Identification of adjunctive, oral pharmacotherapies to treat type 1 diabetes (T1D) has been limited by hypoglycemia and ketoacidosis. TTP399 is a liver-selective oral glucokinase activator. In type 2 diabetes (n=190), TTP399 was shown to reduce A1C vs. placebo (PL) -0.9% (p<0.01) without hypoglycemia or ketosis.

The Simplici-T1 trial (NCT03335371) is an adaptive three-part Phase 1b/2 Proof of Concept study of TTP399 as adjunctive therapy for T1D treatment. Safety, pharmacokinetics, and pharmacodynamics were established in a sentinel phase (n=5). In Part 1 (n=19), TTP399 reduced A1C (-0.7%, p=0.03), improved time in range 70-180 mg/dl (TIR; 12%, p=0.04), and reduced bolus insulin vs. PL in patients on insulin pump therapy and continuous glucose monitoring.

In Part 2 (n=85), these data were examined in a broader T1D population. Insulin dose was optimized prior to randomization and throughout the 12 wk double-blind treatment period with specified pre- and post-meal targets. Participants received TTP399 800 mg or matched PL. A1C at randomization was 7.6% (SD 0.6). TTP399 significantly reduced A1C (trial product estimand: -0.32%, 95%CI -0.50, -0.13, p<0.01; ITT: -0.20, 95%CI -0.38, -0.02, p=0.03). A responder analysis (improved A1C; without severe hypoglycemia or increase in insulin dose; nor abnormal beta-hydroxybutyrate or lactic acid) revealed 42% TTP399 responders vs. 12% PL (ITT: p<0.01, hierarchically controlled [HC]). Daytime TIR improved (ITT: 7.81%, 95%CI 0.93, 14.68, p<0.05, HC). Treatment-emergent adverse events were numerically lower with TTP399. No safety signals were identified.

These data suggest that further development of TTP399 as adjunctive therapy in T1D is warranted.


J.B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Neurimmune. Research Support; Self; American Diabetes Association, National Institutes of Health, Novo Nordisk A/S, Patient-Centered Outcomes Research Institute, Sanofi, Tolerion, Inc., vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings, Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg Therapeutics, Novo Nordisk A/S, Senseonics, Inc, vTv Therapeutics, Zafgen, Inc. K. Klein: None. J.L. Freeman: Employee; Self; vTv Therapeutics. Stock/Shareholder; Self; vTv Therapeutics. Stock/Shareholder; Spouse/Partner; vTv Therapeutics. I. Dunn: None. C. Valcarce: Employee; Self; vTv Therapeutics.


JDRF; vTv Therapeutics; National Institutes of Health (UL1TR002489)

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