6461 VRDN-003, a Full Antagonist Antibody to the IGF-1 Receptor for Thyroid Eye Disease (TED): Safety and Pharmacokinetic Results of Subcutaneous Administration in Healthy Volunteers

Abstract Disclosure: K. Foster: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. B. Dickinson: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. A. Matthew: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. J. Vijayaraghavan: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. C. Michalsky: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. V. Bedian: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. Introduction: While VRDN-001 is a full antagonist antibody to the IGF-1 receptor (IGF-1R) with phase 2 proof-of-concept data showing clinically meaningful improvements in thyroid eye disease (TED) symptoms after 2 intravenous (IV) infusions, VRDN-003 is a next-generation half-life extended version of VRDN-001. VRDN-003’s half-life extension has the potential to provide sustained pharmacokinetics (PK) and pharmacodynamics (PD) with less frequent administration. We present results from an ongoing study to assess the safety, PK, PD, and bioavailability of VRDN-003 for subcutaneous (SC) administration. Methods: Healthy volunteers (HVs) were randomized to receive a single dose of VRDN-003 or placebo in the following 4 IV or SC dose cohorts: IV 5.0 mg/kg, IV 15.0 mg/kg, SC 300 mg, or SC 600 mg. Preliminary treatment-emergent adverse events (AEs) were assessed through December 12, 2023, and will continue to be assessed through study exit (120 days). Preliminary PK parameters including bioavailability were assessed by noncompartmental analysis, and a 2-compartment Population PK model was employed to simulate exposures following repeat SC dosing. Results: Twenty-eight HVs received either VRDN-003 IV (n=8), VRDN-003 SC (n=12), placebo IV (n=4), or placebo SC (n=4). AEs were reported by 25% (2/8) of participants who received VRDN-003 IV, 25% (3/12) who received VRDN-003 SC, and 13% (1/8) who received placebo. Of the AEs, 3 were deemed treatment related, all occurring in VRDN-003 SC-treated patients and all grade 1/mild as follows: injection site reaction, insomnia, and hepatic enzyme increased. No serious AEs were reported. VRDN-003 half-life was estimated at 40-50 days, 4-5 times longer than VRDN-001; bioavailability is currently estimated to be approximately 60% after SC administration. Simulated dosing regimens show the potential for VRDN-003 to be administered SC Q4W or Q8W and reach exposure levels observed with the VRDN-001 parent molecule in its prior phase 2 study. Conclusions: A single dose of VRDN-003 administered IV or SC to HVs was well tolerated and showed favorable PK for SC administration including a half-life of 40-50 days, 4-5 times longer than its parent molecule, VRDN-001. These results show the potential for VRDN-003 SC dosing regimens with the goal of reducing the treatment burden associated with achieving IGF-1R blockade in TED. Safety and efficacy of VRDN-003 SC will be further assessed in planned clinical studies enrolling patients with TED. Presentation: 6/1/2024