Acelyrin, Inc. has announced positive proof-of-concept data from its Phase 1/2 trial of lonigutamab in patients with thyroid eye disease (TED). The trial results indicate that lonigutamab, a subcutaneously delivered humanized IgG1 monoclonal antibody targeting the insulin-like growth factor-1 receptor (IGF-1R), shows promise as a treatment for this vision-threatening autoimmune condition.
Clinical Trial Results
The Phase 1/2 trial (NCT05683496) was a multi-center, dose-ranging study evaluating the safety and efficacy of lonigutamab in TED patients. Cohort 1 was placebo-controlled, with six patients receiving lonigutamab 40mg every three weeks and two receiving placebo. Cohort 2 was open-label, with six patients receiving a 50mg loading dose followed by 25mg weekly. The study demonstrated rapid improvements in proptosis and clinical activity score (CAS) within three weeks of the first subcutaneous dose.
Specifically, in Cohort 1, 50% of lonigutamab-treated patients achieved a ≥ 2 millimeter reduction in proptosis from baseline, 100% achieved a ≥ 2 point reduction in CAS, and 25% showed improvement on a double vision scale. In Cohort 2, the response rates were 67%, 83%, and 40% for proptosis, CAS, and diplopia, respectively. No such improvements were observed in the placebo group.
Safety and Tolerability
Lonigutamab was generally well-tolerated across the clinical experience to date. There were no reports of hyperglycemia or hearing impairment, and no serious adverse events were observed.
Mechanism of Action and Potential Advantages
Lonigutamab targets the IGF-1R, a validated mechanism of action for TED. Unlike the current standard of care, teprotumumab (Tepezza), which is administered intravenously, lonigutamab is delivered subcutaneously. This route of administration may offer several advantages, including convenience and a potentially favorable safety profile by avoiding high maximal concentrations associated with IV administration.
Shao-Lee Lin, MD, PhD, Founder and CEO of ACELYRIN, stated, "The data support our hypothesis that lonigutamab has the potential to optimize benefit-risk by enabling longer-term subcutaneous dosing to increase depth and durability of clinical response while attempting to limit safety liabilities by avoiding the high maximal concentrations resulting from IV administration, while maintaining optimal therapeutic levels."
Future Development
Based on these positive results, Acelyrin plans to initiate a Phase 2b/3 trial in the second half of 2024. This trial is designed to be the first of two registrational trials for lonigutamab in TED.
Market Context
Thyroid eye disease affects an estimated 100,000 people in the United States. Teprotumumab (Tepezza), marketed by Amgen following its acquisition of Horizon Therapeutics, achieved blockbuster status with nearly $2 billion in net sales in 2022. Lonigutamab, if approved, would compete in this market, potentially offering a more convenient subcutaneous administration option.
However, Viridian Therapeutics is also developing similar medicines, with one intravenous version already in Phase 3 testing and a subcutaneous version potentially following later this year.
Expert Commentary
Shoaib Ugradar, MD, Department of Orbital and Oculoplastic Surgery, private practice, Beverly Hills, California, commented, "It is very encouraging to see the results of subcutaneous administration of an anti-IGF-1R therapy... Given the growing body of evidence that suggests thyroid eye disease may have long-term sequelae, the convenience of a subcutaneous administered medication with a potentially favorable side effect profile becomes critical."
