VK0612 for Type 2 Diabetes
Overview and Profile
VK0612 is a potent, orally available, inhibitor of fructose-1,6-bisphosphatase. VK0612 has successfully completed six Phase 1 trials and a Phase 2a proof of concept study. Five of the Phase 1 trials demonstrated the safety, tolerability, and pharmacokinetic profile of VK0612 in healthy volunteers. The sixth Phase 1 trial was a Phase 1b study in patients with poorly-controlled type 2 diabetes. The Phase 1b and 2a studies demonstrated the safety and clinical proof-of-concept for inhibition of fructose-1,6-bisphosphatase as a potential therapy for type 2 diabetes.
Phase 2a Proof-of-Concept Summary
The Phase 2a proof‐of‐concept trial was conducted in patients with moderate to severe type 2 diabetes. In this trial, patients received either placebo or VK0612 (10, 50, 100 or 200 mg capsule) once-daily for 28 days. At the highest dose, a statistically significant and clinically meaningful reduction in fasting plasma glucose (FPG) from baseline was achieved on Day 28 relative to placebo (mean placebo‐adjusted change of ‐28.9 mg/dL). In the subgroup of patients with baseline FPG ≥ 180 mg/dL treated with 200 mg, the decrease in FPG was even more substantial (‐49.7 mg/dL, placebo‐adjusted). The overall incidence of treatment‐emergent adverse events during the trial was low, including GI events. Moreover, mean fasting plasma lactate levels remained within normal limits in all groups, and no sustained lacticemia (lactate >4.5 mM on two consecutive visits) was observed.
Statistically and clinically significant glucose lowering
Efficacy further improves with increasing disease severity, subjects with baseline FPG > 180 mg/dL experienced -49.7 mg/dL improvement (p = 0.0099); compares favorably to current therapies.
Phase 1b Results: Promise In Poorly-Controlled Type 2 Diabetes
Subsequent to the successful Phase 2a trial, a superior formulation was developed that provided significantly higher drug exposures relative to that used in the Phase 2a study. This formulation was evaluated in a Phase 1b study
VK0612: 14-Day Phase 1b Efficacy Results
Efficacy results include dose-related declines in FPG, clinically and statistically significant effect on FPG, promising potential HbA1c effect.
Substantial Reductions in Fasting and 24-Hour Glycemia Measures
The Phase 1b study was a 14-day, randomized, double‐blind, placebo‐controlled, ascending multiple dose trial to assess the safety, tolerability, PK, and efficacy of VK0612 in 42 patients with type 2 diabetes. Doses of 50 mg, 200 mg, and 400 mg BID compared to placebo were evaluated. After 14 days of treatment, a rapid and pronounced dose‐related decrease in FPG was observed. Despite the relatively small study size, the results demonstrated a statistically significant impact on fasting plasma glucose levels. In addition, there were substantial dose‐related decreases in 24 hour weighted mean glucose levels, with all doses achieving statistical significance.
Inhibition of FBPase: A Potent Mechanism for Glucose Control
The combined Phase 1b and Phase 2a results demonstrate that inhibition of FBPase is an effective mechanism for lowering fasting and postprandial hyperglycemia in patients with poorly-controlled Type 2 diabetes. Importantly, VK0612 was safe at all doses, with the maximum tolerated dose in Phase 1b identified as 200 mg twice daily.