Abstract Listings 2024

Purpose

VRDN-001 and VRDN-003 are full antagonist antibodies to the IGF-1 receptor (IGF-1R). They have the same binding domain but VRDN-003 contains half-life extension modifications. Prior phase 2 data for VRDN-001 showed clinically meaningful improvements in TED signs and symptoms after 2 intravenous (IV) infusions administered every 3 weeks (Q3W). Here we show phase 1 data comparing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of VRDN-003 vs VRDN-001 administered as a subcutaneous (SC) injection.

Methods

In separate studies, healthy volunteers (HVs) received either VRDN-003 SC (1 or 2 doses given 28 days apart) or VRDN-001 SC (1 dose). Preliminary data, including adverse events (AEs), PK, and PD (increases in IGF-1 serum levels) were assessed, and simulated exposures were generated for repeat VRDN-003 SC dosing.

Results

HVs received either VRDN-003 SC (300 mg [n=6]; 600 mg [n=6]; 600 + 300 mg [n=4]) or VRDN-001 SC (300 mg [n=8]). AEs were reported in 31% (5/16) for VRDN-003 and 38% (3/8) for VRDN-001, with no treatment related discontinuations, no hearing-related AEs, and no serious AEs. Half-life was ~40–50 days for VRDN-003 vs ~10-12 days for VRDN-001. IGF-1 serum levels were similar for both antibodies (>4-fold above baseline) but sustained longer for VRDN-003 (>40 days). Dosing simulations indicated that VRDN-003 SC could be administered less frequently than VRDN-001 IV while achieving similar exposures.

Conclusion

At 2 dose levels, single and repeat SC injections of VRDN-003 in HVs were well tolerated, had a 4-5 times longer half-life than VRDN-001, and demonstrated sustained increases in IGF-1 levels—potentially enabling low-volume SC dosing as infrequently as Q8W, while achieving exposures in the range of those observed with VRDN-001 IV dosing Q3W. The safety and efficacy of VRDN-003 SC will be assessed in clinical studies enrolling patients with TED.

Additional Authors

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