Third Harmonic Bio (THRD) has reported encouraging results from its Phase 1 single and multiple ascending dose clinical trial of THB335, positioning the oral KIT inhibitor for advancement into Phase 2 studies for chronic spontaneous urticaria (CSU).
The comprehensive Phase 1 trial evaluated THB335 across multiple dose levels in both single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. SAD evaluations included doses ranging from 21 mg to 205 mg, while MAD cohorts received once-daily doses of 21 mg to 205 mg over 14 days.
Pharmacokinetic Profile and Dosing Advantages
THB335 demonstrated favorable pharmacokinetic properties with a half-life of approximately 40 hours, supporting a convenient once-daily dosing regimen. The drug showed dose-dependent increases in exposure across all cohorts, with trough plasma levels exceeding the KIT IC90 at MAD doses of 41 mg and above. Researchers also observed a mild positive food effect.
Biomarker Response and Efficacy Signals
A key finding was the dose-dependent reduction in serum tryptase, an important biomarker of mast cell activation. By Day 15, mean reductions from baseline ranged from 13% to 84%. Notably, the 41 mg, 82 mg, and 164 mg dose cohorts achieved serum tryptase reduction levels that suggest potential clinical benefit for CSU treatment.
Safety and Tolerability Profile
THB335 demonstrated a generally favorable safety profile in SAD cohorts. In the MAD cohorts, three subjects experienced isolated, transient asymptomatic transaminase elevations, with two occurring in placebo recipients and one in the 164 mg active treatment group. After expert review, management concluded that the single transaminase event in the active subject was unlikely to be drug-related.
Expected effects related to KIT biology were observed, including hair color changes and reductions in hemoglobin and neutrophil counts. These events showed dose dependence and resolved during follow-up. The study noted a stronger phlebotomy effect compared to the company's first-generation KIT inhibitor, THB001, potentially contributing to the increased hemoglobin-related adverse events.
Development Timeline and Strategic Plans
Third Harmonic Bio is proceeding with development activities through the first half of 2025, focusing on completing ongoing subchronic toxicology studies and preparing regulatory submissions. The company aims to initiate a 12-week, placebo-controlled Phase 2 study in CSU by mid-2025.
In parallel with these clinical development activities, the company has announced the initiation of a strategic review process to explore opportunities for maximizing shareholder value.
