Endocrine Abstracts

Objectives: TSH receptor (TSHR) autoantibodies (TRAb) which mimic the actions of TSH are responsible for hyperthyroidism in Graves’ disease (GD) which is often associated with Graves’ orbitopathy (GO). K1-70 is a TSHR specific human monoclonal autoantibody which binds to the TSHR with high affinity and prevents stimulation of the TSHR by TSH and TRAb. Safety, tolerability, pharmacokinetic, pharmocodynamic and immunogenic effects of K1-70 in patients with GD were assessed in a phase 1 clinical trial.

Methods: K1-70^TM was administered to 18 GD patients stable on anti-thyroid drugs in ascending doses of 0.2 mg, 1 mg, 5 mg and 25 mg by intramuscular (im) or 50 mg and 150 mg intravenous (iv) routes in 6 cohorts of 3 subjects each. The subjects were followed up for 100 days post dosing.

Results: K1-70^TM was well tolerated in all subjects at all doses with no reported deaths or Serious Adverse Events. The reported Adverse Events were mild or moderate and none were directly related to K1-70^TM. No significant immunogenic responses were observed in any of the subjects. The iv administration resulted in improved systemic exposure compared to im administration indicating this was the correct dosage route for future stages of drug development. The half-life of K1-70^TM given iv was about 500 hours. Subjects receiving higher doses of K1-70 (25 mg and above) demonstrated expected pharmocodynamic effects with fT3, fT4 and TSH progressing into hypothyroid ranges. At 28 days post dose 11/18 (61%) of patients were in a hypothyroid state while for higher dose cohorts 9/9 (100%) progressed to the hypothyroid state on or before day 28. This corresponded to clinically observed and patient reported improvements in symptoms of both GD and GO. Patients reported improvements in tremor, sleep, mental focus, toilet urgency, aches, pains and general wellbeing. Clinically significant reductions in exophthalmos measurements (>2 mm) were observed in subjects receiving higher doses of K1-70^TM. In addition, patients reported improvements in photosensitivity, gritty eyes sensation, conjunctival redness and gaze-evoked pain.

Conclusions: Our phase 1 trial demonstrated that K1-70^TM was safe and well tolerated in all subjects. Systemic exposure following iv administration was as expected and the risk-benefit profile for K1-70 was favourable for later phases of drug development. The pharmacokinetic/pharmacodynamic relationship exceeded the expectations of the phase 1 trial design and the beneficial effects of K1-70 on patients’ eye signs support suggestions of a key role for TRAb stimulation of orbital TSHRs in GO.