Preclinical Pharmacokinetics of VRDN-003, A Next-Generation Half-life Extended Antibody to the IGF-1 Receptor for Thyroid Eye Disease

Abstract

Purpose : Clinical and preclinical studies have demonstrated IGF-1 receptor (IGF-1R) antagonism reduces the inflammation and proptosis that occur in thyroid eye disease (TED). VRDN-001 is a full antagonist to IGF-1R with subnanomolar affinity, while VRDN-003 is a next-generation, half-life extended version of VRDN-001 designed to enable subcutaneous administration via a fixed dose patient-controlled pen. We compared the pharmacokinetic (PK) parameters of VRDN-003 with those of VRDN-001 in non-human primates.

Methods : VRDN-001 and VRDN-003 were administered to cynomolgus monkeys as a single dose by either intravenous (IV) infusion or subcutaneous (SC) injection at 7.5 mg/kg. PK samples were collected at 12 time points (VRDN-001 group) or 15 time points (VRDN-003 group). Data were analyzed using the WinNonlin non-compartmental model.

Results : When administered via either IV infusion or SC injection, half-life was approximately two times as long, AUC_inf approximately 65% greater, and clearance approximately 40% less for VRDN-003 vs VRDN-001 (Table 1). Bioavailability (ratio AUC-SC/AUC-IV) was similar for the two antibodies: 71% for VRDN-003 and 70% for VRDN-001.

Conclusions : VRDN-003 demonstrated a desirable PK profile in non-human primates, with approximately twice the half-life of first generation anti-IGF-1R antibodies, suggesting potential for convenient, low-volume, SC self-administration for TED patients.

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

 

Table 1. IV and SC PK Parameters of VRDN-001 and VRDN-003