VRDN-002, a Next-Generation Half-life Extended Antagonist Antibody to IGF-1 Receptor for Thyroid Eye Disease (TED): Safety and Pharmacokinetic/Pharmacodynamic (PK/PD) Results in Healthy Volunteers

Abstract

Purpose : VRDN-002 is a next-generation, half-life extended antagonist antibody to the IGF-1 receptor (IGF-1R) in development for the treatment of TED. Clinical and preclinical studies have confirmed that IGF-1R antagonism reduces inflammation and proptosis that occur in TED. We present safety and pharmacokinetic/pharmacodynamic (PK/PD) results from our study evaluating VRDN-002 dosed at 3–20 mg/kg in healthy volunteers (HVs) as well as modeling results to evaluate potential subcutaneous administration.

Methods : Adult HVs were randomized to 4 arms of 1 intravenous infusion as follows: placebo or 3 mg/kg, 10 mg/kg, or 20 mg/kg of VRDN-002. PK/PD parameters and adverse events (AEs) were assessed through 85 days. Additionally, to evaluate possible subcutaneous administration, a 2-compartment model with linear and Michaelis-Menten clearance was employed to estimate C_min and exposure for a range of dosing regimens.

Results : Three HVs received placebo (n=3). Nine HVs received VRDN-002, either 3 mg/kg (n=3), 10 mg/kg (n=3), or 20 mg/kg (n=3). VRDN-002 demonstrated an extended half-life up to 43 days. All VRDN-002 doses elicited rapid and sustained increases in IGF-1 serum levels, a biomarker for target engagement and IGF-1R inhibition. Mean IGF-1 serum levels increased within a day and reached levels 2–3 fold above baseline by Day 15 for all doses; they remained elevated through Day 85 for the 10 and 20 mg/kg groups. No increases in IGF-1 serum levels occurred in the placebo cohort. Four HVs in the drug group had transient and mild AEs (dizziness, headache, elevated blood pressure, hypotension). No hyperglycemia, muscle spasms, serious AEs, infusion reactions, or hearing impairment was observed. The model simulated potential subcutaneous dosing regimens for clinical evaluation.

Conclusions : A single dose of VRDN-002 administered intravenously at 3–20 mg/kg to HVs was well tolerated and indicated maximal target engagement as early as 15 days, with an extended half-life up to 43 days. These results suggest that VRDN-002 could be administered as a low-volume subcutaneous injection. A trial to test that hypothesis is planned, and if clinically meaningful efficacy is confirmed, VRDN-002 could reduce the treatment burden for IGF-1R blockade in TED.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.