Sling Therapeutics' linsitinib, an oral small molecule, has demonstrated significant efficacy in reducing proptosis among patients with thyroid eye disease (TED). The Phase 2b/3 LIDS trial, a randomized, double-masked, placebo-controlled study, evaluated the safety, pharmacokinetics, and efficacy of linsitinib in patients with active, moderate to severe TED.
The trial enrolled 90 patients who were randomized 1:1:1 to receive either linsitinib 150mg BID, linsitinib 75mg BID, or placebo for 24 weeks across 35 sites in five countries. The primary endpoint was the percentage of subjects who were proptosis responders at week 24, defined as at least a two-millimeter reduction in proptosis from baseline.
Key Findings from the LIDS Trial
The LIDS trial met its primary endpoint with statistical significance for the 150mg BID dose. The proptosis responder rate (PRR) was 52% (p = 0.01) at Week 24, indicating a clinically meaningful reduction in proptosis. Linsitinib also validated the safety profile seen in prior oncology studies and demonstrated a favorable safety profile on key adverse events (AEs) of interest for the IGF-1R target.
Specifically, the 150mg BID arm showed:
- No drug-related hearing impairment reported (1 unrelated report out of 29 patients)
- 0% tinnitus placebo-adjusted rate
- 3% rate of hyperglycemia (1 report out of 29 patients with no intervention required)
- 0% menstrual cycle changes reported
Treatment emergent AEs greater than or equal to 10% 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%). Hepatic transaminases were all quickly resolved and not associated with any elevations of total bilirubin, alkaline phosphatase, hepatic dysfunction, or other signs or symptoms of drug-induced liver injury. No QTc prolongation was observed in any patient with rigorous ECG monitoring throughout the study.
Clinical Significance
"The positive data from this trial establish the clinical significance of linsitinib and represent the first ever successful clinical trial of an oral small molecule for the treatment of TED," said Ryan Zeidan, Ph.D., President and Chief Executive Officer of Sling Therapeutics. "We believe linsitinib can be a potential new treatment option that could enable a broader number of physicians across multiple therapeutic disciplines to treat patients diagnosed with TED."
Raymond Douglas, M.D., Ph.D., Professor at Cedars-Sinai Medical Center and Chief Scientific Officer at Sling Therapeutics, emphasized the potential benefits for patients: "In this trial, patients demonstrated significant improvement in disease with no drug-related hearing impairments or significant hyperglycemia. These side effects are the largest barriers for current medical treatments, making linsitinib an important potential new therapy for patients with TED. 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."
About Thyroid Eye Disease (TED)
Thyroid Eye Disease (TED) is a serious, progressive, and vision-threatening rare autoimmune disease that affects approximately 70,000 people in the U.S. and has a similar prevalence in the EU. TED often occurs in people living with Graves' disease and hyperthyroidism and is caused by dysfunction in the IGF-1R signaling pathway which results in fibrous tissue growth behind the eyes. This leads to several negative symptoms that may have long-term, irreversible damage as the tissue growth pushes the eyes forward or causes the eyes and eyelids to become red and swollen. As the disease progresses it can lead to pain, eye bulging (proptosis), and double vision (diplopia), thus dramatically impacting a patient's quality of life.
Next Steps
Sling Therapeutics is engaging with regulatory authorities to discuss the confirmatory Phase 3 trial design, which is on track to commence in 2025. Full results of this Phase 2b/3 trial will be presented at an upcoming medical conference.
