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.

Disclosure

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.

Funding

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

© 2020 by the American Diabetes Association
2020
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