Thyroid eye disease (TED) represents a challenging intersection of autoimmune thyroid dysfunction and ophthalmic complications, often resulting in disfigurement, discomfort, and, in severe cases, vision loss.
To explore innovative approaches to treating TED, Ophthalmology Times spoke with Alon Kahana, MD, PhD, of Kahana Oculoplastic & Orbital Surgery in Livonia and Ann Arbor, Michigan, about the potential of targeting interleukin-6 (IL-6) inflammation.
A key program in the pipeline for Tourmaline Bio is pacibekitug, an anti-IL-6inhibitor, a mechanism which has shown promise in treating TED, with topline data from the pivotal spiriTED Phase 2b trial expected in the second half of 2025.
According to Tourmaline, spiriTED (NCT06088979) is a multicenter, randomly assigned, double-masked, placebo controlled, dose ranging Phase 2b study of pacibekitug in patients diagnosed with TED. Pacibekitug is being evaluated in a first-line use setting.
The role of IL-6 in TED
“Interleukin-6, or IL-6, is a signaling molecule that acts as a master regulator of the immune system,” Kahana explains. “While it plays a critical role in managing infections, its dysregulation is central to many autoimmune conditions, including autoimmune thyroid diseases like Graves’ disease and Hashimoto’s thyroiditis.”
Kahana notes that TED stems from autoimmune activity targeting orbital tissues, causing inflammation and congestion. Research highlights IL-6 as a key player in this pathological cascade, regulating T cells, B cells, and other inflammatory mediators.
Comparing current treatments to IL-6 targeting
Currently, teprotumumab (Tepezza) is the only FDA-approved therapy for TED. It works by inhibiting the insulin-like growth factor 1 receptor (IGF-1R) pathway. “While teprotumumab addresses the symptoms, such as proptosis and orbital congestion, it does not target the underlying autoimmune process,” Kahana observes.
In contrast, IL-6 targeting offers a more upstream intervention.
“Blocking the IL-6 pathway could address the root cause of the autoimmune dysregulation,” he says.
However, existing IL-6 pathway inhibitors, such as tocilizumab, face limitations, including potential side effects and challenges related to feedback loop receptor upregulation. There are also no IL-6 pathway inhibitors that are currently approved for treating thyroid eye disease.
A new generation of IL-6 targeting therapies
Among the promising developments is pacibekitug, formerly known as TOUR006, a monoclonal antibody designed to block IL-6 activity by targeting its ligand rather than the receptor.
“By preventing the IL-6 ligand from binding to its receptor, this approach may avoid the feedback loop that can increase receptor expression,” Kahana explains.
Delivered via subcutaneous injection, pacibekitug demonstrated a favorable safety profile in prior trials conducted in other autoimmune diseases and also in healthy volunteers.
“Unlike IGF-1R inhibitors, which act directly on orbital fibroblasts, IL-6 ligand blockers modulate the upstream immune response. This distinction may translate to longer-lasting disease control,” he adds.
Challenges in clinical translation
Despite its promise, bringing IL-6 inhibitors to clinical use for TED involves significant hurdles.
“Pharmacokinetics, dosing optimization, and patient recruitment for clinical trials are all critical factors,” says Kahana. TED is considered an orphan disease, making trial recruitment particularly challenging.
He emphasizes the importance of a robust clinical trial design, including placebo controls and diverse patient populations.
“We must ensure that therapies are not only effective but also safe and representative of the broader patient community,” he says.
The role of personalized medicine
Looking ahead, Kahana envisions a future where treatment for TED and other autoimmune conditions is tailored to individual patients.
“Advances in biomarkers will help us identify specific autoimmune triggers, allowing us to customize therapy,” he predicts. “In the same way oncology has embraced targeted treatments, we can foresee a similar revolution in autoimmune and inflammatory eye diseases.”
Fatemeh Rajaii, MD, PhD, an associate professor at Wilmer Eye Institute, Johns Hopkins, discusses emerging therapies in thyroid eye disease (TED) from her presentation at the recent American Academy of Ophthalmology annual meeting in Chicago in a separate interview with Ophthalmology Times.
According to Rajaii, with the FDA approval of teprotumumab, there is increasing pharmaceutical interest in developing new treatments. These therapies target 3 main mechanisms: anti-IGF-1 receptor agents like teprotumumab, anti-IL-6 receptor agents, and anti-FcRn receptor agents.
“I think it is an exciting time to be treating people with thyroid eye disease,” she said. “In the next 3 to 5 years, we are going to have a lot more in our armamentarium to take care of these patients.”
Conclusion
Targeting IL-6 represents an exciting frontier in managing TED. By addressing the root causes of autoimmune inflammation, therapies like pacibekitug hold the promise of more durable disease control and improved patient outcomes.
As Kahana puts it, “We’re at the cusp of transforming how we approach autoimmune diseases—by not just treating symptoms but tackling the triggers at their core.”
This evolving landscape underscores the need for continued research and innovation in TED treatment, offering new hope for patients grappling with this debilitating condition.
Leave a Reply