Single and Multiple Oral Doses of LGD-4665, a Small Molecule Thrombopoietin Receptor Agonist, Increase Platelet Counts in Healthy Male Subjects

LGD-4665, an oral thromobopoietin receptor agonist, is being developed as a new generation small molecule thrombopoietin (TPO) mimetic. LGD-4665 is a highly selective and potent agonist of the TPO receptor and induces differentiation and proliferation of megakaryocytes. A single-center, randomized, placebo-controlled, double-blind, escalating dose group study was conducted to assess the pharmacodynamics, pharmacokinetics (PK), and safety of LGD-4665 in healthy male subjects after single and multiple doses. In the single dose phase of the study, 5 dose cohorts of 6 subjects each were randomized at a ratio of 2:1 (LGD-4665: Placebo). LGD-4665 doses of 1, 5, 10, 20, and 40 mg were escalated sequentially. In the multiple dose phase, 8 subjects received 5 mg of study drug or placebo at a ratio of 3:1, respectively, once daily for 14 days. Clinical assessments were conducted for 21 and 35 days following treatment initiation in the single and multiple dose phases, respectively. Platelet count increases were determined as the maximal observed increase in post-dose platelet value relative to baseline, expressed both as absolute value and percent increase. Following single dose administration, a statistically-significant (p=0.011) platelet count increase compared to placebo was observed following a 40 mg LGD-4665 dose. In subjects receiving this dose, individual maximum increases in platelet counts ranged between 53 and 83 x1000/μL (mean = 65 x1000/μL; 29% increase from baseline). Following multiple dose administration of 5 mg daily for 14 days, increases in platelet counts over baseline were observed in all drug-treated subjects (n=6) with a mean maximal increase from baseline of 43%. From PK measurements, a dose-proportional increase in systemic exposure after single doses of LGD-4665 was observed among the dose groups. Mean area-under-the-curve from time zero to infinity (AUC_0-inf) increased from 2.88 to 155 μg·h/mL following single doses of 1 to 40 mg, respectively, with AUC_0–24h values of 0.43 – 25.3 μg·h/mL. Maximum LGD-4665 concentrations (C_max) increased from 0.029 to 1.56 μg/mL following administration of 1 to 40 mg single doses, respectively. In the multiple phase, 5 mg daily doses for 14 days resulted in a mean C_max of 0.83 μg/mL and the C_max were reached at 4 hours post dose. The mean steady-state AUC_{0 to 24h} was 17.4 μg·h/mL. Overall, LGD-4665 was safe and well tolerated at all dose levels tested during both phases of the study. All AEs were appraised as mild to moderate. The majority of AEs were not related to LGD-4665 and no apparent dose-relationship was observed. No serious AEs were reported. No subjects discontinued the study due to AEs. No clinically significant laboratory abnormalities, effects on electrocardiograms and vital signs were observed. In summary, LGD-4665 increase platelet counts following single and multiple dose administration and was well tolerated.