Safety, pharmacokinetics, and potential benefits of TSH-receptor-specific monoclonal autoantibody K1-70TM in Japanese Graves' disease patients: results of a phase 1 trial

Abstract

This phase 1 dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of K1-70^TM, a TSH-receptor-specific monoclonal autoantibody that inhibits ligand binding and receptor activation, in Japanese Graves' disease (GD) patients. Twelve patients were enrolled, divided into four dosage cohorts (5 mg, 25 mg, 75 mg, and 150 mg), and monitored for 100 days post-administration. The primary objective was to assess safety and tolerability, and the secondary objectives were evaluation of PK and thyroid function. Exploratory analyses focused on the dynamics of the anti-TSH receptor antibodies and Thyroid eye disease (TED). K1-70^TM demonstrated a favorable safety profile, with no reports of serious adverse events. Mild to moderate treatment-emergent adverse events, such as headache and fatigue, were observed in 83.3% of the participants, but none were deemed severe. PK analysis revealed a dose-dependent increase in half-life, suggesting prolonged systemic exposure at higher doses. Thyroid function remained stable at lower doses, but there were dose-dependent reductions at higher doses that were managed with adjunctive L-thyroxine therapy. Marked reductions in TSAb levels were observed across all cohorts, indicating effective suppression of TSH receptor activity. An improvement in proptosis was noted in 50% of the eyes, suggesting a potential therapeutic benefit against inactive-phase TED. These findings support K1-70^TM as a promising targeted therapy for GD and TED, and they warrant further studies involving larger patient populations and active disease phases to confirm its efficacy and safety (jRCT Registration Number: JRCT2080224902).

Keywords: Graves’ disease; Graves’ ophthalmopathy; K1-70TM; Pharmacokinetics; Safety profile.

Fig. 1. Chronology of the screening, treatment, and follow-up visit schedule

Screening period (Day –28 to Day –3) Hospitalization (Day –1 to Day 3). Single dose of K1-70^TM on Day 1 96-day follow-up period (Day 4 to Day 100)

Fig. 2. Serum concentrations of K1-70^TM in all cohorts following intravenous (IV) infusion

Vertical bars indicate the range. The times shown were measured from the end of the IV infusion.

Fig. 3. Changes in TSAb in the 12 subjects up to 100 days after IV infusion of K1-70^TM

Graphical Abstract