of DPP IV inhibition determined in the in vitro assay underestimates that obtained in vivo. This discrepancy is due to MK-431 being a competitive, rapidly reversible inhibitor and the fact that the activity assay requires plasma (and hence inhibitor) dilution, and the presence of a substrate, which competes with the inhibitor for enzyme binding [580635].

Toxicity

No toxicological information has so far been released for MK-431. However, data relating to the impact of inhibitor selectivity on the toxicology of related compounds are available.

In a 2-week toxicity study in rats, a series of inhibitors with similar pharmacokinetic profiles, but differing selectivity for DPP IV, DPP 8/9 and QPP, were tested at doses of 10, 30 and 100 mg/kg/day [580658]. All doses of the DPP 8/9-selective inhibitor were associated with severe toxicities, including alopecia, thrombocytopenia, anemia, enlarged spleen, multiple pathologies and mortality. The DPP 8/9-selective inhibitor was lethal in both wild-type and DPP IV-deficient mice, suggesting that the toxicity was not due to inhibition of DPP IV. Reductions in reticulocytes were observed with the highest dose of the QPP-selective inhibitor, but in contrast no toxicities were observed for the DPP IV-selective inhibitor.

In dogs treated for 2 weeks in an acute tolerability study, inhibition of DPP 8/9 with a selective inhibitor (10

mg/kg/day) resulted in bloody diarrhea, emesis and tenesmus, but no adverse effects were reported to be associated with the QPP- or DPP IV-selective inhibitors (also at 10 mg/kg/day) [580658].

Because of the role of DPP IV (also known as the T-cell marker CD26) in the immune system, where it has

the capacity to influence T-cell activity, concerns have been raised that DPP IV inhibition may adversely affect immune function. Furthermore, DPP IV inhibitors such as Lys[Z(NO2)]-thiazolidide, Lys[Z(NO2)]-piperidide,

Lys[Z(NO2)]-pyrrolidide and Val-boro-Pro have been reported to produce effects on immune cells, including inhibition of T-cell proliferation and alteration of cytokine expression and secretion [580659], [580666], [580669]. However, it is uncertain whether it is the inhibition of the catalytic activity itself that is responsible for this effect. Moreover, the precise selectivity of many of these DPP IV inhibitors is unknown. For example, Lys[Z(NO2)]-pyrrolidide and related compounds are not wholly selective for DPP IV, but also inhibit the activity of DPP 8/9 (IC50 value < 1 mM) [580671], while Val-boro-Pro, which has a Ki value of 2 nM for DPP IV, inhibits QPP with a Ki of 125 nM [580673], and has also been reported to inhibit FAPalpha [580674].

In vitro, the non-selective DPP IV inhibitor Val-boro-Pro and a selective DPP 8/9 inhibitor were found to inhibit

T-cell proliferation (IC50 values of 10 and 500 nM, respectively), while Val-boro-Pro also inhibited IL-2 release 2013 THOMSON REUTERS. For more information go to 4717d33831126edb6f1a102c/copyright/

(IC50 value ~ 500 nM). A QPP-selective inhibitor and a close structural analog of MK-431 were without effect, suggesting that certain of the previously reported immunological effects of some DPP IV inhibitors may have been due to their modulation of DPP 8/9 or FAPalpha, rather than of DPP IV itself [580671].

It is of note that no toxicological problems have been reported so far for other DPP IV inhibitors currently in clinical development.

Clinical Development

Phase I

To date, only the results from one single-dose, randomized, placebo-controlled phase I clinical study with

MK-431 have been reported [541525], [557243], [580679]. This trial was designed to assess the glucose-lowering ability, safety and tolerability of MK-431 in patients with type 2 diabetes (n = 56). In this study, subjects received single oral doses of either MK-431 (25 or 200 mg) or placebo following overnight fasting, separated by 7-day washout periods. Oral glucose tolerance tests were performed 2 h following drug or placebo administration. The drug treatment was generally well tolerated and produced significant reductions in glycemic excursion. A single dose of MK-431 (200 mg) was reported to inhibit plasma DPP IV activity by 80% [557243], which was coincident with reductions in the glucose excursion following an oral glucose load. Further preliminary results from the same three-period cross-over study were presented at the 2004 annual meetings of the American Diabetes Association and the European Association for the Study of Diabetes. Glucose tolerance was improved in patients receiving MK-431 (25 or 200 mg), with reductions in the area under the glucose curve of ~ 22 (p < 0.001) and ~ 26% (p <0.001), respectively, compared with placebo. MK-431 at both doses resulted in a doubling of concentrations of active GLP-1 and in the ratio of active to total GLP-1 (p < 0.001). MK-431 (25 and 200 mg) treatment was also associated with increased plasma insulin (22 and 23%, respectively; p < 0.001) and C-peptide (13 and 21%, respectively; p < 0.001) concentrations, and reduced plasma glucagon (8 and 14%, respectively; p < 0.0015 and 0.001) concentrations [541525], [580679]. Levels of active, glucose-dependent insulinotropic polypeptide (GIP), which is the other important incretin hormone, were also increased by MK-431 treatment [580679].

Phase II/III

Full phase II results have not yet been published, but MK-431 was reported to be safe and well tolerated in phase IIb trials and to lower blood glucose levels effectively. It is anticipated that dosing frequency will be once daily [520117]. Phase III clinical trials with MK-431 were initiated in the first half of 2004 [550239]; however, the publication of results is not expected before 2006 [554454].

Side Effects and Contraindications

Due to the limited clinical data released so far, few details of side effects are available. Tolerability has thus

far only been reported following single-dose administration. In such a study in type 2 diabetic patients treated with diet and exercise, MK-431 (25 or 200mg) was reported to be generally well tolerated, although no specific details were given [541525], [580679]. However, it is worthy of note that vildagliptin, the only other DPP IV inhibitor in clinical development for which long-term (up to 1 year) data is available, is also reported to be well tolerated. When vildagliptin was given as monotherapy or in combination with metformin for 12 weeks, no

drug-related serious adverse events resulted and the overall incidence of observed adverse events did not very between drug- and placebo-treated subjects [541529], [580783]. Across patients treated with vildagliptin

in combination with metformin for a 12-month period, there was one serious adverse event (an episode of peripheral edema) that was suspected to be drug related [580783].

Patent Summary

Merck & Co Inc have made numerous patent applications relating to the synthesis and use of a variety of DPP IV inhibitors. The synthesis of pyrazine derivatives with a (3R)-4-aryl-3-amino-butyryl side chain, and their

use as DPP IV inhibitors, is claimed in the patent application WO-2004085661. This application, published

in October 2004, highlighted the potential use of these compounds for the treatment of type 2 diabetes.

Merck's related application (WO-2004085378) claims a method for the preparation of chiral beta-amino acid derivatives via asymmetric hydrogenation, in the presence of a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand. Also published in October 2004, this application claims the potential use

of these compounds as DPP IV inhibitors for the treatment of type 2 diabetes. Merck also published the PTC

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