Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator

Abstract

The therapeutic success of interventions targeting glucokinase (GK) activation for the treatment of type 2 diabetes has been limited by hypoglycemia, steatohepatitis, and loss of efficacy over time. The clinical characteristics of patients with GK-activating mutations or GK regulatory protein (GKRP) loss-of-function mutations suggest that a hepatoselective GK activator (GKA) that does not activate GK in β cells or affect the GK-GKRP interaction may reduce hyperglycemia in patients with type 2 diabetes while limiting hypoglycemia and liver-associated adverse effects. Here, we review the rationale for TTP399, an oral hepatoselective GKA, and its progression from preclinical to clinical development, with an emphasis on the results of a randomized, double-blind, placebo- and active-controlled phase 2 study of TTP399 in patients with type 2 diabetes. In this 6-month study, TTP399 (800 mg/day) was associated with a clinically significant and sustained reduction in glycated hemoglobin, with a placebo-subtracted least squares mean HbA1c change from baseline of −0.9% (P < 0.01). Compared to placebo, TTP399 (800 mg/day) also increased high-density lipoprotein cholesterol (3.2 mg/dl; P < 0.05), decreased fasting plasma glucagon (−20 pg/ml; P < 0.05), and decreased weight in patients weighing ≥100 kg (−3.4 kg; P < 0.05). TTP399 did not cause hypoglycemia, had no detrimental effect on plasma lipids or liver enzymes, and did not increase blood pressure, highlighting the importance of tissue selectivity and preservation of physiological regulation when targeting key metabolic regulators such as GK.

Diabetic‑induced alterations in hepatic glucose and lipid metabolism: The role of type 1 and type 2 diabetes mellitus (Review)

“…unfortunately, the majority of the drugs that target GK activation for the treatment of T2dM have not been clinically successful due to side effects, such as hypoglycemia, steatohepatitis and loss of efficacy over time (8). However, TTP399, a hepato-elective GK activator, was assessed in a recently reported double-blind, 6-month study and it was found that TTP399 did not cause hypoglycemia and exhibited limited or no detrimental effect on plasma lipids or liver enzymes (34). Moreover, it is a liver specific GK activator without side effects of hypertension, highlighting the importance of liver selectivity when targeting GK activity (34).…”

<p>A Recent Achievement In the Discovery and Development of Novel Targets for the Treatment of Type-2 Diabetes Mellitus</p>

“…Some agents like AZD6370, piragliatin, DS-7309, and ARRY-403 also terminated their drug development due to toxicity and loose of effectiveness with long-term administration. [47][48][49][50][51] Some examples of the GK activator presented in Table 3 with their stage of development and company.…”

Efficacy and safety of glucokinase activators for type 2 diabetes mellitus therapy: A meta-analysis of double-blind randomized controlled trials

“…The study selection process is depicted in Figure 1 . Finally, seven independent, double-blind, randomized, controlled trials (a total of 762 patients) were included in the current meta-analysis 14,15,[19][20][21][22][23] . All the seven trials were of high quality with modified Jadad scores[?]…”

“…The seven trials are multi-center clinical trials, among which 3 of them 14,19,21 are transnational multicenter trials. The category of GKA is different among the 7 trials, including MK-0941 14 , AZD1656 19 , LY2599506 20 , PF-04937319 21 , RO4389620 22 , HMS5552 23 , and TTP399 15 . In addition, all these 7 studies use identification of HbA1c as a criterion for patient inclusion, and the absence of glutamic acid decarboxylation antibody at admission is used to exclude patients with type 1 diabetes.…”

“…Four included trials reported the AEs during the trial phase 14,15,19,23 , and 307 out of a total of 605 patients had at least one AE. As shown in Figure 5 , GKAs did not significantly increase the incidence of at least one AE compared with placebo (RR 1.11, 95% CI: 0.95 to 1.…”