Dose Escalating and Bioavailability Phase 1 Studies Assessing Safety and Tolerability and Pharmacokinetics of Tildacerfont, a Small-Molecule CRF1 Receptor Antagonist

Background: Tildacerfont (SPR001; LY2371712), a second generation, potent, selective, nonsteroidal, oral small-molecule antagonist of corticotropin-releasing factor type-1 (CRF1) receptors in the pituitary gland, is in late stage development as a potential treatment for adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). We report the results of 3 randomized Phase 1 studies of safety, tolerability, and pharmacokinetics (PK) of tildacerfont in healthy adults and compare the relative bioavailability of 2 tildacerfont formulations. Methods: Two Phase 1 studies were double-blind, placebo-controlled and evaluated escalating doses (2–800 mg QD) as single doses (SAD; n=18) and 50-200mg as multiple doses (MAD; n=47). The studies also included pilot food effect and drug-drug interaction sub studies, respectively. A randomized, balanced, open-label, crossover study (n=42) examined the relative bioavailability (BA) of single oral doses of 2 tildacerfont formulations, 200 mg powder-in-capsule (PIC) compared to 200 mg low-drug load tablet. Results: In the SAD and MAD studies, the most common, non-procedural adverse events were headache and cough. In the BA study, the most common, non-procedural adverse events were constipation and headache. There were no study drug-related serious adverse events (SAEs) in any study. In the SAD and MAD (PIC formulation), tildacerfont concentrations declined in a multi-exponential manner with C(max) occurring moderately late, ~5 hours post dose, and a high degree of variability was observed in AUC and C(max) (CV range: 54–122%). A food effect was observed in the SAD. Fourteen days of dosing achieved near steady state exposure with an AUC accumulation ratio of 2.51 to 3.65 in the MAD study. Midazolam, a sensitive probe substrate for CYP3A4 exhibited ~2-fold increase in AUC and a 1.8 increase in C(max) when co-administered with tildacerfont suggesting moderate CYP3A4 inhibition. The tablet formulation reduced the variability (AUC and C(max) CV range: 69–72%) compared to the PIC formulation resulting in a more predictable pharmacokinetic profile. The half-life of the tablet was ~60 hrs. Bioequivalence in AUC was established with the tablet and PIC formulations (fed state) with C(max) ~20% higher for tablet than PIC due to a reduction in and more consistent T(max), median [range], from 6 [4.5, 24] hours to 3 [2, 6] hours. Conclusions: These results suggest that tildacerfont is safe and generally well-tolerated in healthy adults and suitable for further study in patients with CAH. The tablet formulation provided a more consistent pharmacokinetic profile with reduced variability in all parameters and is being evaluated in late stage studies of tildacerfont in adult CAH.