ETA2023 45th Annual Meeting of the European Thyroid Association ETA 2023 Oral Session 9: Thyroid Eye Disease (5 abstracts)
VRDN-001, a full antagonist antibody to IGF-1 receptor: in vitro pharmacology and phase 1/2 results in patients with thyroid eye disease (TED)
Raymond Douglas 1 , Shoaib Ugradar 2 , Roger Turbin 3 , Kimberly Cockerham 4 , Rosa Tang 5 , Navdeep Nijhawan 6 , Andrea Kossler 7 , Chantal Boisvert 8 , Wendy Lee 9 , Michael Yen 10 , David Kaufman 11 , Michael Yoon 12 , Vahe Bedian 13 & Barrett Katz 13
1Cedars-Sinai Medical Center, Division of Ophthalmology Director, Orbital and Thyroid Eye Disease Program, Cedars Sinai Medical Center, Los Angeles, California, United States; 2Ucla Stein Eye Institute, Los Angeles, California, United States; 3Rutgers New Jersey Medical School, Department of Ophthalmology, Newark, New Jersey, United States; 4Byers Eye Institute at Stanford University, Senta Clinic, Palo Alto, California, United States; 5Eye Wellness Center--Neuro-Eye Clinical Trials, Inc., Bellaire, Texas, United States; 6Oshawa Clinic, Oshawa, Ontario, Canada; 7Byers Eye Institute at Stanford University, Palo Alto, California, United States; 8Duke Eye Center, Durham, North Carolina, United States; 9Bascom Palmer Eye Institute, Miami, Florida, United States; 10Baylor College of Medicine, Alkek Eye Center, Houston, Texas, United States; 11Msu Neurology, East Lansing, Michigan, United States; 12Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States; 13Viridian Therapeutics Inc, Waltham, Massachusetts, United States
Objectives: Antagonism of the IGF-1 receptor (IGF-1R) has been shown to reduce TED-related inflammation and proptosis. VRDN-001, a high-affinity antagonist antibody to IGF-1R, has distinct pharmacological properties that may enable differentiated dosing and better efficacy than observed with other antibodies. We assessed VRDN-001 in vitro pharmacology compared with teprotumumab and clinical proof of concept in a phase 1/2 randomized controlled trial (NCT05176639).
Methods: Inhibition of biotinylated IGF-1 binding to IGF-1R expressing FreeStyle™ 293-F cells was assessed by flow cytometry; inhibition of IGF-1 mediated signaling (phosphorylation of IGF-1R and AKT) was assessed in primary human ocular choroidal fibroblasts. In the phase 1/2 trial, adults with active moderate-to-severe TED and clinical activity score (CAS) ≥4 were randomized to 2 infusions 3 weeks apart of either 3, 10, or 20 mg/kg VRDN-001 or placebo. Safety and efficacy through 6 weeks were assessed.
Results: In the in vitro studies, VRDN-001 provided near-complete inhibition of IGF-1 binding and IGF-1 mediated signaling at concentrations ≥50 nM; in contrast, teprotumumab provided only partial inhibition of IGF-1 binding and IGF-1R signaling. In the phase 1/2 trial of VRDN-001 (n =21) vs placebo (n =6), baseline characteristics were similar between groups. All 3 doses of VRDN-001 showed similar reduction in proptosis and clinical activity at 6 weeks. Across all doses, the overall responder rate (% of patients with ≥2-mm reduction in proptosis and ≥2-point reduction in CAS) was 67% (14/21; VRDN-001) vs 20% (1/5; placebo). Mean reduction in CAS was 4.1 (VRDN-001) vs 1.8 (placebo), and CAS decreased to 0 or 1 for 62% (13/21; VRDN-001) vs 20% (1/5; placebo). Complete resolution of diplopia occurred for 54% (7/13; VRDN-001) vs 0% (0/3; placebo). AEs were mostly mild, with no severe or serious AEs reported.
Conclusions: VRDN-001 provides near-complete inhibition of IGF-1 binding and IGF-1R signaling, which may explain the rapid, marked reductions in proptosis and clinical activity in patients with TED enrolled in the phase 1/2 trial. The potential clinical efficacy and safety of VRDN-001 in TED will be further assessed in the THRIVE phase 3 randomized controlled trial.
Volume 92
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Endocrine Abstracts
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