Third Harmonic Bio (THRD) Study Update summary

Study design and objectives

• Phase I trial of oral KIT inhibitor THB335 in healthy adults included single and multiple ascending dose cohorts, focusing on safety, pharmacokinetics (PK), and pharmacodynamics (PD) as measured by serum tryptase.

• Doses ranged from 21 to 164 mg once daily, with most MAD cohorts enrolling women due to exclusion of non-vasectomized males; each cohort had 6 subjects, plus 8 on placebo.

• PK showed dose-dependent increases in exposure, long half-life (~40 hours), and a mild positive food effect; doses above 41 mg exceeded KIT IC90 coverage.

• PD demonstrated dose-dependent reductions in serum tryptase, with up to 84% reduction at 164 mg by day 15 post-dosing.

• Study achieved objectives of characterizing PK, PD, safety, and tolerability in healthy volunteers.

Participant characteristics

• Median age ranged from 51.5 to 58 years; majority were White and Hispanic or Latino.

Safety and adverse events

• Adverse events were consistent with on-target KIT inhibition: hair color change, hemoglobin decreases, and neutrophil/white blood cell count reductions at higher doses.

• Three liver enzyme elevation AEs occurred (two placebo, one active), all resolving without exceeding drug-induced liver injury thresholds and not considered drug-related.

• Hemoglobin and neutrophil declines were dose-dependent, resolved in follow-up, and all hemoglobin AEs were grade 1 under CTCAE guidelines.

• No discontinuations due to drug-related AEs; all events resolved without intervention.

• Severity grading differences between studies attributed to different AE grading scales; most hemoglobin AEs would be grade 1 or 2 by absolute value.