Teprotumumab Only FDA-Approved Drug for TED

At the American Academy of Ophthalmology 2020 Virtual meeting, Raymond S. Douglas, MD, PhD, director of the Thyroid Eye Disease Program at Cedars Sinai, gave a presentation updating clinicians on thyroid eye disease (TED) and its newly approved treatment teprotumumab.

TED is a serious, progressive, and debilitating autoimmune disease. It is commonly associated with Graves’ disease but is distinct and may cause irreversible damage including poor clinical outcomes, disfigurement, and sight-threatening complications.

The underlying mechanisms and pathogenesis of TED is known to emanate from the insulin-like growth factor-1 (IGF-1) receptor and the autoantibody activation of this receptor. IGR-1 receptor is  overexpressed in TED and activation of this receptor stimulates inflammatory cytokines and production of hyaluronan causing the disease manifestations, Dr. Douglas said.

Teprotumumab is a fully human monoclonal antibody inhibitor of IGF-1 receptor. It bind specifically to the IGF-1 receptor and stops TSH receptor signaling at the source, thus reducing inflammation and reversing retro-orbital tissue expansion and hyaluronan production, according to Dr. Douglas.

Currently, teprotumumab is the only FDA-approved treatment for TED. It was approved based on the results of two clinical studies – a phase-2 and a phase-3 study – both published in The New England Journal of Medicine. 

These studies enrolled patients with TED aged 18 to 80 years and randomly assigned them to teprotumumab infusions every 3 weeks for a 24-week period or placebo infusions. The primary endpoint was reduction in proptosis at week 24.

“The demonstration of data was quite profound,” Dr. Douglas said.

Reduction in proptosis was well over 3 mm in patients assigned to teprotumumab in both studies with very little change seen in patients assigned to placebo. The pace of the change was also rapid, Dr. Douglas said, with nearly 56% of patients achieving the response criteria as early as 6 weeks.

Dr. Douglas detailed an example of the responses seen by a patient assigned to teprotumumab. In the example, the baseline MRI showed marked enhancement of the inferior rectus muscle and orbital fat, findings indicative of inflammation and edema. At week 24, the MRI showed resolution of the enhancement of the inferior rectus muscle and orbital fat. The size of the inferior rectus muscle was reduced b 49% according to volumetric analysis and the volume of the medial rectus muscle was reduced by 41%.

“This is very much in contrast to steroids, which have largely demonstrated no change in proptosis over a series of well-controlled studies demonstrating less than 1 mm change in proptosis over the cumulation of these studies,” Dr. Douglas said.

Teprotumumab was also useful in reversing diplopia. At week 24 there was a difference of 39% between patients assigned the study drug compared with placebo.

The majority of teprotumumab proptosis responders at week 24 maintained their response at week 72 off treatment. Of the small number of patients who relapsed, greater than 60% experienced another 2 mm proptosis improvement with additional teprotumumab treatment.

Over 75% of patients receiving teprotumumab had improvement of 2 mm or more at last known follow up, Dr. Douglas said.

The majority of treatment-emergent adverse events were mild to moderate in intensity and no serious events led to discontinuation. The efficacy in comparison to decompression surgery still need to be fully sorted out Dr. Douglas said.