Report the interim safety and pharmacodynamic (PD) results for healthy volunteers from a phase 1/2 clinical trial (NCT05176639) evaluating VRDN-001 intravenously administered at 3–20 mg/kg.

Adult healthy volunteers were randomized 3:1 to receive 2 intravenous infusions 3 weeks apart of either placebo or 3, 10, or 20 mg/kg VRDN-001. PD parameters (IGF-1 serum levels) and adverse events (AEs) were assessed up to 50 days.

Thirteen participants received VRDN-001 3 mg/kg (n=3), 10 mg/kg (n=3), 20 mg/kg (n=4), or placebo (n=3). Mean age was 49 years (range: 25?73) and 5 were female. All VRDN-001 doses elicited rapid, sustained, and similar increases in IGF-1 serum levels, a biomarker for IGF-1R inhibition. Following the first infusion, IGF-1 increased within a day, reaching 3–5-fold above baseline by Day 8. Increases were sustained until the second infusion, and then further increased to 5–7-fold above baseline (>500 ng/mL), and sustained through Day 50. No increases in serum IGF-1 occurred for placebo. Eleven of the 13 participants experienced 19 AEs (16 mild and 3 moderate). Transient hypotension (10 mg/kg group) and muscle spasm (placebo group) were the only AEs to be deemed treatment-related by the masked investigator. No treatment-related hyperglycemia or hearing impairment was observed.

VRDN-001 administered to healthy volunteers at 3–20 mg/kg indicated maximal target engagement at all doses and was generally safe and well-tolerated, with no observed treatment-related hyperglycemia or hearing impairment. Results from the ongoing evaluation of VRDN-001 dosed at 3–20 mg/kg in TED patients will further inform potential treatment regimens.