Preclinical Pharmacokinetics and Bioavailability of VRDN-002, a Next-Generation Half-Life Extended Antagonist Antibody to IGF-1 Receptor for Thyroid Eye Disease (TED)

Abstract

Purpose : Clinical and preclinical studies have demonstrated IGF-1 receptor (IGF-1R) antagonism reduces the inflammation and proptosis that occur in TED. VRDN-002 is a next-generation, antagonist antibody to the IGF-1 receptor with modification to the Fc region to extend half-life in development for TED. We conducted 2 studies in cynomolgus monkeys to evaluate the pharmacokinetics (PK) and bioavailability (F) of VRDN-002.

Methods : Naïve cynomolgus female monkeys were administered a single dose of VRDN-002 via subcutaneous (SC) injection or 30-minute intravenous (IV) infusion. In the 1^st study, monkeys received 10 mg/kg VRDN-002 SC (n=3) or IV (n=3); in the 2^nd study, monkeys received 30 mg/kg VRDN-002 SC (n=3) or 100 mg/kg VRDN-002 SC (n=3) or IV (n=3). Serum samples were collected on Day 0 before dosing and up to 8 hours post dose, and on Day 1 through Day 56 post dose. VRDN-002 concentrations were measured using a human IgG specific sandwich ELISA method and analyzed using a noncompartmental approach.

Results : VRDN-002 mean half-life (t_1/2) estimates ranged from 11.2 to 14.4 days across all study groups. For the 10 and 100 mg/kg IV groups, the mean volume of distribution at steady state (V_ss) ranged from 85.7 to 92.7 mL/kg, and clearance (CL) ranged from 4.40 to 4.89 mL/day/kg. For the 10, 30, and 100 mg/kg SC groups, CL/F ranged from 6.94 to 7.49 mL/day/kg and volume of distribution of the terminal phase (V_z)/F ranged from 111 to 142 mL/kg. Estimated SC bioavailability (ratio of mean area under the curve [AUC_inf] for SC vs. IV) was 60% for 10 mg/kg VRDN-002 (1390 µg*day/mL vs. 2300 µg*day/mL) and 69% for 100 mg/kg VRDN-002 (14400 µg*day/mL vs. 20800 µg*day/mL).

Conclusions : A single dose of VRDN-002 administered either intravenously or subcutaneously at 10-100 mg/kg to cynomolgus monkeys demonstrated high bioavailability and an extended half-life compared with unmodified IgG1 antibodies, which may enable treatment with low doses and/or more convenient administration regimens. These results along with those from our phase 1 study will help determine SC dosing regimens of VRDN-002 in patients with TED.

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