A double-blind, placebo-controlled, randomized multiple dose phase 1b trial of a CDK4/6 inhibitor, TCK-276, in patients with active rheumatoid arthritis.

OBJECTIVE: The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and efficacy (as an exploratory endpoint) of TCK-276, a novel CDK4/6 inhibitor, after multiple oral doses for 7 days in patients with active RA. METHODS: This multicentre, randomized, placebo-controlled, dose-ascending, double-blind, phase 1b, multiple-dose study included 32 patients with active RA in 4 cohorts of 8 patients (6 active and 2 matching placebo), each receiving an oral dose of TCK-276 or matching placebo for 7 days (once daily). The doses of TCK-276 were 10, 25, 75, and 175 mg/day. Safety and pharmacokinetic endpoints, and exploratory disease activity parameters for RA were assessed. RESULTS: There were no deaths, serious adverse events, notable clinically meaningful laboratory findings (including hematological changes), clinically meaningful vital sign changes, or clinically meaningful electrocardiogram or cardiac telemetry changes. TCK-276 was rapidly absorbed and the half-life time ranged approximately from 6 to 12 hours. No obvious accumulation was observed, and the increase in TCK-276 exposure was dose proportional. At day 7, DAS28-CRP responses (EULAR good or moderate responses) were observed in 40%, 80%, and 66.7% at 25, 75, and 175 mg/day TCK-276, respectively, versus 12.5% in placebo; ACR20 responses were 33.3%, 60%, and 50% respectively, versus none in placebo. CONCLUSION: TCK-276 (≤175 mg) was well tolerated with no clinically meaningful safety signals in patients with active RA. Together with the preliminary efficacy (≥25 mg/day), these data warrant further study of TCK-276 for the treatment of active RA. TRIAL REGISTRATION: ClinicalTrails.gov, NCT05437419.

The role of IgE and repeated challenge in the induction of persistent increases in scratching behavior in a mouse model of allergic dermatitis.

Previously, we indicated that athymic BALB/c-nu/nu (nude) mice that had been repeatedly treated with 2,4,6-trinitrochlorobenzene (TNCB) failed to exhibit chronic scratching behavior in spite of the accumulation of dermal mast cells in the lesion. The mice also failed to produce specific IgE or potent dermatitis. In the present study, therefore, we aimed to examine the role of IgE and repeated hapten treatment in the induction of scratching behavior and dermatitis using nude mice and trinitrophenol (TNP)-specific IgE-transgenic mice. The ears of nude mice were treated with TNCB 6 times at intervals of 48 h, and TNP-specific IgE was administered to the mice intravenously before the sixth TNCB treatment. The nude mice that had been supplemented with IgE exhibited a persistent increase in scratching behavior and continuous degranulation of mast cells. Furthermore, a potent immediate ear swelling was induced, although no biphasic dermatitis pattern was observed. On the other hand, the IgE-transgenic mice failed to exhibit persistent increases in scratching behavior after a single TNCB treatment, although biphasic ear swelling was observed. These results indicate that specific IgE plays an essential role in the induction of persistent increases in scratching behavior and continuous degranulation of mast cells. Furthermore, repeated challenge with the hapten also plays an important role in persistent increases in scratching behavior through accumulation and continuous activation of mast cells.