Michigan-based Sling Therapeutics has dosed the first patients in the ORBIT pivotal trial, a global Phase III study of linsitinib in moderate to severe active thyroid eye disease (TED), according to the company. The enrollment milestone moves the only oral small molecule in late-stage TED development into a registrational study designed to support an eventual regulatory submission.
Linsitinib inhibits the insulin-like growth factor-1 receptor (IGF-1R) and the insulin receptor, blocking downstream signaling that drives orbital fibroblast activation, inflammation, and the proptosis characteristic of TED. The ORBIT trial is randomized, double-masked, and placebo-controlled, enrolling approximately 130 adults in a 1:1 ratio to receive oral linsitinib 150 mg or placebo twice daily for 24 weeks. The primary endpoint is the proportion of proptosis responders at week 24, defined as a reduction of at least 2 mm in the study eye without corresponding worsening in the fellow eye. Secondary endpoints include mean proptosis change from baseline, overall responder rate, Clinical Activity Score (CAS), and the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire. Patients completing the double-masked period are eligible for a 24-week open-label extension.
The trial is the second pivotal study of linsitinib in TED. The Phase IIb/III LIDS trial, which reported positive topline results in January 2025, met its primary endpoint with statistical significance at the 150 mg twice-daily dose, achieving a 52% proptosis responder rate at week 24 (p = 0.01). No drug-related hearing impairment was reported in the 150 mg arm, with a 0% placebo-adjusted tinnitus rate and a 3% rate of hyperglycemia — a safety profile that Sling said differentiates linsitinib from the hearing-related adverse events associated with intravenous IGF-1R-targeting biologics. Elevated liver transaminases were observed but resolved without signs of drug-induced liver injury.