Oral IGF-1R Inhibitor Enters Phase 3 in TED: Validated Target, Unproven Modality, Structural HTA Trap

Sling Therapeutics Doses First Patients in Phase 3 ORBIT Trial

Sling Therapeutics has announced the dosing of the first patients in its global Phase 3 ORBIT pivotal trial for linsitinib, an oral small molecule inhibitor of IGF-1R, targeting moderate to severe active thyroid eye disease (TED). This randomized, double-masked, placebo-controlled study aims to enroll approximately 130 participants, who will receive either 150 mg of linsitinib 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 proptosis. Linsitinib is positioned as the first and only oral IGF-1R inhibitor in Phase 3 development, offering a potential oral alternative to current infused biologic therapies for TED.

• The ORBIT trial is a global, randomized, double-masked, placebo-controlled Phase 3 study evaluating linsitinib for moderate to severe active TED. As the second pivotal study for linsitinib in TED, it aims to build on existing evidence supporting its potential as an effective, disease-modifying oral therapy. This trial is crucial for establishing linsitinib as a differentiated option compared to currently available infused biologics, addressing treatment burden and safety concerns.
• Thyroid Eye Disease is a serious, progressive, and vision-threatening rare autoimmune condition affecting over 200,000 people in the U.S., often leading to irreversible damage. Current treatments, primarily invasive surgery or lengthy infusions, present significant limitations including potential adverse events like hearing loss and the burden of frequent clinic visits. Linsitinib, as an oral IGF-1R inhibitor, seeks to overcome these barriers by providing a convenient and accessible treatment option.
• The ORBIT trial's primary endpoint focuses on the proportion of proptosis responders at Week 24, defined as a reduction of at least 2 mm in proptosis without worsening in the fellow eye. Key secondary endpoints include mean change in proptosis, overall responder rate, Clinical Activity Score (CAS), and Graves’ Ophthalmopathy Quality of Life (GO-QoL). Linsitinib has an established safety profile from over 900 patients across 15 clinical trials and has received Fast Track Designation from the U.S. FDA.

Overcoming Treatment Burden and Limitations in Thyroid Eye Disease

Despite meaningful advances in TED therapeutics, significant clinical and practical challenges persist across both established and emerging treatment modalities. The heterogeneity of disease presentation — spanning acute inflammatory phases to chronic, fibrotic sequelae — complicates treatment selection and limits the generalizability of trial findings to real-world populations.

• Glucocorticoid limitations: Oral and intravenous glucocorticoid therapy has been used for decades in active TED, but efficacy is variable, results may be temporary, and side effects are significant. Long-term cardiovascular, renal, and infectious risks are substantially elevated compared to teprotumumab, including higher rates of acute myocardial infarction, heart failure, acute kidney failure, pneumonia, and severe sepsis.

• Surgical complexity and variable outcomes: Strabismus surgery in dysthyroid ophthalmopathy has historically yielded success rates ranging from 43% to 82%, with no demonstrated difference in outcome between correction of restricted duction versus deviation. Orbital decompression prior to teprotumumab treatment is associated with statistically significant reductions in both diplopia response (46.7% vs. 77.5%, p = 0.014) and proptosis response (75.0% vs. 90.9%, p = 0.045) compared to surgery-naïve patients.

• Teprotumumab adverse event burden: AEs occur in 81.7% of treated patients, with a median of 4 AEs per patient. While most are mild, 28.2% of patients experience moderate AEs and 8.4% severe AEs. The most common types are musculoskeletal (58.0%), gastrointestinal (38.2%), and ear and labyrinth disorders (30.5%), with 12.2% of patients discontinuing therapy due to AEs. Hearing loss, in particular, may be persistent — with hypoacusis reported as an ongoing complication at 18 months post-treatment in published case reports.

• Heightened risk in geriatric populations: In patients aged 75 and older, 34.0% discontinued teprotumumab due to treatment-related adverse events. The most common TAEs in this cohort were muscle cramps (42.0%), hearing impairment (38.0%), and hyperglycemia (36.0%). Proptosis regression occurred in 62.5% of patients at 2.5 years, and 27.9% experienced TED reactivation at an average of 49.8 weeks post-treatment completion, underscoring the need for selective use and long-term monitoring in this population.

• Metabolic and inflammatory comorbidity management: Hyperglycemia, resulting from disrupted growth hormone feedback and potentially worsened by prior glucocorticoid use, requires careful pre-treatment screening — particularly in patients with existing diabetes. Teprotumumab can exacerbate existing hyperglycemia and may trigger inflammatory bowel disease flares, necessitating exclusion or close monitoring of at-risk patients.

• Incomplete response in recalcitrant disease: Among patients who failed prior therapy, diplopia response to teprotumumab was 69.1% — lower than proptosis (85.9%) and CAS (93.8%) responses — indicating that diplopia remains the most refractory outcome. Patients with prior orbital decompression represent a particularly challenging subgroup with meaningfully reduced treatment response across multiple endpoints.

Unpacking the ORBIT Phase 3 Pivotal Trial Design for Linsitinib

Several pivotal and prospective trials have evaluated disease-modifying therapies for active, moderate-to-severe TED, spanning IGF-1R inhibitors, IL-6 receptor antagonists, and placebo-controlled designs. The table below summarizes key study design parameters and endpoints across these trials.

Linsitinib: An Oral IGF-1R Inhibitor with a Differentiated Safety Profile

Across phase I dose-escalation studies in patients with advanced solid tumors, linsitinib (OSI-906) demonstrated a manageable safety profile at its established maximum tolerated doses. In the continuous dosing phase I study (N=86 treated), dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3), with MTDs established at 400 mg once daily and 150 mg twice daily — the latter designated as the recommended phase II dose. The intermittent dosing phase I study identified an MTD of 600 mg for both the days 1–3 every 14 days and days 1–7 every 14 days schedules, with dose-limiting toxicities comprising grade 3–4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval; common lower-grade events included nausea, vomiting, fatigue, and diarrhea. In the phase I study combining linsitinib with erlotinib (N=91 treated), seven patients experienced dose-limiting toxicities — QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1) — while common adverse events across schedules included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), and vomiting (40%), with no evidence of drug-drug interaction identified.

In combination studies, the tolerability picture was broadly consistent with single-agent experience, though additive toxicity was observed in certain settings. In the phase Ib study of linsitinib plus everolimus in refractory metastatic colorectal cancer (N=18), dose-limiting toxicities at the 100 mg BID / 10 mg QD level included grade 3 mucositis (2 patients) and grade 3 thrombocytopenia (1 patient), considered related to everolimus; at the amended 100 mg BID / 5 mg QD level, DLTs included grade 3 thrombocytopenia with bleeding and inability to receive 75% of doses due to neutropenia/thrombocytopenia, establishing the MTD at OSI-906 50 mg BID and everolimus 5 mg QD. Common adverse events across all dose levels in that study included grade 1/2 fatigue (50%) and anorexia (50%). In the phase I linsitinib plus irinotecan study (N=17), 94% of patients experienced at least one treatment-related adverse event; neutropenia was the only grade >3 toxicity (4%), and no significant hyperglycemia or QT interval prolongation was noted, with the MTD established at linsitinib 450 mg daily on days 1–3 every 7 days and irinotecan 125 mg/m² on days 1 and 8 of a 21-day cycle.

In randomised phase II studies, linsitinib-containing arms were associated with higher rates of treatment-related adverse events and discontinuations relative to control arms, despite broadly similar tolerability profiles. In the maintenance NSCLC study comparing linsitinib plus erlotinib versus placebo plus erlotinib (N=205), treatment-related adverse events and discontinuations were more frequent in the linsitinib group, with no drug-drug interaction implicated. In the EGFR-mutation positive NSCLC study (N=88), linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days on erlotinib: 228 vs. 305), with most adverse events graded ≤2. In the single-arm phase II study in metastatic castration-resistant prostate cancer (N=17), the most common adverse events included fatigue, nausea/vomiting, AST/ALT changes, and prolonged QT interval, and single-agent linsitinib was characterised as safe and well tolerated. Preclinical data further indicated that OSI-906 worsened glucose tolerance in a dose-dependent manner in mice and suggested the potential to exacerbate diabetes, particularly in patients with insulin resistance — a metabolic signal consistent with the hyperglycemia observed clinically across multiple studies.

Oral IGF-1R Inhibition: A Pivotal Moment for Thyroid Eye Disease?

The initiation of Sling Therapeutics' Phase 3 ORBIT trial for linsitinib represents a significant step forward in the quest for more accessible and convenient treatments for thyroid eye disease (TED). With the current landscape dominated by an effective but infused biologic, the prospect of an oral IGF-1R inhibitor could be a game-changer for patients. The scientific rationale for targeting IGF-1R in TED is robust, as orbital fibroblasts, central to the disease's pathology, express this receptor, and its inhibition has shown profound benefits in reducing proptosis and improving other key clinical measures.

However, this promising development is not without its complexities and risks. Linsitinib, while targeting a validated pathway in TED, has a history of failing to meet primary endpoints in a Phase 3 oncology trial. This prior outcome, though in a different indication, underscores the inherent challenges in drug development and necessitates careful scrutiny of the upcoming efficacy data. Furthermore, linsitinib's dual inhibition of both IGF-1R and the insulin receptor could lead to a unique safety profile, potentially including metabolic side effects such as hyperglycemia, which clinicians will need to monitor closely, similar to observations with other IGF-1R inhibitors.

Strategically, a successful outcome for linsitinib would not only offer a much-needed oral alternative, enhancing patient quality of life and treatment adherence, but also introduce a formidable competitor into the TED market. This could reshape the competitive landscape, potentially influencing pricing and market dynamics for existing therapies. For Sling Therapeutics, it would validate a strategic repurposing of an asset, establishing a strong foothold in a high-value orphan disease market. The ORBIT trial's results will therefore be pivotal, not just for Sling Therapeutics, but for the broader TED community and the future direction of autoimmune disease therapeutics.