VRDN-002, A Second-Generation Insulin Like Growth Factor-1 Receptor (IGF-1R) Inhibitory Antibody for Thyroid Eye Disease: Preclinical Pharmacokinetics and Clinical Promise

Abstract

Purpose : VRDN-002 is a novel anti-IGF-1R monoclonal antibody intended for treatment of Thyroid Eye Disease (TED). It is engineered to incorporate Fc modifications for half-life extension to enable convenient dosing. TED is most prevalent in patients with Graves’ Disease and is driven by Thyroid Stimulating Hormone Receptor (TSHR) agonistic autoantibodies and crosstalk between TSHR and IGF-1R. We sought to compare the pharmacokinetic (PK) parameters of VRDN-002 in cynomolgus monkeys to the marketed IGF-1R antibody, teprotumumab, and to estimate potential human exposures for various dosing paradigms.

Methods : VRDN-002 was administered to cynomolgus monkeys by 30 min intravenous (IV) infusion at 2, 10, and 50 mg/kg, and by subcutaneous (SC) injection at 2 and 10 mg/kg. Teprotumumab 10 mg/kg was also administered by 30 min IV infusion. PK samples were collected at 30 min, 2 and 8 hrs, and 1, 3, 7, 10, 14, 21, 28, 35, 42, 49, and 56 days. VRDN-002 and Teprotumumab levels in serum were measured using a human IgG specific ELISA. Data were analyzed using the WinNonlin non-compartmental model. In addition, a semi-mechanistic model incorporating target-mediated drug disposition (TMDD) was constructed based on a population pharmacokinetic model of teprotumumab in TED patients, as well as VRDN-002 and teprotumumab PK in NHPs. The model was used to estimate human PK for VRDN-002.

Results : VRDN-002 PK administered by IV infusion was approximately linear between 10 and 50 mg/kg doses, suggesting TMDD was saturated at these doses. At 10 mg/kg, VRDN-002 half-life and AUC_inf were 14 ± 4 days and 2,300 ± 312 µg.day/mL, respectively, vs. 6.4 ± 0.3 days and 779 ± 79 µg.day/mL for teprotumumab. Bioavailability of VRDN-002 administered via SC injection was 62%. Human exposure estimates of VRDN-002 for various dosing regimens were generated from the semi-mechanistic model.

Conclusions : VRDN-002 demonstrated a desirable PK profile in non-human primates, suggesting potential as a novel therapeutic monoclonal antibody for the treatment of TED. The prolonged half-life of VRDN-002 may enable lower frequency of IV infusion and/or low-volume SC injection; each possibility awaits clinical confirmation.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.