PII-081 - PHARMACOKINETICS OF THB001, AN ORALLY AVAILABLE, POTENT AND HIGHLY SELECTIVE SMALL MOLECULE INHIBITOR OF WILD TYPE KIT RECEPTOR TYROSINE KINASE, IN HEALTHY VOLUNTEERS

P. Dogterom¹, S. Sweeney², C. Voors-Pette³, H. Maarse³, G. Keaney⁴, G. Parry⁵, E. Connor⁶, D. Nix⁷, N. Rioux⁸, A. DiRico⁹, S. Yoo¹⁰; ¹QPS Netherlands, QPS Netherlands, Groningen, The Netherlands, ²Aliada Therapeutics, Boston, MA, US, ³QPS Netherlands, Groningen, Netherlands, ⁴Rapport Therapeutics, Boston, MA, USA, ⁵Third Harmonic Bio, Boston, MA, USA, ⁶Third Harmonic Bio, San Francisco, CA, USA, ⁷Certara, Princeton, NJ, USA, ⁸Certara, Radnor, PA, USA, ⁹Third Harmonic Bio, Cambridge, MA, USA, ¹⁰Third Harmonic Bio, Newton, MA, USA.

Background: Mast cells play a central role in the pathophysiology of allergic diseases. Mast cell activation, proliferation and survival is dependent on tyrosine kinase (KIT) signaling. THB001 is an inhibitor of wild type KIT and has undergone a series of phase I studies prior to entering phase 2 for indications of mast cell driven diseases. At all doses tested during phase 1, no safety or tolerability issues were identified which preclude further development. Here we report on different elements of the pharmacokinetic properties of THB001, collected during the phase 1 program.

Methods: Three different studies were conducted in healthy male and female volunteers (18-65 years): a double-blind, randomized, placebo-controlled single and multiple ascending dose study (study 1), a randomized, open label, single dose bio-comparison and food effect study (study 2) and a drug interaction study (study 3). In all studies, a THB001 free base capsule formulation was used. In study 2, in addition, a THB001 HCL salt in capsule formulation was used. THB001’s effect on CYP1A2, 3A4 and 2C19 activities were evaluated under steady state conditions by means of the CYP substrates caffeine (1A2), omeprazole (2C19) and midazolam (3A4).

Results: THB001, given as a free base over the single dose range of 10 to 600 mg, had an exposure that increased approximately dose proportional. Its half-life was about 24 hours, independent of the dose. At 200 and 500 mg QD no or minimal accumulation occurred while at 200 and 400 mg BID peak and overall exposure showed a 3 to 7-fold accumulation between Days 1 and 14.. Food increased THB001’s Cmax and AUClast with a factor of 1.5 and 2.5, respectively, and slightly delayed the absorption. The HCL salt, as compared to the free base (both at a dose of 200 mg) resulted in a higher Cmax and AUCinf: an increase by a factor of about 2 and 3, respectively. Food increased the Cmax and AUCinf values upon dosing the HCL salt at a dose of 400 mg by a factor of about 1.5 and 1.6 respectively and delayed the absorption. Ten days of once daily dosing of 400 mg THB001 reduced exposures of caffeine and paraxanthine by 30 to 40% but had no effects on the exposures of omeprazole and midazolam and their metabolites.

Conclusion: THB001, administered orally as single or multiple doses and as free base and HCL salt, showed a favorable pharmacokinetic profile suitable for dosing in phase 2 studies.