Third Harmonic Bio (THRD) Study Update summary

Study design and objectives

• Phase I trial of oral KIT inhibitor THB335 included single and multiple ascending dose (SAD/MAD) cohorts in healthy adults aged 18–65.

• Main objectives: assess safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) via serum tryptase.

• MAD cohorts received once-daily doses of 21, 41, 82, and 164 mg, each with 6 subjects, plus 8 on placebo.

• Baseline demographics were balanced except for sex, with most participants being women; median age ranged from 51.5 to 58 years, majority White and Hispanic or Latino.

• Exclusion of non-vasectomized males in MAD cohorts due to ongoing reproductive toxicology studies.

Pharmacokinetics and pharmacodynamics

• Dose-dependent increases in plasma exposure observed, with half-life ~40 hours supporting once-daily dosing and mild positive food effect.

• Exposure at 41 mg and above exceeded KIT IC90, with 164 mg reaching nearly sevenfold higher.

• Dose-dependent reductions in serum tryptase observed, with mean changes from baseline at day 15 ranging from 13%-84%.

• Peak tryptase reductions occurred at day 15, indicating maximal effect post-dosing.

• PK/PD relationships in SAD mirrored those in MAD, with consistent dose-dependent effects.

Safety and adverse events

• Most common adverse events: hair color change/depigmentation, hemoglobin decreases (82/164 mg), neutrophil and WBC decreases (41/82/164 mg), all known on-target effects of KIT inhibition.

• Three liver enzyme elevation AEs: two in placebo, one in active subject; all resolved without intervention.

• No discontinuations due to drug-related AEs; one unrelated discontinuation for pre-existing hypertension.

• Dose-dependent reductions in ANC and hemoglobin were observed, with all values normalizing by follow-up; all hemoglobin AEs were grade 1.

• Hemoglobin effects more pronounced at higher doses, influenced by phlebotomy and baseline values.