TTP399: an investigational liver-selective glucokinase (GK) activator as a potential treatment for type 2 diabetes

References

• Ogurtsova K, Da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017 Jun;128:40–50. PubMed PMID: 28437734.
   PubMed Web of Science ®Google Scholar
• American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2019. Diabetes Care. 2019 Jan;42(Suppl 1):S13–S28. PubMed PMID: 30559228.
   PubMed Web of Science ®Google Scholar
• Adams JD, Vella A. What can diabetes-associated genetic variation in TCF7L2 teach us about the pathogenesis of type 2 diabetes? Metab Syndr Relat Disord. 2018 Oct;16(8):383–389. PubMed PMID: 29993315; PubMed Central PMCID: PMCPMC6167616.
   PubMed Web of Science ®Google Scholar
• Turner RC, Holman RR, Stratton IM, et al. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK prospective diabetes study (UKPDS) group. Lancet. 1998 Sep 12;352(9131):854–865. PubMed PMID: 9742977.
   PubMed Web of Science ®Google Scholar
• Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981 Dec;68(6):1456–1467. PubMed PMID: 7033284; PubMed Central PMCID: PMCPMC370948.
   PubMed Web of Science ®Google Scholar
• Shah P, Basu A, Basu R, et al. Impact of lack of suppression of glucagon on glucose tolerance in humans. Am J Physiol. 1999 Aug;277(2):E283–90. PubMed PMID: 10444424.
   PubMedGoogle Scholar
• Shah P, Vella A, Basu A, et al. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000 Nov;85(11):4053–4059. PubMed PMID: 11095432.
   PubMed Web of Science ®Google Scholar
• Smushkin G, Vella A. Genetics of type 2 diabetes. Curr Opin Clin Nutr Metab Care. 2010 Jul;13(4):471–477. . PubMed PMID: 20473152; PubMed Central PMCID: PMCPMC2953639.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. New hope for glucokinase activators in type 2 diabetes? Lancet Diabetes Endocrinol. 2018 Aug;6(8):591–593. PubMed PMID: 29735393.
   PubMed Web of Science ®Google Scholar
• Nakamura A, Terauchi Y. Present status of clinical deployment of glucokinase activators. J Diabetes Investig. 2015 Mar;6(2):124–132. PubMed PMID: 25802718; PubMed Central PMCID: PMCPMC4364845.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Investigational insulin secretagogues for type 2 diabetes. Expert Opin Investig Drugs. 2016;25(4):405–422. PubMed PMID: 26881467
   PubMed Web of Science ®Google Scholar
• Zhu D, Gan S, Liu Y, et al. Dorzagliatin monotherapy in Chinese patients with type 2 diabetes: a dose-ranging, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Diabetes Endocrinol. 2018 Aug;6(8):627–636. PubMed PMID: 29735394.
   PubMed Web of Science ®Google Scholar
• Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J. 2008 Aug 15;414(1):1–18. PubMed PMID: 18651836.
   PubMedGoogle Scholar
• Peter A, Stefan N, Cegan A, et al. Hepatic glucokinase expression is associated with lipogenesis and fatty liver in humans. J Clin Endocrinol Metab. 2011 Jul;96(7):E1126–30. PubMed PMID: 21490074.
   PubMed Web of Science ®Google Scholar
• Shiota C, Coffey J, Grimsby J, et al. Nuclear import of hepatic glucokinase depends upon glucokinase regulatory protein, whereas export is due to a nuclear export signal sequence in glucokinase. J Biol Chem. 1999 Dec 24;274(52):37125–37130. PubMed PMID: 10601273.
   PubMed Web of Science ®Google Scholar
• Sparso T, Andersen G, Nielsen T, et al. The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes. Diabetologia. 2008 Jan;51(1):70–75. PubMed PMID: 18008060.
   PubMed Web of Science ®Google Scholar
• Beer NL, Tribble ND, McCulloch LJ, et al. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet. 2009 Nov 1;18(21):4081–4088. PubMed PMID: 19643913; PubMed Central PMCID: PMCPMC2758140.
   PubMed Web of Science ®Google Scholar
• Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998 Jan 22;338(4):226–230. PubMed PMID: 9435328.
   PubMed Web of Science ®Google Scholar
• Byrne MM, Sturis J, Clement K, et al. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest. 1994 Mar;93(3):1120–1130. PubMed PMID: 8132752; PubMed Central PMCID: PMCPMC294056.
   PubMed Web of Science ®Google Scholar
• Basu A, Basu R, Shah P, et al. Type 2 diabetes impairs splanchnic uptake of glucose but does not alter intestinal glucose absorption during enteral glucose feeding: additional evidence for a defect in hepatic glucokinase activity. Diabetes. 2001 Jun;50(6):1351–1362. PubMed PMID: 11375336.
   PubMed Web of Science ®Google Scholar
• Basu A, Basu R, Shah P, et al. Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism: evidence for a defect in hepatic glucokinase activity. Diabetes. 2000 Feb;49(2):272–283. PubMed PMID: 10868944.
   PubMed Web of Science ®Google Scholar
• Haeusler RA, Camastra S, Astiarraga B, et al. Decreased expression of hepatic glucokinase in type 2 diabetes. Mol Metab. 2015 Mar;4(3):222–226. PubMed PMID: 25737948; PubMed Central PMCID: PMCPMC4338311.
   PubMed Web of Science ®Google Scholar
• Perreault L, Faerch K, Kerege AA, et al. Hepatic glucose sensing is impaired, but can be normalized, in people with impaired fasting glucose. J Clin Endocrinol Metab. 2014 Jul;99(7):E1154–62. PubMed PMID: 24731008; PubMed Central PMCID: PMCPMC4079303.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus: draft. 2018. [cited 2019 Apr 15]. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-clinical-investigation-medicinal-products-treatment-prevention-diabetes-mellitus_en.pdf
   Google Scholar
• Tahrani AA, Barnett AH, Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol. 2016 Oct;12(10):566–592. PubMed PMID: 27339889.
   PubMed Web of Science ®Google Scholar
• Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006 Dec 7;355(23):2427–2443. PubMed PMID: 17145742.
   PubMed Web of Science ®Google Scholar
• Grimsby J, Sarabu R, Corbett WL, et al. Allosteric activators of glucokinase: potential role in diabetes therapy. Science. 2003 Jul 18;301(5631):370–373. PubMed PMID: 12869762.
   PubMed Web of Science ®Google Scholar
• Sarabu R, Berthel SJ, Kester RF, et al. Novel glucokinase activators: a patent review (2008–2010). Expert Opin Ther Pat. 2011 Jan;21(1):13–33. PubMed PMID: 21155690.
   PubMed Web of Science ®Google Scholar
• Efanov AM, Barrett DG, Brenner MB, et al. A novel glucokinase activator modulates pancreatic islet and hepatocyte function. Endocrinology. 2005 Sep;146(9):3696–3701. PubMed PMID: 15919746.
   PubMed Web of Science ®Google Scholar
• Coope GJ, Atkinson AM, Allott C, et al. Predictive blood glucose lowering efficacy by Glucokinase activators in high fat fed female Zucker rats. Br J Pharmacol. 2006 Oct;149(3):328–335. PubMed PMID: 16921397; PubMed Central PMCID: PMCPMC2014270.
   PubMed Web of Science ®Google Scholar
• Futamura M, Yao J, Li X, et al. Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat. Diabetologia. 2012 Apr;55(4):1071–1080. PubMed PMID: 22234649.
   PubMed Web of Science ®Google Scholar
• Matschinsky FM. GKAs for diabetes therapy: why no clinically useful drug after two decades of trying? Trends Pharmacol Sci. 2013 Feb;34(2):90–99. . PubMed PMID: 23305809.
   PubMed Web of Science ®Google Scholar
• Bonadonna RC, Heise T, Arbet-Engels C, et al. Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study. J Clin Endocrinol Metab. 2010 Nov;95(11):5028–5036. PubMed PMID: 20739378.
   PubMed Web of Science ®Google Scholar
• Meininger GE, Scott R, Alba M, et al. Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes. Diabetes Care. 2011 Dec;34(12):2560–2566. PubMed PMID: 21994424; PubMed Central PMCID: PMCPMC3220852.
   PubMed Web of Science ®Google Scholar
• Kiyosue A, Hayashi N, Komori H, et al. Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013 Oct;15(10):923–930. PubMed PMID: 23522182.
   PubMed Web of Science ®Google Scholar
• Wilding JP, Leonsson-Zachrisson M, Wessman C, et al. Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin. Diabetes Obes Metab. 2013 Aug;15(8):750–759. PubMed PMID: 23464532.
   PubMed Web of Science ®Google Scholar
• O’Doherty RM, Lehman DL, Telemaque-Potts S, et al. Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia. Diabetes. 1999 Oct;48(10):2022–2027. PubMed PMID: 10512368.
   PubMed Web of Science ®Google Scholar
• Challis BG, Harris J, Sleigh A, et al. Familial adult onset hyperinsulinism due to an activating glucokinase mutation: Implications for pharmacological glucokinase activation. Clin Endocrinol (Oxf). 2014 Dec;81(6):855–861.
   PubMed Web of Science ®Google Scholar
• Santoro N, Zhang CK, Zhao H, et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology. 2012 Mar;55(3):781–789. PubMed PMID: 22105854; PubMed Central PMCID: PMCPMC3288435.
   PubMed Web of Science ®Google Scholar
• Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007 Jun 1;316(5829):1331–1336. PubMed PMID: 17463246.
   PubMed Web of Science ®Google Scholar
• Wang P, Liu H, Chen L, et al. Effects of a novel glucokinase activator, HMS5552, on glucose metabolism in a rat model of type 2 diabetes mellitus. J Diabetes Res. 2017;2017:5812607. PubMed PMID: 28191470; PubMed Central PMCID: PMCPMC5278194 declare that they have no conflict of interests.
   PubMedGoogle Scholar
• Xu H, Sheng L, Chen W, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study. Drug Des Devel Ther. 2016;10:1619–1626. PubMed PMID: 27274195; PubMed Central PMCID: PMCPMC4869670.
   PubMed Web of Science ®Google Scholar
• Zhu XX, Zhu DL, Li XY, et al. Dorzagliatin (HMS5552), a novel dual-acting glucokinase activator, improves glycaemic control and pancreatic beta-cell function in patients with type 2 diabetes: A 28-day treatment study using biomarker-guided patient selection. Diabetes Obes Metab. 2018 Sep;20(9):2113–2120. PubMed PMID: 29707866.
   PubMed Web of Science ®Google Scholar
• Pfefferkorn JA. Strategies for the design of hepatoselective glucokinase activators to treat type 2 diabetes. Expert Opin Drug Discov. 2013 Mar;8(3):319–330. . PubMed PMID: 23289965.
   PubMed Web of Science ®Google Scholar
• Amin NB, Aggarwal N, Pall D, et al. Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes. Diabetes Obes Metab. 2015 Aug;17(8):751–759. PubMed PMID: 25885172.
   PubMed Web of Science ®Google Scholar
• Denney WS, Denham DS, Riggs MR, et al. Glycemic effect and safety of a systemic, partial glucokinase activator, PF-04937319, in patients with type 2 diabetes mellitus inadequately controlled on metformin-a randomized, crossover, active-controlled study. Clin Pharmacol Drug Dev. 2016 Nov;5(6):517–527. PubMed PMID: 27870481.
   PubMed Web of Science ®Google Scholar
• Ramanathan V, Vachharajani N, Patel R, et al. GKM-001, a liver-directed/pancreas-sparing glucokinase modulator (GKM), lowers fasting and post-prandial glucose without hypoglycemia in type 2 diabetic (T2D) patients. Diabetes. 2012;61(S1):Abstract 76.
   Google Scholar
• Kimura T, Sakurai K, Morino K, et al. Pharmacokinetics, pharmacodynamics and tolerability of a novel glucokinase activator TMG-123, after single oral ascending doses in Japanese healthy submects (Abstract). Diabetologia. 2015;58(S1):Abstract37.
   Google Scholar
• Vella A, Freeman JLR, Dunn I, et al. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Sci Transl Med. 2019 Jan 16;11(475): DOI:10.1126/scitranslmed.aau3441. PubMed PMID: 30651321.
   PubMed Web of Science ®Google Scholar
• Valcarce C, Grimes I, Gustafson B, et al. TTP399, a liver-selective glucokinase activator (GKA), lowers glucose and does not increase lipids in subjects with type 2 diabetes mellitus (T2DM). Diabetes. 2016;63(suppl. 1):A32.
   Google Scholar
• Valcarce C, Dunn I, Freeman J. TTP399, a liver-selective glucokinase activator: Results from a 10-day pilot study in patients with type 2 diabetes mellitus (T2DM) naive to drug [abstract]. Diabetes. 2016;65(suppl. 1):A299.
   Google Scholar
• National institute of health. U.S national library of medicine. Evaluation of TTP399 in patients with type 1 diabetes (simpliciT1). [ cited 2019Aug 1] Available from: https://clinicaltrials.gov/ct2/show/NCT03335371?term=ttp399&rank=1
   Google Scholar
• Rubenstrunk A, Hanf R, Hum DW, et al. Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta. 2007 Aug;1771(8):1065–1081. PubMed PMID: 17428730.
   PubMed Web of Science ®Google Scholar
• Phung OJ, Scholle JM, Talwar M, et al. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA. 2010 Apr 14;303(14):1410–1418. PubMed PMID: 20388897.
   PubMed Web of Science ®Google Scholar
• Sharma A, Varghese RT, Shah M, et al. Impaired insulin action is associated with increased glucagon concentrations in nondiabetic humans. J Clin Endocrinol Metab. 2018 Jan 1;103(1):314–319. PubMed PMID: 29126197; PubMed Central PMCID: PMCPMC5761487.
   PubMed Web of Science ®Google Scholar