The Janus kinases (JAKs) are a family of intracellular tyrosine kinases of the class I and II receptor superfamily that consists of four members: JAK1, JAK2, JAK3, and Tyrosine kinase 2 (TYK2). Activation of JAKs occurs when a cytokine binds to its receptor, inducing multimerization of receptor subunits that brings JAKs into proximity with each other for transactivation. Activated JAKs then phosphorylate signal transducer and activation of transcription (STAT) proteins, resulting in their dimerization. Phosphorylated STAT dimers translocate to the nucleus to modulate the expression of the JAK/STAT target gene. Thus, JAKs play a critical role in the JAK/STAT signaling cascade to transmit information from extracellular cytokine cues to the nucleus, leading to DNA transcription and expression of genes involved in immunity, proliferation, differentiation, apoptosis, and oncogenesis (1).

The discovery of numerous cytokines underlying the pathogenesis of allergic, inflammatory, and autoimmune disorders has provided the basis for developing drugs targeting cytokines and cytokine receptors for treating autoimmune disorders. Many of these cytokines, such as Type I and Type II cytokines, signaling via JAK/STAT pathway is well established in various genetic models from mutagenized cell lines engineered with human genes and knockout mice (2). A critical role of JAK/STAT in Type I and Type II cytokine signalings, such as gamma chain (γc) cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), IL-6, IL-12, IL-23, and IFNγ, strongly argue that interfering with the activity of these kinases could lead to a new class of immunomodulatory (2, 3). Several JAK inhibitors have been approved for the treatment of rheumatoid arthritis (RA) and ulcerative colitis (UC), and several JAK inhibitors are at various stages of clinical development for the treatment of autoimmune diseases (4). These pieces of evidence support the importance of the JAK/STAT pathway in autoimmune diseases. Constitutive activation of JAK/STAT pathways is also associated with a wide variety of malignancies and are implicated in tumor escape from chemo- and targeted- therapies (5, 6). Inhibition of the JAK/STAT pathway by ruxolitinib, a JAK1/JAK2 inhibitor, showed promising anti-tumor activity in patients with advanced T cell malignancies, especially tumors with JAK/STAT pathway aberrations (7).

Moreover, less optimal efficacy is likely caused by the short half-life of ruxolitinib and less durable modulation of JAK/STAT. Amongst the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and activation of signaling pathways. Thus, targeting JAK/STAT3 pathway is an attractive therapeutic approach for patients with Peripheral T-cell lymphoma (PTCL). Non-clinical efficacy and PK/PD studies of golidocitinib (also named as AZD4205 or DZD4205) in xenograft model allow for increased and longer suppression of JAK1/STAT3 signaling and subsequent better anti-tumor activity as compared to ruxolitinib (Jason G. 7, 8).

Golidocitinib is an investigational, potent, ATP-competitive, and JAK1 selective inhibitor. It exhibits greater than 200 folds of selectivity to JAK1 over other JAK family kinases and has a favorable selectivity profile across the kinome (9). Golidocitinib demonstrated in vitro activities against cytokine-induced pSTATs in human blood cells as well as exhibiting promising in vivo efficacy in autoimmune disease and tumor xenograft models in animals.

Golidocitinib has been assessed in two phase I clinical studies, JACKPOT2 (NCT03728023) and JACKPOT3 (CTR20191011). These two studies were conducted in the USA and China, respectively, to compare the PK, safety, and tolerability of golidocitinib among major ethnic groups (Caucasian, Black, and Asian). Golidocitinib is currently being evaluated in a phase I/II study in patients with refractory or relapsed T cell lymphoma (r/r PTCL) (JACKPOT8, NCT04105010) and cutaneous T cell lymphoma (CTCL) (JACKPOT15, CTR20212475) as well as potentially autoimmune diseases. The PK information from these two clinical trials pharmacokinetically lays the foundation to support its global development strategy.

These two studies investigated the PK, safety, and tolerability profile of golidocitinib in healthy adult subjects. The initial starting dose of 5-mg in the First-Time-in-Human study (JACKPOT2) was based on the nonclinical toxicology; Furthermore, PK and pharmacology were also taken into considerations. The initial dose administrated to a subject would be equal to or lower than either the dose calculated following the draft FDA guideline (Guidance for Industry; Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, July 2005), or a dose that is predicted to elicit a minimal pharmacodynamic (PD) effect. No Observed Adverse Effect Level (NOAEL) of 6 mg/kg is determined in the most sensitive species (rat) in one-month toxicology study. The NOAEL toxicology dose is then converted to the Human Equivalent Dose (HED) of 0.972 mg/kg based on body surface area (BSA) conversion. A safety margin of 10-fold was applied to estimate the recommended safe starting dose of 5 mg. Moreover, it is not anticipated to have pharmacological effect based on in vitro pharmacology data and predicted PK. With the reference of safety data from JACKPOT2 SAD cohorts, higher starting dose of 25 mg was selected in the next JACKPOT3 study.

Dose proportionality was demonstrated for C_max and AUC across the range of a single dose of up to 150 mg and once-daily dosing of up to 100 mg. As expected of long half-life, steady-state plasma concentrations of golidocitinib were achieved by day 14 with once-daily dosing. A moderate accumulation of golidocitinib was observed after multiple dosing; C_max and AUC_0-24hr on day 14 increased by 2-3 folds compared to day 1. The estimated glomerular filtration rate (GFR) is 37.3%*7.5 hr/L (free fraction in plasma*GFR) = 2.80 hr/L, comparable to or slightly lower than the renal clearance. This indicates that active transport contributes to a minor extent to the overall elimination of golidocitinib. In the first part of JACKPOT2, a single dose of 50 mg was selected because the limited data available when this study was planned indicated that this therapeutic dose had acceptable safety and tolerability. The 90% CI for the geometric least square mean (GLSM) ratio (fed/fasted) of C_max, AUC_0-t, and AUC_0-inf was totally contained within the range of 0.80 to 1.25, suggesting that high-fat/high-calorie food has minimal effect on the PK of golidocitinib. Compared to approved JAK inhibitors (Tofacitinib, Filgotinib, Upadacitinib) (13), golidocitinib demonstrated a more selective profile of the JAK family and a much longer half-life. It is critical when sustained modulation of JAK/STAT3 pathways is required for efficacy outcomes in refractory and relapsed PTCL indication. A thorough characterization of PK profiles is necessary for dose exploration and optimization for subsequent studies performed in the patients to attain and maintain appropriate plasma exposure.

The inter-ethnic difference in primary PK parameters was evaluated, which suggested slightly higher C_max but comparable AUC was observed in Asian subjects as compared to Caucasian and/or Black subjects, while it is not expected that variability affects the efficacy and safety profiles to clinically meaningful extents. The following properties of golidocitinib make it less likely to be sensitive to ethnic factors with the reference of ICH E5 guidance: (1) PK is dose-proportional from 5 mg to 150 mg following a single oral dose; (2) Multiple pathways are involved in clearance of golidocitinib, which mitigate the potential interaction as a victim. Available data showed a primary hepatic clearance (up to 70-80%) with moderate involvement of renal excretion (approximately 20-30%). Moreover, two separate enzymatic systems implicated in the metabolism of golidocitinib were CYP3A4/5 and flavin-containing monooxygenase enzyme (FMO); (3) High oral bioavailability (>80%) can be concluded in the view of the metabolic profile of golidocitinib in human from a radiolabeled mass balance study in 8 healthy participants (JACKPOT5, NCT04225208). Additionally, golidocitinib has high permeability and high solubility (the clinical dose remains soluble in the intestinal fluid of 250 mL). Thus, efflux of golidocitinib via gut transporters is unlikely to limit oral absorption; (4) Only ~ 63% of golidocitinib is bound to human plasma of Caucasian and Chinese in vitro. Thus fluctuations of alpha1 acid glycoprotein (AAG) in plasma between ethnic groups are unlikely to affect free drug exposure; (5) Diet unlikely affect the PK of drugs to a clinically meaningful extent in the view of clinical investigation with a high-fat meal; (6) genetic polymorphism of metabolizing enzymes less likely affect the PK of the drug because of multiple pathways involved in metabolism and excretion, neither polymorphism of transporters impacts the PK of golidocitinib because of high passive permeability and high solubility.

Following single oral administration, golidocitinib is absorbed more slowly with larger t_max at lower doses than at higher doses. In vitro experiments showed that golidocitinib is a P-glycoprotein (P-gp) substrate, but active transport can be saturable at high concentrations. Additionally, golidocitinib has high solubility and high permeability in vitro. Thus, delayed t_max at the low dose levels may be caused by active efflux and metabolism via gut P-gp and CYP3A4; however, high permeability and high solubility of golidocitinib minimizes the impact but ends with lower C_max and comparable AUC at the same dose levels between JACKPOT2 and JACKPOT3 studies. Drugs undergoing active transport, efflux of P-gp, and gut metabolism via CYP3A4 are most likely to show the inter-ethnic difference in drug absorption (14–16). These observations may be associated with polymorphism and/or expression differences between major ethnic groups. However, no clear studies show variations in drug absorption between Asians and Caucasians. The interplay between CYP3A4 and P-gp and high variable expression among individuals make it difficult to elucidate the ethnic difference in oral absorption of golidocitinib. It was speculated that C_max difference would be minimized following multiple dosing due to accumulation. Therefore, the absorption phase of the single dose will contribute less to C_max at steady state.

Single doses of golidocitinib up to 150 mg and 14-day dosing up to 100 mg once daily were well-tolerated in Asian and non-Asian healthy adult participants. In these two studies, TEAEs were mainly mild or moderate in severity and were reversible without any clinical sequelae. There were no golidocitinib-related Grade 3 or higher TEAEs or SAEs. Moreover, vital signs, ECG, and laboratory parameters showed no consistent clinically relevant trends or changes. Overall, no vital risk of golidocitinib was identified in both studies. The safety of golidocitinib will be further evaluated in ongoing studies in patients with PTCL (ClinicalTrials.gov Identifier: NCT04105010).

These studies had several limitations. Firstly, the inter-ethnic comparison is based on PK data of golidocitinib from the SAD cohorts among these ethnic groups. It is currently unknown whether multiple-dose PK behaves similarly or not between these races. Secondly, other limitations include the short duration (14-day) in the MAD cohorts relative to the long half-life and the inclusion of healthy subjects instead of cancer patients. The study population was young and not representative of the age demographic of the target population for which golidocitinib is intended. Long-term safety was investigated in the phase I/II study performed in patients with NSCLC (ClinicalTrials.gov Identifier: NCT03450330) and r/r PTCL, in which PK, PD, and safety assessments were assessed in patients with different ethnic backgrounds.

The major strength of JACKPOT2 and JACKPOT3 is that they provided a thorough demonstration of golidocitinib PK behavior. It was demonstrated that no racial differences and food effects were observed in these two studies. Further investigations of PK in patients, as well as population PK modeling, are required to corroborate the results here.

No inter-ethnic difference in PK was observed among healthy Caucasian, Black, and Asian subjects. Secondly, high-fat/high-calorie food had minimal effect on the PK of golidocitinib. Thus, data accumulated so far did not suggest different dosing regimens in the intended patient population for multinational clinical studies. Importantly, golidocitinib was well tolerated in healthy participants, which warrants further clinical development.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

JACKPOT2 study were conducted in Frontage Clinical Research Center in Secaucus, New Jersey, USA. JACKPOT3 study was conducted in Peking Union Medical College Hospital in Beijing, China. Both the studies were performed in compliance with the ethical principles originating in, or derived from, the Declaration of Helsinki, as well as in compliance with all International Conference on Harmonization Good Clinical Practice guidelines. In addition, all local regulatory requirements were followed, and JACKPOT2 study was registered on ClinicalTrials.gov (NCT03728023) and JACKPOT3 on cde.org.cn (CTR20191011). JACKPOT2 study was approved by IntegReview IRB and ethics committee. JACKPOT3 was approved by the Institutional Review Board and ethics committee in Peking Union Medical College Hospital. All participants provided written, informed consent before joining the studies.

RC, KC, and ZY designed and organized the clinical trial. KC analyzed the data and wrote the manuscript. KC, XG, YZ, ZL, XD and DL were involved in the discussion of results. RC, KC, ZY, YZ, ZL, XD, and PH reviewed and edited the manuscript. All the authors have read and approved the final manuscript. All authors contributed to the article and approved the submitted version.