Background/Purpose: TCK-276 is a highly potent, orally active, and selective cyclin dependent kinase 4/6 (CDK4/6) inhibitor that is in development as a novel synthetic disease modifying antirheumatic drug targeting the hypertrophy of synovial fibroblasts. To investigate the safety, tolerability, and pharmacokinetics (PK) of oral doses of TCK-276, we conducted two phase 1 studies in the United States; one was the single ascending dose (SAD) study in healthy subjects and the other is an ongoing multiple ascending dose (MAD) study in patients with rheumatoid arthritis (RA).

Methods: The SAD study was a single-center, randomized, placebo-controlled, double-blind study, which enrolled 48 healthy subjects into 6 cohorts. Six subjects in each cohort received TCK-276 (5, 15, 50, 100, 150, or 185 mg) and 2 subjects in each cohort (total of 12 subjects) received placebo. The MAD study (NCT05437419) is a multicenter, randomized, placebo-controlled, double-blind study, which is planned to enroll a total of 32 RA patients into 4 cohorts. Six patients in each cohort received TCK-276 and 2 patients in each cohort received placebo for 7 days, respectively.

Results: In the SAD study, 5 subjects (10.4%) experienced 7 treatment-emergent adverse events (TEAEs). All TEAEs were mild. Only one TEAE (headache) was considered possibly related to TCK-276 at 150 mg, and all the other TEAEs were considered either unlikely to be related or unrelated. No action was taken for the TEAEs. There were no deaths, serious TEAEs, or TEAEs leading to discontinuation reported during the study. No clinically significant findings were noted in the clinical laboratory evaluations (clinical chemistry, hematology, coagulation, and urinalysis). After administration of 5 to 185 mg TCK-276, geometric mean C_max, AUC_0-inf, and t_1/2 values of TCK-276 ranged from 11.5 to 481 ng /mL, 53.9 to 2260 ng*h/mL, and 3.70 to 13.0 h, respectively. Across the 5 mg to 185 mg dose range, an increase in TCK-276 exposure approximately proportional to dose was observed. In the MAD study, a total of 16 patients have been enrolled as of May 26, 2023; 12 patients received TCK-276 (10 mg/day or 25 mg/day for 7 days) and 4 patients received placebo, respectively. There were no safety concerns identified, and the safety review committee concluded that the study can proceed with the next higher dose. PK profiles in RA patients after administration of 10 or 25 mg/day TCK-276 were confirmed to be similar to those in healthy subjects.

Conclusion: Safety results indicated that TCK-276 was well tolerated at a dose of up to 185 mg for a single administration and up to 25 mg/day over 7 days of administration. In addition, no safety concerns have been observed such as anemia, neutropenia, leukopenia, and thrombocytopenia, which are often observed with other CDK4/6 inhibitors. TCK-276 showed faster elimination than other CDK4/6 inhibitors, which may be related to the observed safety profile. Safety, tolerability, and PK of the higher TCK-276 dose cohorts in the MAD study will be available at the presentation. The safety and efficacy of TCK-276 in the treatment of RA will be further evaluated in a phase 2 trial in the future.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-tolerability-and-pharmacokinetics-of-a-novel-synthetic-disease-modifying-antirheumatic-drug-tck-276-after-single-ascending-dose-in-healthy-subjects-and-multiple-ascending-doses-in-patients/