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williamxiang木蟲 (著名寫手)
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FDA批準第一個SGLT-2抑制劑類降血糖藥－canagliflozin 已有4人參與
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美國FDA于當?shù)貢r間2013年3月29日發(fā)布消息稱，該機構于日前批準了第一個鈉－葡萄糖同向轉運體－2抑制劑類Ⅱ型糖尿病治療用藥－來自強生制藥的canagliflozin，商品名Invokana。 但是，F(xiàn)DA在做出批準的同時還要求強生公司于該藥上市后進行5項研究，包括心血管研究、藥物監(jiān)測研究、骨骼安全性研究與兩項兒科研究。 Thomson Reuters的分析人士稱，Invokana有望于2016年實現(xiàn)4.68億美元的銷售額。 田邊制藥株式會社于2004年7月30日所申請的第200480022007.8號專利是為canagliflozin在中國的化合物專利，該專利申請及其分案申請均尚處于實質審查階段。 [ Last edited by williamxiang on 2013-4-2 at 11:11 ] |
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- FDA批準強生Canagliflozin用于2型糖尿病
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2樓2013-04-01 11:34:27
3樓2013-04-01 12:55:30
williamxiang
木蟲 (著名寫手)
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4樓2013-04-01 13:14:17
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小木蟲: 金幣+0.5, 給個紅包，謝謝回帖
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Thomson Reuters的報告沒有提供數(shù)據(jù)， 見下： Sales Comment Consensus forecast data for Johnson & Johnson (J&J) and Mitsubishi Tanabe Pharma are presented. In July 2000, Tanabe (now Mitsubishi Tanabe) licensed the worldwide development and marketing rights, excluding Japan and parts of Asia, to J&J [377554]. In March 2012, Mitsubishi Tanabe and Daiichi Sankyo entered into a strategic alliance to copromote canagliflozin in Japan [1269148]. 不知樓主從哪里得到的市場信息？ |
5樓2013-04-02 13:39:46
williamxiang
木蟲 (著名寫手)
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6樓2013-04-02 14:24:20
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小木蟲: 金幣+0.5, 給個紅包，謝謝回帖
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最早的專利是2005申請 Patents Company Title Publication details Type Inventors Janssen Pharmaceutica NV [Johnson & Johnson] (Patent Assignee/Owner) Formulation for co-therapy treatment of diabetes WO-2012006298.12-JAN-2012 ( 06-JUL-2010 ) . . Component of Combination Delaet, Urbain, Alfons Clementina; Faure, Anne; Heyns, Philip, Erna Hortentia Gilbert; Jans, Eugeen, Maria Jozef; Railkar, Aniruddha Janssen Pharmaceutica NV [Johnson & Johnson] (Patent Assignee/Owner) Pharmaceutical formulations comprising 1-(beta-D-glucopyranosyl)-2-thienylmethylbenzene derivatives as inhibitors of SGLT WO-2011143296.17-NOV-2011 ( 11-MAY-2010 ) . . Formulation Wang, Wenhua; Outwin, Todd; Joseph, Thomas C. Mitsubishi Tanabe Pharma Corp [Mitsubishi Chemical Holdings Corp] (Patent Assignee/Owner) Canagliflozin containing tablets WO-2011142478.17-NOV-2011 ( 11-MAY-2010 ) . . Formulation Sugimoto Masaaki; Kinoshita Hajime; Tokuda Takayuki Janssen Pharmaceutica NV [Johnson & Johnson] (Patent Assignee/Owner) Process for the preparation of compounds useful as inhibitors of SGLT2 WO-2011047113.21-APR-2011 ( 14-OCT-2009 ) . . Process Farina, Vittorio; Lemaire, Sebastien, Francois Emmanuel; Houpis, Ioannis, N. Janssen Pharmaceutica NV [Johnson & Johnson] (Patent Assignee/Owner) Crystallisation process for 1-(ß-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene WO-2011003976.13-JAN-2011 ( 10-JUL-2009 ) . . Process Rammeloo, Thomas Joachim Landewald; De Keyser, Ruben; Schildermans, Gustaaf Jozef Petrus Janssen Pharmaceutica NV [Johnson & Johnson] (Patent Assignee/Owner); Mitsubishi Tanabe Pharma Corp [Mitsubishi Chemical Holdings Corp] (Patent Assignee/Owner) Process for the preparation of compounds useful as inhibitors of SGLT WO-2010043682.22-APR-2010 ( 17-OCT-2008 ) . . Process Filliers, Walter Ferdinand Maria; Broeckx, Rudy Laurent Maria; Nieste, Patrick Hubert J.; Hatsuda, Masanori; Yoshinaga, Masahiko; Yada, Mitsuhiro Mitsubishi Tanabe Pharma Corp [Mitsubishi Chemical Holdings Corp] (Patent Assignee/Owner) Combination therapy comprising SGLT inhibitors and DPP-4 inhibitors WO-2009091082.23-JUL-2009 ( 17-JAN-2008 ) . . Component of Combination Ueta, Kiichiro; Arakawa, Kenji; Matsushita, Yasuaki Janssen Pharmaceutica NV [Johnson & Johnson] (Patent Assignee/Owner); Mitsubishi Tanabe Pharma Corp [Mitsubishi Chemical Holdings Corp] (Patent Assignee/Owner) Process for the preparation of compounds useful as inhibitors of SGLT WO-2009035969.19-MAR-2009 ( 10-SEP-2007 ) . . Process; Product (derivative) Abdel-Magid, Ahmed F.; Chisholm, Maureen; Mehrman, Steven; Scott, Lorraine; Wells, Kenneth M.; Zhang-Plasket, Fan; Nomura, Sumihiro; Hongu, Mitsuya; Koga, Yuichi Mitsubishi Tanabe Pharma Corp [Mitsubishi Chemical Holdings Corp] (Patent Assignee/Owner) Crystalline form of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate WO-2008069327.12-JUN-2008 ( 04-DEC-2006 ) . . Product (derivative) Nomura, Sumihiro; Kawanishi, Eiji Janssen Pharmaceutica NV [Johnson & Johnson] (Patent Assignee/Owner); Tanabe Seiyaku Co Ltd [Mitsubishi Chemical Holdings Corp] (Patent Assignee/Owner) Substituted indazole-O-glucosides WO-2005011592.10-FEB-2005 ( 01-AUG-2003 ) . . Product Patel, Mona; Rybczynski, Philip; Urbanski, Maud; Zhang, Xiaoyan |
7樓2013-04-02 15:15:45
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小木蟲: 金幣+0.5, 給個紅包，謝謝回帖
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謝謝樓主！ http://www.forbes.com/sites/mela ... pproved-by-the-fda/ Some financial commentators cited Invokana’s “first-in-class” status as a reason to expect high sales. According to a compilation by Thomsen Reuters, market analysts estimated Invokana’s potential sales at 416 billion by 2016. |
8樓2013-04-02 18:05:11
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niebiao2008: 金幣+1, 歡迎交流 2013-04-03 08:04:40
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Pharmaproject 顯示在很多國家還在III期臨床階段： Main Details Drug Name World Status Pharma Status canagliflozin Phase III Clinical Trial Active canagliflozin (capsule) canagliflozin (liquid suspension) canagliflozin (tablet) JNJ-24831754-ZAE JNJ-24831754-ZAE (capsule) JNJ-24831754-ZAE (liquid suspension) JNJ-24831754-ZAE (tablet) JNJ-28431754 JNJ-28431754 (capsule) JNJ-28431754 (liquid suspension) JNJ-28431754 (tablet) JNJ-28431754-AAA JNJ-28431754-AAA (capsule) JNJ-28431754-AAA (liquid suspension) JNJ-28431754-AAA (tablet) TA-7284 TA-7284 (capsule) TA-7284 (liquid suspension) TA-7284 (tablet) Latest Change Updated On By Latest Change 8 Feb 2012 PP183 Consideration for development in combination with MTP-513 and enrollment details of Phase III trials TA-7284-05 & TA-7284-06 reported Company Status Data Originator Country Development Stage Mitsubishi Tanabe Pharma Japan Phase III Clinical Trial Licensee Johnson & Johnson USA Phase III Clinical Trial Activity Data Therapy Description Code Therapy Status Antidiabetic A10B Phase III Clinical Trial Anorectic/Antiobesity A8A3 Phase II Clinical Trial Pharmacology Description Code Sodium/glucose cotransporter 2 inhibitor TRN-NAG2- Therapy Code Pharmacology Code A10B A8A3 TRN-NAG2- TRN-NAG2- Route of Administration Route of Administration Code Alimentary, po A-PO Indication Indication Status Diabetes, Type 2 Phase III Clinical Trial Obesity Phase II Clinical Trial Target Data Target Name LocusLink/Entrez Gene ID solute carrier family 5 (sodium/glucose cotransporter), member 2 6524 Target Family Group(s) Transporter > Porters (uni-, sym- and anti-) Chemical Data Origin of Material Code Description CH-SY Chemical, synthetic CAS Registry Number Rotatable Bonds Molecular Formula 842133-18-0 928672-86-0 9 C48H52F2O11S2 Hydrogen Bond Acceptors Hydrogen Bond Donors AlogP Molecular Weight 7 4 3.74 444.52 Chemical Name D-Glucitol, 1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-, hydrate (2:1), (1S)- Structure New Chemical Entity Yes Patent Data Country Number Priority Country Priority Date EP 850948 JP 26 December 1996 Country Data Country Name Country Status Year Launched Licensing Op. Argentina Phase III Clinical Trial No Australia Phase III Clinical Trial No Austria - No Belgium Phase III Clinical Trial No Brazil Phase III Clinical Trial No Canada Phase III Clinical Trial No Chile - No China - Unknown Colombia Phase III Clinical Trial No Denmark Phase III Clinical Trial No Finland Phase III Clinical Trial No France Phase III Clinical Trial No Germany Phase III Clinical Trial No Greece Phase III Clinical Trial No Hong Kong Phase III Clinical Trial Unknown India Phase III Clinical Trial Unknown Ireland - No Israel Phase III Clinical Trial No Italy - No Japan Phase III Clinical Trial Unknown Luxembourg Phase III Clinical Trial No Malaysia Phase III Clinical Trial Unknown Mexico Phase III Clinical Trial No Netherlands Phase III Clinical Trial No New Zealand Phase III Clinical Trial No Norway Phase III Clinical Trial No Peru Phase III Clinical Trial No Philippines Phase III Clinical Trial Unknown Portugal Phase III Clinical Trial No Russian Federation Phase III Clinical Trial No South Africa Phase III Clinical Trial No South Korea Phase III Clinical Trial Unknown Spain Phase III Clinical Trial No Sweden Phase III Clinical Trial No Switzerland - No Thailand Phase III Clinical Trial Unknown Turkey Phase III Clinical Trial No UK Phase III Clinical Trial No USA Phase III Clinical Trial No Venezuela - No Major Events Event Date Act/Est Event Details 25 Sep 2009 Est Change in Status Phase III Clinical Trial 15 Jul 2009 Act New Chemical Structure New 7 May 2008 Est Change in Status Phase II Clinical Trial 12 Jun 2007 Act New Indication Obesity 12 Jun 2007 Act Development Continuing 16 Aug 2006 Act No Development Reported 1 Apr 2005 Act New Product in Pharmaprojects Ratings Novelty Market Size Speed Total 2nd, 3rd or 4th Compound (5) US$ 2001-5000 million (3) Faster than Average (4) 12 Detailed Information Canagliflozin (TA-7284) is a sodium/glucose cotransporter 2 (SGLT2) inhibitor, under development by Mitsubishi Tanabe Pharma (Tanabe Seiyaku before the merger) for the treatment of obesity and Type 2 diabetes (Press release, Tanabe, 8 Jun 2007; Company Web Page, Mitsubishi Tanabe, 1 Nov 2007). It inhibits glucose reabsorption by interfering with sodium glucose transport in renal tubules, resulting in increased glucose excretion in urine. MTP may consider developing a combination drug with MTP-513 (teneligliptin) (FY2011 3rd Quarter Business Results (Apr - Dec 2011), Mitsubishi Tanabe Pharma, 31 Jan 2012, Slide 9 of PDF, http://www.mt-pharma.co.jp/e/ir/ ... resen120131_K.pdf). Marketing Approvals ________________ Diabetes, Type 2 Mitsubishi Tanabe Pharma Japan; approval is expected before 2015 (R&D Meeting, Mitsubishi, 1 Dec 2010, Slide 5, http://www.mt-pharma.co.jp/e/ir/meeting/pdf/e_presen101201.pdf). Filings ________________ Diabetes, Type 2 Mitsubishi Tanabe Pharma China; filing planned by 2013 (Company presentation, J&J, 4 Jun 2009). India; a filing is planned by 2013 (Company presentation, J&J, 4 Jun 2009). Japan; an NDA filing is planned (BIO 2011 (Washington, DC)). Diabetes, Type 2 Johnson & Johnson EU; a filing is expected in the 1st half of 2012 (Company presentation, J&J, 24 Jan 2011, Page 65, http://files.shareholder.com/dow ... 0Presentation.pdf). USA; a filing is expected in the 1st half of 2012 (Company presentation, J&J, 24 Jan 2011, Page 65, http://files.shareholder.com/dow ... 0Presentation.pdf). Clinical Phase III Diabetes, Type 2 Johnson & Johnson A 26wk randomized, double-blind, placebo-controlled, 3-arm, parallel-group Phase III trial (CR017008) with a 26wk extension in 240 subjects with Type 2 diabetes mellitus who have moderate renal impairment in Australia, Belgium, Brazil, Canada, France, Germany, India, Korea, Latvia, Malaysia, Mexico, New Zealand, Poland, Romania, Russia, S Africa, Spain and the US, to evaluate canagliflozin 100 or 300mg once-daily on efficacy, safety and tolerability is ongoing, but not recruiting participants (ClinicalTrials.gov, 20 Oct 2010 & 2 Dec 2011, http://clinicaltrials.gov/ct2/show/NCT01064414). A 18wk, randomized, double-blind, placebo-controlled, parallel-group Phase III trial (CR018541; 28431754DIA3014) in 642 subjects with Type 2 diabetes with inadequate glycaemic control on metformin alone or in combination with a sulphonylurea in China and Malaysia, to evaluate canagliflozin 100 or 300mg po capsule on efficacy, safety, and tolerability is planned (ClinicalTrials.gov, 29 Jun 2011, http://clinicaltrials.gov/show/NCT01381900). It is in a randomized, double-blind, placebo-controlled, 3-arm, parallel-group Phase III trial (CANTATA-MP) in 344 Type 2 diabetes patients with inadequate glycaemic control on metformin and pioglitazone therapy in Brazil, Canada, Finland, France, Germany, Greece, India, Mexico, Portugal, Spain, Thailand, the UK and the US, to evaluate canagliflozin 100 or 300mg capsule once-daily x52wk with stable doses of metformin and pioglitazone on efficacy, safety and tolerability is ongoing, but not recruiting participants (ClinicalTrials.gov, 20 Oct 2010 & 16 Jun 2011, http://clinicaltrials.gov/ct2/show/NCT01106690). A randomized, double-blind, placebo and active-controlled, 4-arm, parallel-group Phase III trial (CANTATA-D) in 1284 subjects with Type 2 diabetes with inadequate glycaemic control on metformin monotherapy in Argentina, Brazil, Bulgaria, Czech Republic, Estonia, Greece, India, Latvia, Malaysia, Mexico, Peru, Poland, Portugal, Puerto Rico, Russia, Singapore, Slovakia, Thailand, Turkey, Ukraine and the US, to evaluate canagliflozin 100 or 300mg capsule once-daily x52wk compared to sitaliptin 100mg capsule once-daily x52wk on efficacy, safety and tolerability is ongoing, but not recruiting participants (ClinicalTrials.gov, 20 Oct 2010 & 6 Jun 2011, http://clinicaltrials.gov/ct2/show/NCT01106677). A randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase III trial (CR017014) in 716 older subjects with Type 2 diabetes inadequately controlled on glucose lowering therapy in Australia, Brazil, Canada, Colombia, France, Greece, Hong Kong, India, New Zealand, Poland, S Africa, Spain, Ukraine and the US, to evaluate canagliflozin 100 or 300mg capsules once-daily x104wk on efficacy, safety and tolerability is ongoing, but not recruiting participants (ClinicalTrials.gov, 20 Oct 2010 & 24 May 2011, http://clinicaltrials.gov/ct2/show/NCT01106651). A randomized, multicenter, double-blind, parallel, placebo-controlled Phase III trial (CANVAS) sponsored by Johnson & Johnson in collaboration with George Institute, Australia in 4329 adult subjects with Type 2 diabetes in Argentina, Australia, Belgium, Brazil, Canada, Czech Republic, Estonia, France, Germany, Hungary, India, Israel, Luxembourg, Malaysia, Mexico, the Netherlands, New Zealand, Norway, Poland, Russia, Spain, Sweden, Ukraine, the UK and the US, to assess the effects of canagliflozin 100 or 300mg once-daily x4yr on cardiovascular outcomes is ongoing, but not recruiting participants (ClinicalTrials.gov, 20 Oct 2010 & 11 Apr 2011, http://clinicaltrials.gov/ct2/show/NCT01032629). A randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase III trial (CANTATA-M) in 680 Type 2 diabetics inadequately controlled with diet and exercise in Costa Rica, Estonia, Guatemala, India, Korea, Lithuania, Malaysia, Mexico, Philippines, Poland, Puerto Rico, Romania, S Africa, Spain, Sweden and the US, to assess canagliflozin 100 or 300mg capsule once-daily x26 or 52wk on efficacy, safety and tolerability is ongoing, but not recruiting participants (ClinicalTrials.gov, 20 Oct 2010 & 8 Mar 2011, http://clinicaltrials.gov/ct2/show/NCT01081834). A randomized, double-blind, placebo-controlled, 3-arm, parallel-group, multicentre Phase III (CANTATA-MSU) trial in 420 subjects with Type 2 diabetics with inadequate glycaemic control on metformin and sulphonylurea therapy in Australia, Belgium, France, Guatemala, Hungary, Israel, Mexico, Puerto Rico, Russia, Spain, the UK and the US, to assess canagliflozin 100 or 300mg capsule once-daily x52wk with protocol-specified doses of metformin and sulphonylurea on efficacy, safety and tolerability, is ongoing, but not recruiting participants (ClinicalTrials.gov, 20 Oct 2010 & 14 Feb 2011, http://clinicaltrials.gov/ct2/show/NCT01106625). A 2yr, randomized, double-blind, 3-arm, parallel-group, multicenter Phase III trial (CANTATA-SU) in 1455 Type 2 diabetics not optimally controlled on metformin, to compare canagliflozin 100 or 300mg once-daily to glimepiride 1mg increased to 6 or 8mg once-daily on efficacy, safety, and tolerability, change in Hb1Ac and % change in body weight at 52wk is ongoing, but not recruiting participants (ClinicalTrials.gov, 5 Mar 2010 & 27 Jan 2011, http://clinicaltrials.gov/ct2/show/NCT00968812). It is in a randomized, double-blind, active-controlled, multicenter Phase III trial (CANTATA-D2) in 720 subjects with Type 2 diabetes mellitus with inadequate glycaemic control on metformin and sulphonylurea therapy in Belgium, Brazil, Canada, Denmark, France, Germany, India, Israel, Korea, Malaysia, the Netherlands, New Zealand, Ukraine and the US, to evaluate canagliflozin 300mg capsule once-daily x52wk compared to sitagliptin 100mg capsule once-daily x52wk on efficacy, safety and tolerability (ClinicalTrials.gov, 20 Oct 2010, http://clinicaltrials.gov/ct2/show/NCT01137812). Diabetes, Type 2 Mitsubishi Tanabe Pharma A Japanese open-label Phase III trial (TA-7284-06) in 1200 subjects with Type 2 diabetes mellitus, to evaluate the long-term safety, tolerability and efficacy of TA-7284 is ongoing, but not recruiting participants (ClinicalTrials.gov, 11 Jul 2011 & 8 Feb 2012, http://clinicaltrials.gov/show/NCT01387737). A Japanese randomized, double-blind, placebo-controlled, parallel-group Phase III trial (TA-7284-05) in 240 subjects with Type 2 diabetes, to evaluate TA-7284 po low or high dose as monotherapy x24wk on efficacy, safety and tolerability is ongoing, but not recruiting participants (ClinicalTrials.gov, 13 Aug 2011 & 7 Feb 2012, http://clinicaltrials.gov/show/NCT01413204). Phase II Diabetes, Type 2 Johnson & Johnson A randomized, double-blind, placebo-controlled, 3-arm, parallel-group Phase II trial (CR017914) in 270 subjects with Type 2 diabetes with inadequate glycaemic control on metformin, to assess canagliflozin 50, 150mg bid po capsule on efficacy, safety and tolerability is ongoing, but not recruiting participants (ClinicalTrials.gov, 25 Apr 2011, & 13 Jan 2012, http://clinicaltrials.gov/ct2/show/NCT01340664). In a double-blind, multiple-dose trial in 97 Type 2 diabetics on an isocaloric diet after stopping anti-hyperglycaemic medications for 2wk, canagliflozin 30, 100, 200, 400mg once-daily and 300mg bid x2wk showed 69, 76, 88, 113 and 88g mean 24hr urinary glucose excretion from day -1 to 16, respectively compared to -10g on placebo. The mean 24hr renal threshold for glucose excretion at day -1 and 16 were 259, 243, 247, 261 and 240mg/dl and 152, 116, 101, 90 and 90mg/dl on the 30, 100, 200, 400mg once-daily and 300mg bid doses compared to 241 and 232mg/dl on placebo, respectively. The mean 24hr plasma glucose at day -1 were 223, 212, 221, 242 and 206 mg/dl on the respective doses compared to 223mg/dl on placebo. The mean 24hr plasma glucose at day -1 to day 16 were -23, -47, -56.8, -64.2 and -55mg/dl on the doses compared to -18mg/dl on placebo. The fasting plasma glucose at day -1 were 199, 205, 208, 208 and 199mg/dl on the doses compared to 210mg/dl on placebo. The mean fasting plasma glucose at day -1 to day 16 were -20, -54, -65, -60 and -66mg/dl on the doses compared to -26mg/dl on placebo. Adverse events were transient, mild-to-moderate in intensity, and balanced across groups. One episode of vaginal candidiasis occurred in a canagliflozin treated subject. It reduced weight, was well tolerated and did not cause hypoglycaemia, consistent with the renal threshold with canagliflozin remaining above the hypoglycaemic threshold. Urine volume, electrolyte excretion, renal function, and lab safety values did not change meaningfully (69th Meet Am Diabetes Assoc (New Orleans), 2009, Abs 511-P; 70th Meet Am Diabetes Assoc (Orlando), 2010, Abs 568-P, http://professional.diabetes.org ... P=1&CID=79516). In a double-blind, placebo-controlled, dose-ranging trial in Type 2 diabetes with inadequate glycaemic control on metformin, canagliflozin 50, 100, 200, 300mg once-daily or 300mg bid x12wk was well tolerated and showed -16.2, -25.2, -32.4, -32.4 and -30.6mg/dl and -0.45, -0.51, -0.54, -0.71 and -0.73% change from baseline in fasting plasma glucose and A1C, with maximum and similar decreases observed at 300mg once-daily and bid doses compared to -18mg/dl and -0.56% on sitagliptin 100mg once-daily, respectively. Significant, dose-related weight reductions of -1.3, -1.5, -1.6, -2.3 and -2.3kg were observed across the canagliflozin arms but not with sitagliptin. Adverse events were transient, mild-to-moderate in intensity, and balanced across arms except for a non dose-dependent increase in symptomatic genital infections of 3-8% on canagliflozin arms, 2% on placebo and 2% on sitagliptin. 3-9% urinary tract infections were reported on canagliflozin arms, without dose-dependency compared to 6 and 2% on placebo and sitagliptin, respectively. 0-6% hypoglycaemia was reported on canagliflozin arms, without dose-dependency compared to 2 and 5% on placebo and sitagliptin, respectively. In canagliflozin arms, no safety signals in laboratory studies, ECG, or vital signs were observed (70th Meet Am Diabetes Assoc (Orlando), 2010, Abs 0077-OR, http://ww2.aievolution.com/ada10 ... Abs&abs=12778). It is in a randomized, double-blind, placebo-controlled, dose-ranging Phase II trial in 420 Type 2 diabetics aged 18-65yr, conducted by J&J, to evaluate the safety, efficacy and tolerability of canagliflozin 50, 100 and 500mg vs sitagliptin phosphate (ClinicalTrials.gov, 31 Mar 2008, http://clinicaltrials.gov/ct2/show/NCT00642278; Scrip Daily Online, 4 Nov 2008, S01012738). Diabetes, Type 2 Mitsubishi Tanabe Pharma A Japanese randomized, double-blind, placebo-controlled, parallel-group, dose-ranging Phase II (TA-7284-04) trial in 375 Type 2 diabetes patients, to evaluate TA-728 po on efficacy, safety, and tolerability was completed (ClinicalTrials.gov 2 Dec 2009 & 8 Jun 2011, http://clinicaltrials.gov/ct2/show/NCT01022112). An earlier Phase I/II trial in 60 Japanese patients with Type 2 diabetes was completed (ClinicalTrials.gov, 2 Jul 2009, http://clinicaltrials.gov/ct2/show/NCT00707954). Obesity Johnson & Johnson In a double-blind, ascending multiple-dose 14-day trial in 80 obese male and female subjects with a fixed weight-maintaining diet x15 days prior dosing and thought out the trial, canagliflozin 30, 100, 300, 600mg once-daily and 300mg bid showed 9, 33, 47, 50 and 61g increase in 24hr urinary glucose excretion on days 1-14, respectively compared to 0.1g on placebo. There were no meaningful changes in FPG, mean 24hr plasma glucose or insulin levels. -2.9, -2.7, -2.1, -3.4 and -3.5kg change in body weight were observed on 30, 100, 300, 600mg once-daily and 300mg bid doses, respectively compared to -1.4kg on placebo. There were no meaningful changes in self-reported appetite and satiety measures. The renal threshold (RT) for glucose excretion decreased in a dose-dependent manner with maximal effect on lowering of the RT to 64mg/dl. The 100mg dose provided near-maximal lowering of RT during the first 13hr post dosing. The 300mg bid and 600mg once-daily doses provided near-maximal lowering over the 24hr period. It was well tolerated, with no hypoglycaemia. Adverse events were transient and mild-to-moderate in severity. One woman in the 300mg bid arm experienced an asymptomatic urinary tract infection post-treatment. There were no clinically meaningful changes in urine volume or frequency, vital signs, ECGs, or laboratory tests (70th Meet Am Diabetes Assoc (Orlando), 2010, Abs 567-P, http://professional.diabetes.org ... P=1&CID=79515). Obesity Johnson & Johnson; Mitsubishi Tanabe Pharma Phase II trials for obesity in the EU and the US were completed (Company presentation, Mitsubishi, 14 May 2010, Slide 5, http://www.mt-pharma.co.jp/e/ir/meeting/pdf/e_presen100514_M.pdf; Company pipeline, Mitsubishi, 29 Oct 2010, Page 3, http://www.mt-pharma.co.jp/e/dev ... _pipeline1009.pdf). Phase I Johnson & Johnson An open-label, fixed-sequence Phase I trial (CR018736) in 14 healthy subjects, to assess the effects of multiple-dose probenecid on the multiple-dose pharmacokinetics of canagliflozin 300mg tablet po once-daily on days 1-14 and on days 15-17 was completed (ClinicalTrials.gov, 8 Sep & 30 Dec 2011, http://clinicaltrials.gov/show/NCT01428284). A randomized, open-label, parallel-group Phase I trial (CR017695) in 27 healthy subjects in Belgium, to assess the single and multiple dose pharmacokinetic and pharmacodynamic characteristics of canagliflozin 50, 100 and 300mg po tablet once-daily on day 1 and on days 4-9 was completed (ClinicalTrials.gov, 7 Mar & 29 Dec 2011, http://clinicaltrials.gov/ct2/show/NCT01281579). A US single-dose, open-label, randomized, 2-period, 2-sequence, crossover Phase I trial (CR018016; 284317541043) in 24 healthy subjects, to assess the effect of food coadministration on the pharmacokinetics of canagliflozin 300mg po tablet with or without a meal was completed (ClinicalTrials.gov, 2 Nov 2011, http://clinicaltrials.gov/ct2/show/NCT01343290). A US non-randomized, open-label, fixed-sequence Phase I trial (CR018604; 28431754DIA1029) in 14 healthy subjects, to assess the effects of steady-state rifampin on the single dose pharmacokinetics of canagliflozin 300mg tablet on day 1 and 10 was completed (ClinicalTrials.gov, 28 Oct 2011, http://clinicaltrials.gov/ct2/show/NCT01395927). A randomized, double-blind, placebo-controlled, 2-period, crossover US Phase I trial (CR017224; 28431754DIA1022) in 26 healthy subjects, to evaluate the effect of a single dose of canagliflozin in period 1 followed by single dose of placebo in period 2 and then crossover to 1 dose of placebo in period 1 followed by 1 dose of canagliflozin in period 2 on gastrointestinal glucose absorption and metabolism was completed (ClinicalTrials.gov, 24 Jan 2011 & 21 Oct 2011, http://clinicaltrials.gov/ct2/show/NCT01173549). A randomized, open-label, single-dose, 3-period, crossover Phase I trial (CR018277) in 24 healthy subjects in Belgium, to evaluate the pharmacokinetic dose proportionality of canagliflozin 50, 100 and 300mg po tablet under fasted conditions was completed (ClinicalTrials.gov, 6 Jun & 15 Sep 2011, http://clinicaltrials.gov/ct2/show/NCT01340677). An open-label, 2-period, fixed-sequence Phase I trial (CR017851; 28431754DIA1034) in 30 healthy subjects in Belgium, to explore the effects of multiple doses of hydrochlorothiazide 25mg po tablet once-daily x28 days followed by multiple doses of canagliflozin 300mg tablet once-daily x7 days on the pharmacodynamics, pharmacokinetics and safety was completed (ClilnicalTrials.gov, 7 Apr & 23 Jul 2011, http://clinicaltrials.gov/ct2/show/NCT01294631). An open-label, multiple-dose US Phase I trial (CR017824) in 34 healthy subjects, to assess canagliflozin 100 and 300mg once-daily compared to 50 and 150mg bid on steady-state pharmacokinetics, pharmacodynamics and safety was completed (ClinicalTrials.gov, 7 Mar & 13 Jun 2011, http://clinicaltrials.gov/ct2/show/NCT01286103). An open-label, fixed sequence Phase I trial (CR017815) in 18 healthy subjects, to assess the pharmacokinetic and pharmacodynamic interaction between single-dose metformin 1000mg tablet bid on day 1 and multiple-dose canagliflozin 300mg tablet once-daily on days 4-8 was completed (ClinicalTrials.gov, 12 Jan & 26 Feb 2011, http://clinicaltrials.gov/ct2/show/NCT01273571). An open-label drug interaction Phase I trial (CR017440) in 14 healthy male and female subjects, to assess the pharmacokinetics and pharmacodynamics of warfarin po 30mg on when administered alone and in combination with multiple-dose canagliflozin po 300mg tablet once-daily was completed (ClinicalTrials.gov, 2 Nov & 29 Dec 2010, http://clinicaltrials.gov/ct2/show/NCT01195324). It is in a US open-label Phase I trial (CR017227) in 24 subjects with various degrees of impaired hepatic function compared with subjects of normal hepatic function, to evaluate the pharmacokinetics of a single dose of canagliflozin po 300mg (ClinicalTrials.gov, 15 Oct 2010, http://clinicaltrials.gov/ct2/show/NCT01186588). A first-in-human Phase I trial in 71 healthy male subjects , to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of single-escalating canagliflozin po doses was completed (ClinicalTrials.gov, 13 Aug 2010, http://clinicaltrials.gov/ct2/show/NCT01177150). In a randomized, double-blind, double-dummy, placebo-and positive-controlled 4-way crossover study in 60 healthy adults, canagliflozin demonstrated that the change from baseline in QT interval corrected for heart rate ( QTcP) varied from -2.1ms 30min post dose to 0.5ms 3hr post dose on 300mg and -3.9ms 2hr post dose to -0.7ms 24hr post dose on 1200mg. The upper limits of the 2-sided 90% clearance for the difference in mean QTcP between canagliflozin and placebo were <10ms at each timepoint and for each canagliflozin dose, establishing noninferiority of the effect on QTc of both doses compared to placebo. The mean QTcP difference of moxifloxacin versus placebo was >10ms from 1-4hr post dose and assay sensitivity was established. At the mean maximum canagliflozin concentration, the predicted mean difference in QTcP between canagliflozin and placebo with 90% clearance was -1.3 on 300mg and -3.4 on 1200mg. It was generally well tolerated. No deaths, serious or severe adverse events or treatment-emergent hypoglycaemic episodes were reported (70th Meet Am Diabetes Assoc (Orlando), 2010, Abs 2177-PO, http://professional.diabetes.org ... P=1&CID=81073). In a double-blind, randomized, placebo-controlled, escalating-dose Phase I trial in 63 healthy adult men aged 37yr, canagliflozin liquid suspension 10, 30, 100, 200, 400, 600, 800mg once-daily or 400mg bid administered while fasting was well tolerated at all dose levels and significantly increased urinary glucose excretion in a dose-dependent fashion ranging from 5g at 10mg to a maximum mean 24hr urinary glucose excretion of 70g at doses >200mg. The renal threshold for glucose excretion decreased in a dose-dependent manner with maximal reduction to 61mg/dl. The 100 and 200 mg doses provided near-maximal suppression of renal threshold during the first 13hr after dosing, and doses >200mg provided near-maximal suppression over the 24hr period. Doses >200 mg also lowered the postprandial plasma glucose following breakfast. No hypoglycaemia was observed, and urine volume appeared not to be increased. Adverse events were transient and mild-to-moderate in intensity and were not dose-dependent. There were no clinically meaningful changes in laboratory safety tests, vital signs, or ECGs (70th Meet Am Diabetes Assoc (Orlando), 2010, Abs 0076-OR, http://ww2.aievolution.com/ada10 ... Abs&abs=12777). Diabetes, Type 2 Johnson & Johnson It is in a double-blind, placebo-controlled, randomized, parallel-group Phase I trial (CR100685; 28431754DIA1047; 2011-004117-17), to investigate the effects of canagliflozin on plasma volume and renal function in 40 subjects with Type 2 diabetes mellitus (ClinicalTrials.gov, 3 Dec 2011 & 24 Jan 2012, http://clinicaltrials.gov/ct2/show/NCT01483781). It is in an open-label, randomized, 2-way crossover, single-dose Phase I trial (TA-7284-07), to evaluate the pharmacokinetics, pharmacodynamics and safety of canagliflozin in 24 patients with Type 2 diabetes mellitus who have moderate renal impairment (ClinicalTrials.gov, 21 Jan 2012, http://clinicaltrials.gov/ct2/show/NCT01512849). A US randomized, double-blind, placebo-controlled, crossover Phase I trial (CR018373; 28431754DIA1045) in 36 Type 2 diabetes patients, to evaluate the effect of canagliflozin 300mg po capsule on post-meal glucose levels was completed (ClinicalTrials.gov, 16 Aug & 7 Dec 2011, http://clinicaltrials.gov/ct2/show/NCT01381887). An open-label Phase I trial (CR017719) in 28 Type 2 diabetics in Germany, to compare two methods for determining the renal threshold for glucose with canagliflozin 100mg po capsule once-daily x8 days was completed (ClinicalTrils.gov, 7 Feb & 15 Sep 2011, http://clinicaltrials.gov/ct2/show/NCT01273558). A randomized, double-blind, placebo-controlled, parallel-group Phase I trial (CR014881) in 29 Type 2 diabetes patients not optimally controlled on fixed doses of insulin therapy, to evaluate canagliflozin 100mg once-daily or 300mg bid capsule x4wk on safety, tolerability, pharmacokinetics and pharmacodynamics was completed (ClinicalTrials.gov, 13 Aug 2010, http://clinicaltrials.gov/ct2/show/NCT01177163). Results showed -0.73 and -0.92% A1C change from baseline on 100 and 300mg doses compared to -0.19% on placebo. -38.1 and -42.4mg/dl fasting plasma glucose (FPG) change from baseline was observed on the 100 and 300mg doses compared to 8.7mg/dl on placebo. 71.9 and 125.2g/day urinary glucose excretion (UGE) change from baseline was observed on the dose groups compared to -3.2g/day on placebo. -0.7 and -1.2kg body weight change from baseline was observed on the dose groups compared to 0 on placebo. A trend for blood pressure decrease was observed in canagliflozin-treated subjects. Canagliflozin AUC and Cmax increased with increasing dose and the mean t1/2 ranged from 12-15hr and was independent of dose. Plasma canagliflozin concentrations achieved steady-state within 7 days of dosing. No deaths or serious adverse events were observed. The incidence of treatment-emergent adverse events was similar across groups. There were no treatment-emergent adverse events related to urinary tract or genital infections. Overall, 12 subjects experienced > or =1 non severe hypoglycaemic episode. There were no severe hypoglycaemic events or discontinuations due to hypoglycaemia. There were no clinically meaningful changes in routine laboratory safety tests, vital signs, or ECGs (70th Meet Am Diabetes Assoc (Orlando), 2010, Abs 564-P, http://professional.diabetes.org ... P=1&CID=79512). A randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase I trial in 39 patients with Type 2 diabetes, to assess canagliflozin 50, 100 and 300mg po once-daily x7 days on pharmacokinetic and pharmacodynamic characteristics was completed (ClinicalTrials.gov, 27 Jul 2010, http://clinicaltrials.gov/ct2/show/NCT01128985). Preclinical in vivo In diabetic mice and rats, and in obese dogs, it dose-dependently increased urinary glucose excretion, with a minimum effective dose (MED) of 0.3-1.0mg/kg (69th Meet Am Diabetes Assoc (New Orleans), 2009, Abs 534-P). In normal mice, Zucker diabetic fatty rats and obese dogs, single-dose canagliflozin po before an oral glucose chanllenge significantly increased urinary glucose excretion and urine volume, with a resulting significant decrease in blood glucose during oral glucose tolerance tests. In diabetic mice and rats, canagliflozin x4wk lowered fed and fasting blood glucose levels and HbA1c, with a MED of 0.3-1.0mg/kg. It also improved β-cell function as reflected in increased plasma insulin levels. There was no hyperglycaemia (69th Meet Am Diabetes Assoc (New Orleans), 2009, Abs 534-P). In a 4wk study in ob/ob mice, diet-induced obese mice or Zucker fatty rats, there was a signifcant reduction in body weight and decrease in food efficiency. It also resulted in a significant reduction in plasma free fatty acid levels and a significant decrease in respiratory exchange ratio and a marked increase of oxygen consumption (69th Meet Am Diabetes Assoc (New Orleans), 2009, Abs 534-P). It was well tolerated, without associated hypoglycaemia or weight gain and demonstrated potential for weight loss (Company presentation, J&J, 7 Jun 2007). It showed positive proof-of-concept. In a Type 2 diabetes rat model, canagliflozin administered at 7wk of age x32wk significantly decreased both blood glucose and haemoglobin levels and partially ameliorated oral glucose tolerance. Insulin resistance was reversed and there was a reduction of the thermal response in tail-flick testing following long-term hyperglycaemia. There was a significant prevention in the development of diabetic neuropathy (J Life Sci, 2005, 76, 2655). In vitro Further C-glucosides with a thiophene ring have been synthesized with increased stability (238th ACS (Washington, DC), 2009, MEDI 151). In cells overexpressing human SGLT2, it was 200x less potent on human SGL1 inhibition than on SGLT2, with an IC50 910nM. At 10μM, it did not interact with human SGLT3 or rat GLUT1 (69th Meet Am Diabetes Assoc (New Orleans), 2009, Abs 534-P). Licensing Agreements ________________ Johnson & Johnson Worldwide except Asia; Johnson & Johnson (J&J) licensed exclusive worldwide development rights, excluding Japan and certain other Asian countries, for a series of SGLT-2 inibitors, including canagliflozin and an earlier compound T-1095 (Scrip Daily Online, 20 Jul 2000, S00673350). |
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