Endocrine Abstracts

Objectives: Prior phase 2 proof-of-concept results showed the clinical activity of 2 intravenous (IV) infusions of VRDN-001 in active and chronic thyroid eye disease (TED). VRDN-003 is a next-generation antibody that has the same binding epitope as VRDN-001 but includes a half-life extension modification. We present preliminary results from an ongoing phase 1 study showing the effect of VRDN-003’s half-life extension on its pharmacokinetics (PK), pharmacodynamics (PD), and safety profile when administered as IV infusion vs subcutaneous (SC) injection.

Methods: Healthy volunteers (HVs) were randomized to receive a single dose of VRDN-003 or placebo in the following 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 at different intervals (Q2W, Q4W, Q8W).

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 by the investigator, all occurring in VRDN-003 SC–treated participants and all grade 1/mild as follows: injection site reaction, insomnia, and hepatic enzyme increased (both AST and ALT approximately 2 times the upper limit of normal, resolved during follow-up). No serious AEs were reported. VRDN-003 half-life was estimated to be 40–50 days, 4–5 times longer than that of VRDN-001. Bioavailability was estimated to be approximately 60% after SC administration. Based on simulated dosing regimens, VRDN-003 could be administered SC less frequently than the current Q3W regimen for VRDN-001 (e.g., SC Q4W or Q8W) while reaching similar exposure levels observed with VRDN-001 IV Q3W in its prior phase 2 study.

Conclusion: These results show the potential for VRDN-003 SC dosing regimens. A single dose of VRDN-003 was well tolerated with an extended half-life 4–5 times longer than that of its parent molecule, VRDN-001. Safety and efficacy of VRDN-003 SC are planned to be further assessed in clinical studies enrolling patients with TED.