Background/Purpose: Nck is a cytosolic protein that binds a domain of the T cell receptor (TCR) following TCR interaction to amplify responses from low affinity antigens, such as those which drive autoimmune pathobiology. Therefore, inhibition of the Nck-TCR interaction may rebalance dysregulated activation of T cells. Nck is not required for T cell activation driven by high affinity antigens, such as those presented by pathogens. AX-158 is a potent, orally administered inhibitor of the Nck-TCR interaction, currently under evaluation for the treatment of autoimmune and inflammatory diseases.

There has been no previous clinical experience with AX-158 prior to this first-in-human study.

Methods: This was a Phase I, randomized, double-blind, placebo-controlled study to evaluate safety, tolerability and pharmacokinetics (PK) following oral administration of AX-158 in healthy male subjects (N=64) following a single ascending dose (SAD) and multiple ascending doses (MAD), including a Food effect assessment.

The study was conducted in three parts: Part A, SAD phase (n=34); Part B, Food effect (n=8); Part C, MAD phase (n=22). Safety (adverse events [AEs], laboratory results, vital signs) and PK data were reported across all parts. PK parameters were recorded across 10 days, including C_max, AUC, T_max, half-life (T_1/2), and renal clearance.

Part A and C recruited up to 8 patients into each dose cohort (6 active, 2 placebo). SAD cohorts received a dose range of 5–50 mg AX-158 on Day 1; MAD cohorts received a dose range of 5–15 mg AX-158 on Days 1–10. Part B dosing was based on the safety, tolerability and PK data from Part A (single 15 mg oral dose on Day 1 of fed and fasted periods at least 7 days apart).

Results: There were no safety concerns following administration of AX-158 in healthy subjects. The few AEs reported across each study Cohort were mild and not considered related to AX-158. The most common AE was headache, occurring in 12.5% (n=1) and 9% (n=2) of the Food effect and MAD cohorts, respectively. No serious or severe AEs were reported.

After both single and multiple oral doses, AX-158 was absorbed rapidly, and exposure increased with approximate dose proportionality. The elimination phase was well characterized, with no significant changes in T_1/2 with increasing doses.

Accumulation of C_max following a single daily dose through to Day 10 was 11-27% and AUC accumulation ranged from 20-25%, similar to expectations based on AX-158 T_1/2. Equilibrium exposures were reached by Day 3 with no significant accumulation. Renal clearance was below standard GFR, suggesting renal reabsorption or other elimination paths. AX-158 dosing following a high-fat meal resulted in a delayed T_max and lower C_max, but with similar AUC vs fasting conditions.

Conclusion: AX-158 was well tolerated at all oral dose levels. There were no safety concerns following SAD and MAD administration of AX-158 in healthy subjects, with no serious or treatment-related events, and no clinically significant findings. AX-158 demonstrated excellent bioavailability, with predictable PK outcomes supporting dosing independent of food effect. A Phase 2 proof-of-concept study is ongoing in subjects with mild to moderate plaque psoriasis (NCT05725057).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/first-in-human-evaluation-of-the-safety-tolerability-and-pharmacokinetics-of-the-t-cell-receptor-signal-modulator-ax-158/