Oral Linsitinib Reduces Proptosis in Thyroid Eye Disease in Phase 2b/3 Trial

Topline results from the Phase 2b/3 LIDS trial demonstrated the positive efficacy and safety of linsitinib, an oral, small molecule therapy for patients with active, moderate to severe thyroid eye disease (TED).1

Announced by Sling Therapeutics on January 14, 2025, linsitinib met the study’s primary endpoint, achieving a statistically significant reduction in proptosis at the 150 mg twice-daily dose, with a validated safety profile, for patients with TED.

“The positive data from this trial establish the clinical significance of linsitinib and represent the first ever successful clinical trial of an oral small molecular for the treatment of TED,” Ryan Zeidan, PhD, president and chief executive officer of Sling Therapeutics, said in a statement. “We believe linsitinib can be a potential new treatment option that would enable a broader number of physicians across multiple therapeutic disciplines to treat patients diagnosed with TED.”

Nearly 70,000 people in the United States are impacted by TED, a progressive and vision-threatening rare autoimmune disease.2 Common in people living with Graves’ disease and hyperthyroidism, particularly in women, TED is caused by dysfunction in the IGF-1R signaling pathway leading to fibrous tissue growth behind the eyes.

As tissue growth leads to pain, proptosis, and diplopia, a patient’s quality of life can be severely impacted. The standard of care for TED often includes orbital surgery or infusions, with the potential for safety outcomes, including hearing loss, hyperglycemia, or changes in the menstrual cycle.

Sling Therapuetics’ linsitinib has established a tolerable safety profile across 15 clinical trials involving more than 900 patients in numerous disease areas.1 In clinical development for TED, linsitinib inhibits the IGF-1R target, the only validated clinical target in TED, and the sole target for current FDA-approved therapies.

A randomized, double-masked, placebo-controlled study, LIDS was designed to measure the safety, pharmacokinetics, and efficacy of linsitinib, with a primary endpoint of the percentage of participants considered proptosis responders at Week 24. This was defined as a ≥2mm reduction in proptosis from baseline.

Across 35 sites in 5 countries, the Phase 2b/3 study randomized 90 patients with TED 1:1 to receive linsitinib 150 mg twice daily, linsitinib 75 mg twice-daily, or placebo for 24 weeks. Key topline data showed a statistically significant and clinically meaningful proptosis responder rate (PRR) at the 150 mg dose, with a PRR of 52% (P = .01) at Week 24.

Sling Therapeutics indicated the safety profile of linsitinib validated previous results from previous oncology studies, with a favorable impact on key adverse events (AEs) of interest for the IGF-1R target. Trial results reported no drug-related hearing impairment or tinnitus, as well as menstrual cycle changes, with linsitinib 150 mg treatment. These data showed a 3% rate of hyperglycemia, with no required intervention.

Treatment-emergent AEs apparent in ≥10% of cases included diarrhea (20.7%), headache (20.7%), nausea (20.7%), fatigue (17.2%), ALT increase (17.2%), hyperhidrosis (13.8%), AST increase (10.3%), and muscle spasms (10.3%). Most AEs were considered mild or moderate and quickly resolved upon treatment pause or discontinuation. Importantly, results from LIDS revealed no QTc prolongation in any patient, after conducting rigorous ECG monitoring during the study period.

“These side effects are the largest barriers for current medical treatments, making linsitinib an important potential new therapy for patients with TED,” Raymond Douglas, MD, PhD, a professor at Cedars-Sinai Medical Center and chief scientific officer at Sling Therapeutics, said in a statement. “As a practicing physician, it makes sense to start a new patient’s treatment journey with an oral therapy that shows an early response that increases over time.”

In their release, Sling Therapeutics announced they are engaged in discussions with regulatory authorities to confirm the Phase 3 trial design, with plans to begin in 2025. The company also announced full results from LIDS will be presented at an upcoming medical meeting.

“We are excited to continue our clinical program and are on track to initiate our confirmatory Phase 3 registrational trial later this year,” Zeidan added.

References

1. Sling Therapeutics announces positive topline results from phase 2B/3 lids clinical trial of oral small molecule linsitinib in patients with thyroid eye disease. Sling Therapeutics. January 14, 2025. Accessed January 15, 2025. https://www.slingtx.com/2025/01/14/sling-therapeutics-announces-positive-topline-results-from-phase-2b-3-lids-clinical-trial-of-oral-small-molecule-linsitinib-in-patients-with-thyroid-eye-disease/.
2. Shah SS, Patel BC. Thyroid Eye Disease. [Updated 2023 May 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK582134/