Clinical Overview: Teprotumumab Provides a Breakthrough Treatment for Thyroid Eye Disease

Key Takeaways

1. Thyroid eye disease (TED), a rare autoimmune disorder affecting orbital tissues and vision, necessitates vigilant monitoring due to its potential to cause severe proptosis and optic nerve compression, underscoring the need for prompt intervention and management.

2. Teprotumumab, which targets the insulin-like growth factor-1 receptor, has shown remarkable efficacy in reducing proptosis and improving quality of life in TED patients, presenting a promising medical therapy previously unavailable for this condition.

3. Despite its efficacy, the high cost of teprotumumab raises concerns regarding accessibility and affordability, emphasizing the importance of balancing its benefits with addressing financial burdens for patients with TED.

Thyroid eye disease (TED), also known as Graves' orbitopathy or thyroid-associated ophthalmopathy, is a rare and debilitating autoimmune disorder. TED, an autoimmune disorder that poses a significant threat to vision, is defined by inflammation and fibrosis affecting the tissues surrounding the eye, leading to protrusion of the eyeballs from their normal position within the eye sockets.¹

It affects a relatively small percentage of the population, with an incidence rate of 1.9 cases per 10,000 people annually.² This condition, characterized by a complex interplay of inflammation and fibrosis in the orbital and periorbital tissues, poses significant challenges to patients' quality of life and visual function.¹

The disease typically follows a course that transitions from an active and inflammatory phase to a stable, fibrotic, and inactive phase, usually occurring within 1 to 3 years.³ This transition is marked by the remodeling of the orbit and upper face, leading to a wide range of clinical presentations.

In milder cases, patients may experience symptoms such as dry eyes, increased lacrimation, local irritation, and eyelid retraction. However, in more severe cases, symptoms can include pronounced proptosis (bulging of the eyes), diplopia (double vision), and optic nerve compression, potentially resulting in vision loss. Severe cases often necessitate multiple corrective surgical procedures.⁴

Teprotumumab (Tepezza) is a promising treatment for TED, although its precise mechanism of action remains incompletely characterized. It is known to bind to the insulin-like growth factor-1 receptor (IGF-1R), thereby inhibiting its activation and signaling by neutralizing the pathogenic impact of autoantibody-activated orbital fibrocytes.⁵

A phase 3 multicenter trial investigated the efficacy and safety of teprotumumab compared to a placebo in patients with clinically active TED. The primary outcome of this study was a clinically meaningful reduction in proptosis, a common and distressing symptom of the disease.⁶

This trial was groundbreaking because prior to teprotumumab, there was no FDA-approved medical therapy available for treating active TED. The involvement of IGF-1R in the disease's pathogenesis provided a strong rationale for studying teprotumumab.

The randomized, double-blind, placebo-controlled trial involved 83 patients, aged between 18 and 80 years, and who had been diagnosed with Graves' disease. Patients presented with active, moderate to severe TED and met specific criteria related to clinical activity and proptosis. Patients were required to be euthyroid, although mild thyroid dysfunction was allowed at screening.⁶

Exclusion criteria included previous orbital irradiation or surgery for TED, recent worsening of vision, and certain medications. Notably, this study excluded patients who had received rituximab or tocilizumab, highlighting the focus on teprotumumab's unique mechanism of action.⁶

Inflammation was measured consistently across trial sites quantified using the clinical activity score. Reductions in diplopia and improvements in quality of life were also assessed using specific scoring systems. Patients who did not respond to treatment at 24 weeks could enter an open-label extension study, emphasizing the importance of long-term monitoring.⁶

Teprotumumab demonstrated remarkable efficacy in reducing proptosis, with an 83% response rate compared to 10% in the placebo group. Secondary outcomes, including overall response, resolution of inflammation, diplopia improvement, and enhanced quality of life, all favored teprotumumab. Imaging studies even showed reductions in extraocular muscle and orbital fat volume in some patients.⁶

While most adverse events were mild or moderate, 2 serious events, including an infusion reaction, occurred in the teprotumumab group, leading to treatment discontinuation.⁶ These findings emphasize the importance of vigilant monitoring and appropriate management.

Teprotumumab's dosing regimen and adverse reactions were detailed in the study, offering critical guidance for clinicians.⁶ However, it should be noted that the study cohort was small due to the rarity of the disease, and long-term follow-up data were lacking.

Teprotumumab is recommended for the management of TED, regardless of the disease's activity level or duration. Begin the treatment with a dosage of 10 mg/kg for the initial infusion, followed by subsequent infusions of 20 mg/kg every 3 weeks for a total of 7 additional infusions. Medication should be administered via intravenous infusion over a duration of 60 to 90 minutes. Teprotumumabmay cause severe infusion reactions, exacerbate preexisting inflammatory bowel disease, cause hyperglycemia, or cause severe hearing impairment.⁷

Teprotumumab is estimated to be a high-cost treatment, with a significant financial burden for patients. Accessibility and affordability may be major concerns for individuals seeking this groundbreaking therapy.

Teprotumumab represents a significant advancement in the treatment of TED, offering hope for patients with this debilitating condition. Although the study demonstrated impressive results, further research is needed to address the limitations and ensure the therapy's long-term safety and efficacy. Additionally, efforts must be made to make this treatment more accessible to those who can benefit from it, given its potential to transform the lives of individuals living with TED.