12318 Preliminary Safety and Efficacy of Subcutaneous Lonigutamab (anti-IGF-1R) from a Phase 1/2 Proof of Concept Study in Patients with Thyroid Eye Disease

Abstract Disclosure: S. Ugradar: Consulting Fee; Self; Amgen Inc, Viridian Therapeutics, ACELYRIN, INC. D.A. Kostick: Research Investigator; Self; ACELYRIN, INC.. Speaker; Self; Amgen Inc. J. Spadaro: None. A. Grover: Employee; Self; ACELYRIN, INC.. Stock Owner; Self; ACELYRIN, INC. S. Imm: Employee; Self; ACELYRIN, INC.. Stock Owner; Self; ACELYRIN, INC. S. Chesler: Employee; Self; ACELYRIN, INC.. Stock Owner; Self; ACELYRIN, INC. S. Mpofu: Employee; Self; ACELYRIN, INC.. Stock Owner; Self; ACELYRIN, INC. J. Khong: Advisory Board Member; Self; ACELYRIN, INC.. Consulting Fee; Self; ACELYRIN, INC., Amgen Inc. Grant Recipient; Self; Centre for Eye Research Australia. Other; Self; Royal Australian and New Zealand College of Ophthalmologists, Royal Victorian Eye and Ear Hospital. Background: Thyroid eye disease (TED) is a chronic debilitating autoimmune condition with limited effective therapies, affording the opportunity for increased depth and durability of response with long-term subcutaneous (SC) treatment. Overexpression of the IGF-1R pathway underpins the pathophysiology of TED. We present data from the first 2 cohorts of an ongoing phase 1/2 dose-ranging study of SC lonigutamab, a high-affinity humanized anti-IGF-1R monoclonal antibody, in patients (pts) with TED (NCT05683496). Methods: Eligible pts are 18-75 years old and have active TED, with proptosis of ≥3 mm above normal range in the study eye and a Clinical Activity Score (CAS) of ≥4 (on a 7-item scale). Cohort 1 (completed) was double masked and randomized 3:1 to lonigutamab (40 mg every 3 weeks) or matching placebo for 2 doses; wk 6 (on-treatment) and week 12 (off-treatment follow-up) efficacy data are reported. Cohort 2 received open-label lonigutamab for 12 doses (loading dose of 50 mg, then 25 mg weekly for 11 weeks); 6-wk data are reported. Response rates were calculated using nonresponder imputation. Results: In cohort 1, 8 pts were enrolled (lonigutamab, n=6; placebo, n=2 [1 with evaluable post-baseline data]). Treatment-emergent adverse events (TEAEs) occurred in 4/6 (67%) pts receiving lonigutamab and 2/2 (100%) receiving placebo. All but 1 TEAE were grade 1; a single event was grade 2, with no serious TEAEs. In the lonigutamab group, 3 pts had AEs of special interest (AESIs; all tinnitus, no changes on audiogram); 1 pt in the placebo group discontinued due to dysthyroid optic neuropathy. At wks 6 and 12, 3/6 (50%) pts in the lonigutamab group and 0/2 (0%) pts in the placebo group had a proptosis response. Among pts with diplopia at baseline (lonigutamab, 4/6; placebo, 2/2), 1/4 (25%) and 0/2 (0%) pts had a diplopia response at wks 6 and 12. In the lonigutamab group, 6/6 (100%) pts achieved a clinically meaningful reduction (≥2 points) in CAS in the study eye at wk 6, which was retained through wk 12 (vs 0/2 [0%] pts for placebo). In cohort 2, 6 pts receiving lonigutamab had 6-wk data. TEAEs were reported in 5/6 (83%) pts (all grade 1-2); there were no AESIs or serious TEAEs. At wk 6, 4/6 (67%) pts had a proptosis response. Among pts with baseline diplopia (5/6), 2/5 (40%) pts had a diplopia response. At wk 6, 5/6 (83%) pts achieved a ≥2-point reduction in CAS in the study eye. Conclusions: These findings with lonigutamab represent the first proof-of-concept results of a SC anti-IGF-1R in pts with TED (cohort 1). Pts achieved clinical responses across manifestations of disease early and were able to maintain their responses through the time points evaluated, including the wk 12 off-treatment time point, supporting the potential for longer dosing intervals. Data from cohort 2 further substantiate the efficacy seen in cohort 1. Lonigutamab was well-tolerated and warrants further investigation. Presentation: 6/3/2024