First-in-Human Study for a Selective Rearranged During Transfection Tyrosine Kinase Inhibitor, GSK3352589, to Investigate the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers.

Rearranged during transfection (RET), a neuronal growth factor receptor tyrosine kinase, regulates the development of sympathetic, parasympathetic, motor, and sensory neurons in the enteric nervous system. The intended site of action for GSK3352589 is intestinal tissues. GSK3352589 is an RET kinase inhibitor that was administered in double-blind, randomized, placebo-controlled single-dose (SD) and repeat-dose (RD) studies in healthy subjects to investigate its safety/tolerability and pharmacokinetics. In the SD study (n = 28), GSK3352589 was dosed from 2 to 400 mg, including a food effect arm (25 mg). In the RD study (n = 40), GSK3352589 was dosed for 14 days with food twice daily from 5 to 200 mg. With single (fed and fasted) and repeat (fed) doses, bioavailability was low and less than dose-proportional. There was a food effect with 25 mg once daily but may not be clinically relevant. Elimination half-life was ≥17 hours at SD ≥ 15 mg. Accumulation ratios for Cmax , AUCt , AUCtau , and AUC24 after twice-daily dosing to steady state ranged from 1.2 to 1.8 for all doses except the 200-mg dose, which had ratios between 1.9 and 2.7. Administration of GSK3352589 after SD and RD was well tolerated with no safety concerns in healthy subjects.

First-in-Human Studies for a Selective RET Tyrosine Kinase Inhibitor, GSK3179106, to Investigate the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers.

Rearranged during transfection (RET), a neuronal growth factor receptor tyrosine kinase, regulates the development of the sympathetic, parasympathetic, motor, and sensory neurons in the enteric nervous system. GSK3179106 is a RET kinase inhibitor that was administered in double-blind, randomized, placebo-controlled single-dose and repeat-dose studies in healthy subjects to investigate its pharmacokinetics and safety/tolerability. In the single-dose study (n = 16), GSK3179106 was dosed from 10 mg to 800 mg, including a food effect arm. In the repeat-dose study (n = 46), GSK3179106 was dosed for 14 days with food once daily (QD) from 5 mg to 100 mg and twice daily (BID) at 100 mg and 200 mg. With single fasted doses, bioavailability was low and less than dose proportional. A significant food effect was observed with a 100-mg QD dose. Drug exposure after QD and BID repeat dosing with food showed dose dependency up to 100 mg but was not dose proportional. There were no significant differences in exposure between 100-mg and 200-mg BID doses of GSK3179106. Accumulation was observed with both QD and BID dosing. Single doses up to 800 mg and repeat doses up to 400 mg were well tolerated with no safety concerns in healthy subjects.

Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers.

GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open-label relative bioavailability study comparing 20-mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24-hour period for the 60-mg and 120-mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.