Safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral allosteric TYK2 inhibitor ESK-001 using a randomized, double-blind, placebo-controlled study design

Abstract

ESK-001 is a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), which plays an essential role in mediating cytokine signaling in multiple immune-mediated diseases. In 2 phase I studies, a first-in-human single ascending dose (SAD) and multiple ascending dose (MAD) study and a multiple-dose (MD) study, we evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered ESK-001 in healthy participants using a randomized, double-blind, placebo-controlled study design. ESK-001 was rapidly absorbed with systemic exposures generally increasing dose-proportionally across all cohorts. The mean terminal half-life ranged from 8 to 13 h with no to minimal accumulation of ESK-001 following q.d. doses and ~2-fold accumulation following Q12 doses. Less than 1% of unchanged ESK-001 was eliminated in urine. ESK-001 inhibited the downstream TYK2 pathway as shown by inhibition of pSTAT1 expression. Transcriptomic analysis of unstimulated whole blood samples confirmed dose-dependent inhibition of Type I IFN-induced genes and SIGLEC1, a novel TYK2-responsive biomarker. By correlating PK exposure data with PD readouts, a strong PK/PD relationship was demonstrated. There were no deaths, serious treatment-emergent adverse events (TEAEs), nor severe TEAEs, and most TEAEs were mild in severity. In conclusion, ESK-001 was generally safe and well-tolerated in healthy participants, showed linear dose-dependent PK characteristics, and maximally inhibited TYK2-dependent pathways with a predictable concentration-dependent PK/PD relationship. These findings were used to select the dose range of ESK-001 for the STRIDE phase II trial in plaque psoriasis and to support further clinical development of ESK-001 in other TYK2-mediated diseases.

FIGURE 1

Chemical structure of ESK‐001 binding to the JH2 domain of tyrosine kinase 2 (TYK2).

FIGURE 2

Participant disposition of SAD and MD cohorts. FE, food effect; MAD, multiple ascending dose; MD, multiple dose; N, number of participants; Q12, every 12 h; q.d., once daily; SAD, single ascending dose.

FIGURE 3

Plasma concentration–time profiles in healthy participants for SAD and MD cohorts. Arithmetic mean ESK‐001 plasma concentrations in healthy participants (a) over 24 h following administration of a single dose of ESK‐001 liquid formulation (SAD cohorts), (b) over 24 h on Day 1 after the first dose and over 48 h on Day 14 after the last dose following multiple q.d. or Q12 doses of ESK‐001 tablet formulation (MD cohorts). (c) Arithmetic mean ESK‐001 C _trough levels from Day 3 to Day 13 following multiple q.d. or Q12 doses of ESK‐001 tablet formulation (MD cohorts) with in vitro IFNα‐stimulated HWB pSTAT IC₉₀ and IC₅₀ indicated. Mean (±SD) is shown. For a number of participants per cohort please refer to Figure 2. BLQ values of plasma concentration were excluded from the graphs as logarithmic transformed arithmetic means were displayed. Participants receiving placebo had BLQ values at all timepoints. In the MD study, five participants receiving a placebo showed sparse unexpected ESK‐001 plasma concentrations but were excluded as per Sponsor's request. BLQ, below the limit of quantification; C _trough, the concentration at the end of a dose interval; h, hours; HWB IC₅₀, human whole blood 50% inhibitory concentration for ESK‐001; HWB IC₉₀, human whole blood 90% inhibitory concentration for ESK‐001; MD, multiple dose; N, number of participants; pSTAT, phosphorylated signal transducer and activator of transcription; Q12, every 12 h; q.d., once daily; SAD, single ascending dose; SD, standard deviation.

FIGURE 4

Inhibition of TYK2 signaling pathway by ESK‐001. PD parameters were assessed on the whole blood of healthy participants administrated with multiple q.d. or Q12 doses of oral ESK‐001 or placebo tablets in the MD study. (a) Whole blood of each participant on Day 1 (left panel) and Day 14 (right panel) were stimulated with IFNα and analyzed for pSTAT1 expression in T cells (CD45⁺ CD3⁺) by flow cytometry. Individual participant results were recorded for both stimulated and unstimulated samples and reported as corrected values (stimulated – unstimulated). The percentage inhibition of pSTAT1 was calculated for each participant for each timepoint as the percentage change from baseline (Day 1 predose). Mean (±SD) is shown. N = 6 participants, except for Cohort 30 mg Q12 Day 14 (N = 5). Day 0 represents the day of ESK‐001 administration. (b + c) RNA sequencing was performed to analyze type I IFN gene and SIGLEC1 signature, which were defined as the median transcript expression of the Dx Terity panel genes HERC5, RSAD2, IFI27, and IFIT1, and SIGLEC1, respectively. (b) Dx Terity IFN gene signature and (c) SIGLEC1 signature on Day 14 before the last dose (left panel) and 4 h after the last dose (right panel) are presented. Gene counts were normalized with DESEQ2. N = 12 participants for the placebo group and N = 6 participants for each ESK‐001 group. IFN, interferon; N, number of participants; PD, pharmacodynamics; pSTAT1, phosphorylated signal transducer and activator of transcription 1; Q12, every 12 h; q.d., once daily; SD, standard deviation.

FIGURE 5

PK/PD relationship of ESK‐001 in healthy participants. PK/PD relationship is plotted as the PK exposure versus percentage change from predose baseline IFNα‐induced pSTAT1 in whole blood T cells of healthy participants. The whole blood of each participant was stimulated with IFNα and analyzed for pSTAT1 expression in T cells (CD45⁺ CD3⁺) by flow cytometry. Individual participant results were recorded for both stimulated and unstimulated samples and reported as corrected values (stimulated – unstimulated). The percentage inhibition was calculated for each participant for each timepoint as the percentage change from baseline (Day 1 predose). Best‐fit curve based on Day 14 datapoints (Day 1 data omitted) and in vitro IFNα‐stimulated HWB pSTAT IC₉₀ are indicated. (a) Graph showing all individual participant values of Day 1 and Day 14 timepoints, with peak (2–4 h after the last dose on Day 14) and trough (12 [Q12] or 24 [q.d.] hours after the last dose on Day 14) values. In (b) and (c), only Day 14 timepoints are represented within (b) the lowest dose and in (c), the highest dose highlighted. Data were derived from the MD study. Per protocol, PD samples were to be collected on Day 14, but for some participants, the PD samples were collected on Day 13. HWB IC₉₀, human whole blood 90% inhibitory concentration for ESK‐001; IFN, interferon; MD, multiple dose; PD, pharmacodynamics; PK, pharmacokinetics; pSTAT1, phosphorylated signal transducer and activator of transcription 1; Q12, every 12 h; q.d., once daily; TYK2, tyrosine kinase.