默沙东口服糖尿病新药omarigliptin首个III期临床疗效媲美Januvia

默沙东口服糖尿病新药omarigliptin首个III期临床疗效媲美Januvia

                               
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                                                                             发布日期：2014-09-20  来源：生物谷
omarigliptin媲美年销40亿美元Januvia，该药将成为默沙东在口服降糖药市场投下的又一枚重磅炸弹，也是默沙东捍卫其口服降糖药霸主地位的重要筹码，

                               
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默沙东抗癌免疫疗法PD-1抑制剂Keytruda（pembrolizumab）和丙肝（HCV）鸡尾酒MK-5172/MK-8742备受业界关注。近日，默沙东糖尿病管线又传来好消息，每周一次的口服糖尿病新药omarigliptin在首个III期临床中，疗效媲美其自身热销的每日一次口服糖尿病药物Januvia（捷诺维，sitagliptin，西他列汀）。

Januvia在2013年的全球销售高达40亿美元，业界预测，omarigliptin将成为默沙东在糖尿病市场投下的又一枚重磅炸弹，同时omarigliptin将成为默沙东捍卫其口服降糖药市场霸主地位的重要筹码。omarigliptin每周口服一次，而Januvia每日口服一次，2者均属于二肽基肽酶IV（DPP-4）抑制剂，通过阻断DPP-4发挥降糖作用。
目前，默沙东一直在围绕正慢慢消退的Januvia构建产品组合。去年，默沙东用6000万美元抱上辉瑞大腿，共同开发ertugliflozin，该药是一种钠-葡萄糖协同转运蛋白 2(SGLT2)抑制剂。默沙东表示，ertugliflozin有希望作为单药疗法，但搭配其DPP-4抑制剂Januvia，将会有更美好的未来。除了口服降糖药，默沙东也不愿错过仿制药热潮，该公司正在开发的一款药物MK-1293已进入III期阶段，该药是赛诺菲年销80亿美元的来得时（Lantus，甘精胰岛素）的仿制药。
尽管默沙东在DPP-4市场具有领导者地位，但在GLP-1市场中，默沙东仍处于靠后的位置。诺和诺德每日注射一次的GLP-1受体激动剂类药物Victoza在2013年已带来20亿美元的销售，同时该药前景一片光明。另一方面，葛兰素史克已推出了自己的GLP-1抑制剂Tanzeum（albiglutide），礼来的Trulicity（dulaglutide）也于近日获得了FDA的批准，该药在III期临床中，疗效媲美诺和诺德Victoza。同时，赛诺菲已启动登月计划，进入GLP-1市场，该公司本周宣布了开发口服GLP-1药物的计划。
omarigliptin首个III期数据：
默沙东在第50届欧洲糖尿病协会（EASD）年会上公布了omarigliptin III期临床项目的首个III期研究数据：与安慰剂相比，omarigliptin显著降低了糖化血红蛋白（HbA1c）水平，同时具有与每日一次50mg剂量（日本的标准起始剂量）Januvia同等的疗效和耐受性。
omarigliptin是一种超长效DPP-4（二肽基肽酶Ⅳ）抑制剂，每周口服一次，可产生持续的DPP-4抑制作用，具有全新的降血糖机制，同时具有不增加体重、不会引起低血糖反应、不会引起水肿等优越性。
默沙东公布的数据来自在日本2型糖尿病患者中开展的一项III期研究的数据。该项研究是一项双盲、非劣性III期研究，评估了25mg剂量omarigliptin（每周一次）相对于50mg剂量sitagliptin（每天一次）和安慰剂的疗效、安全性和耐受性。主要疗效终点是24周时糖化血红蛋白（HbA1c）从基线的变化。数据表明，与安慰剂相比，omarigliptin使HbA1c水平显著降低幅度达到了-0.8，达到了研究的主要终点，omarigliptin与sitagliptin相比使HbA1c水平降低幅度为-0.02，达到了预先设定的非劣效性标准。与安慰剂相比，omarigliptin与sitagliptin也显著降低了空腹血糖水平和餐后2小时血糖水平。研究中，omarigliptin治疗组与安慰剂组及sitagliptin治疗组在不良事件发生率方面无有意义的差异。
目前，默沙东正在开展一项大型全球临床开发项目用于支持omarigliptin，包括10个III期研究，涉及约8000例2型糖尿病患者。此次公布的是omarigliptin的首批III期数据，是该药日本监管文件的关键组成部分。正如此前所公布的，默沙东计划于2014年底向日本监管部门提交omarigliptin上市申请。
英文原文：Merck Presents First Phase 3 Data in Japanese Patients for Omarigliptin, an Investigational Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes
Omarigliptin significantly reduced HbA1c levels compared to placebo
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of the first data from the Phase 3 clinical development program for omarigliptin, Merck’s investigational once-weekly DPP-4 inhibitor for the treatment of type 2 diabetes. In a study in Japanese patients, omarigliptin provided comparable efficacy and tolerability to Merck’s once-daily DPP-4 inhibitor JANUVIA® (sitagliptin) 50 mg, which is the standard starting dose for sitagliptin in Japan. Merck presented these data on omarigliptin, which has been shown to produce sustained DPP-4 inhibition, at an oral session at the 50th European Association for the Study of Diabetes (EASD) Annual Meeting.
“Despite advances in diabetes care in recent years, many people living with type 2 diabetes are not at recommended blood sugar goals,” said Peter Stein, M.D., vice president, Clinical Research, Diabetes and Endocrinology, Merck Research Laboratories. “Merck is committed to helping patients reduce the complexities of managing diabetes. If approved, omarigliptin, as a once-weekly medication, could provide an important new treatment option to help patients attain their blood sugar goals.”
Merck is supporting omarigliptin with a global clinical development program that includes 10 Phase 3 clinical trials involving approximately 8,000 patients with type 2 diabetes. These are the first Phase 3 data presented for omarigliptin and are the pivotal data for filing in Japan. As previously announced, Merck plans to file for approval in Japan by the end of 2014.
about the study
The Phase 3 double-blind, non-inferiority trial assessed the efficacy, safety and tolerability of omarigliptin 25 mg once-weekly compared to sitagliptin 50 mg once-daily (standard starting dose in Japan), and to placebo. The primary efficacy endpoint was the change in HbA1c1 levels from baseline at week 24.
At baseline, randomized patients (n=414) had a mean HbA1c concentration of 7.9, 8.0 and 8.1 percent in the omarigliptin, sitagliptin and placebo groups, respectively. Mean fasting plasma glucose (FPG) levels were also similar between treatment groups.
The primary objectives of the study were met, demonstrating at 24 weeks a significant change from baseline in lowering HbA1c levels versus placebo, while demonstrating similar efficacy to sitagliptin.
At week 24, omarigliptin significantly reduced HbA1c levels by -0.80 percent from baseline relative to placebo. The change relative to sitagliptin was -0.02 percent and met the prespecified non-inferiority criterion. The pre-specified criterion was based on the upper bound of the 95 percent confidence interval (CI) being less than 0.3 percent. Fasting and two-hour post-meal blood sugar levels also were significantly reduced from baseline with omarigliptin and sitagliptin compared to placebo.
There were no meaningful differences in the incidences of adverse events with omarigliptin compared to placebo and sitagliptin. The most common adverse event that occurred with an incidence of greater than 3 percent in the omarigliptin group was nasopharyngitis, which occurred in 12.7 percent of those treated, compared to 30.5 percent of patients receiving placebo and 11.0 percent of those receiving sitagliptin. Symptomatic hypoglycemia was uncommon across all treatment groups in this study [omarigliptin (0), sitagliptin (1), and placebo (0)]. Omarigliptin was generally weight neutral, with a 0.04 kg mean change from baseline at week 24.
about JANUVIA® (sitagliptin)
JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA. JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.
Selected important risk information about JANUVIA (sitagliptin) 25 mg, 50 mg and 100 mg tablets
There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiating JANUVIA, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA.
Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis. Caution should be used to ensure that the correct dose of JANUVIA is prescribed.
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin.
When JANUVIA was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
The incidences (and rates) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 12.2 percent (0.59 episodes per patient-year) for JANUVIA 100 mg in combination with glimepiride (with or without metformin), 1.8 percent (0.24 episodes per patient-year) for placebo in combination with glimepiride (with or without metformin), 15.5 percent (1.06 episodes per patient-year) for JANUVIA (sitagliptin) 100 mg in combination with insulin (with or without metformin), and 7.8 percent (0.51 episodes per patient-year) for placebo in combination with insulin (with or without metformin).
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA, such as anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes.
Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUVIA.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or with any other antidiabetic drug.
In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in greater than or equal to 5 percent of patients treated with JANUVIA as monotherapy and in combination therapy, and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis and headache.

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