Abstract
Clinical and preclinical studies have confirmed insulin-like growth factor-1 receptor (IGF-1R) antagonism can reduce the inflammation and proptosis occurring in thyroid eye disease (TED). We assessed the preclinical pharmacology, pharmacokinetics, and pharmacodynamics of veligrotug (formerly VRDN-001), an anti-IGF-1R antibody in clinical development for TED. Veligrotug exhibited high-affinity binding to human IGF-1R protein (KD 0.55 nM) and IGF-1R endogenously expressed in HOCF cells (mean EC50 2.41 nM). Veligrotug did not bind to the insulin receptor in ELISA assays or inhibit insulin-mediated receptor phosphorylation in HepG2 cells. Binding epitope and antagonist properties were compared to teprotumumab (Tepezza®), a marketed anti-IGF-1R antibody. Mutational scan analysis demonstrated veligrotug and teprotumumab have overlapping but distinct binding epitopes. Veligrotug behaved as a full antagonist, providing near-complete inhibition of IGF-1 binding at ≥ 50 nM, in contrast to teprotumumab which plateaued at ~50% inhibition. Veligrotug provided near-complete inhibition of IGF-1R autophosphorylation and AKT phosphorylation, in contrast to partial inhibition by teprotumumab. Veligrotug pharmacokinetic parameters in cynomolgus monkeys were consistent with other human/humanized antibodies in monkeys: half-life was ~5-6 days, serum clearance was low (7.6‒12.9 mL/day/kg), and volume of distribution was low (64‒93 mL/kg). A robust pharmacodynamic response was observed after a single dose of veligrotug, with ~2.5-fold increases in IGF-1 levels that remained elevated throughout the dosing period for the 10 mg/kg and 50 mg/kg dose groups. Veligrotug's pharmacologic, pharmacokinetic, and pharmacodynamic characteristics make it a good candidate for clinical development. Indeed, efficacy data at week 15 from two Phase 3 pivotal studies of veligrotug, THRIVE and THRIVE-2, showed statistically significant improvements in TED symptoms based on primary and secondary outcomes.