IGF1-Targeting Teprotumumab Tackles Thyroid Eye Disease

WASHINGTON, DC — Patients with moderate to severe thyroid-associated ophthalmopathy show significant improvements with treatment with teprotumumab (River Vision Development) extending as far out as 72 weeks.

"We found that most proptosis (eye bulging) responders receiving teprotumumab maintained a response at 1 year off the drug and adverse events were moderate and transient," said George J. Kahaly, MD, PhD, of the Department of Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany, who reported the findings here at the 2018 Annual Meeting of the American Thyroid Association (ATA).

"The results show that teprotumumab treatment in patients with thyroid eye disease was efficient and safe, and it's important...this is the first time we are dealing with a disease-modifying drug."

Current therapies for thyroid-associated ophthalmopathy primarily include glucocorticoids and orbital radiotherapy, however their efficacy is inconsistent.

Commenting on the study, Mabel Ryder, MD, Mayo Clinic, Rochester, Minnesota, who is co-chair of the ATA program committee, said the findings are encouraging.

"There are still many questions," she told Medscape Medical News. "For instance, we know thyroid-associated ophthalmopathy sometimes gets better on its own over time, but this study had a control group and not many [in the placebo group] got well on their own over time. And furthermore, the data were done long-term, for more than a year, so this suggests there are indeed some benefits."

Updated Results Out to Almost a Year After Treatment With Teprotumumab

Teprotumumab, a fully human insulin-like growth factor 1 (IGF1) receptor inhibitory monoclonal antibody, was originally investigated as a cancer drug; the receptor is thought to play a key role in the process of inflammation and proliferation of orbital connective tissue that are markers of thyroid-associated ophthalmopathy.

The therapy has received breakthrough drug status from the US Food and Drug Administration; it has been shown to significantly improve clinical activity scores and proptosis scores after 24 weeks in a randomized, double-blind, placebo-controlled study (N Engl J Med. 2017;376:1748-1761), as reported by Medscape Medical News.

In that study, 69% of 42 patients with active and moderate to severe ophthalmopathy treated with teprotumumab showed improvement after 24 weeks compared with 20% of 45 patients in the placebo group.

Progress was rapid, Kahaly said: "Within just 6 weeks we observed a dramatic response, showing clear decreases in clinical activity scores and proptosis in contrast to placebo, and the improvement continued to the end of the treatment period."

Now, at the ATA meeting, Kahaly reported updated findings from the study, describing the patients' status at 28 weeks — 4 weeks after the end of treatment — and at 72 weeks.

The initial treatment had included teprotumumab infusions every 3 weeks, for a total of eight infusions, or placebo. Patients had a duration of disease of approximately 5 months in both groups at baseline and were evenly matched in the placebo and teprotumumab groups in baseline mean proptosis (23.1 mm and 23.4 mm, respectively) and mean clinical activity scores (5.2 vs 5.1, respectively).

In terms of proptosis — an important measure reflecting tissue remodeling in thyroid-associated ophthalmopathy — the updated results showed a sustained response of 73.8% at week 28, compared with 13.3% among controls (P < .001).

And at week 72 (48 weeks following treatment), 53% of patients who responded at week 24 continued to maintain at least a 2-mm improvement compared with baseline.

Those in the treatment group showed significantly greater reductions in clinical activity scores at week 28 compared with baseline and placebo (mean -4.44 vs -2.54; P < 0.001) and the improvement remained relatively unchanged in the teprotumumab group at week 72.

"The response rates at week 28 mean that we didn't have a rebound effect or exacerbation of the disease after stopping the drug, [something] that is usually observed when treating patients with other immunosuppressive treatments," Kahaly remarked.

Adverse events were largely minor, reversible, and transient. Serious adverse events were reported in five patients receiving teprotumumab, however, they were all treated and were also reversible, with no long-term complications reported.

Even More Targeted Therapy on the Way?

Ryder noted the possible emergence of a similar but more focused therapy that targets not the IGF1-receptor pathway but thyroid-stimulating hormone (TSH) receptors, which have been shown in some studies to function interdependently with IGF1 in driving the inflammatory component in thyroid-associated ophthalmopathy.

At the European Thyroid Association's annual meeting earlier this year, she presented an abstract describing a patient with Graves disease, Graves (thyroid-associated) ophthalmopathy, and locally advanced and distant metastatic well-differentiated follicular thyroid carcinoma who was treated with K1-70, a human monoclonal autoantibody to the TSH receptor, and had a "dramatic response," she said.

After 11 months of therapy, there were no grade 1 or higher adverse events and in combination with lenvatinib, the rate of tumor progression was attenuated and the quality of life score significantly improved.

A trial of this treatment in a larger population is underway in the United Kingdom, and while in the early stages, the concept could feasibly upstage the one focusing on IGF1 alone, Ryder said.

"IGF1 receptors are expressed throughout the body, so if you target this pathway, you really could expect some higher side effects,” she explained. “But if you target the TSH receptor pathway specifically with monoclonal antibodies, the risks and side effects are expected to be far fewer."

In the meantime, however, the current study suggests teprotumumab "appears to have therapeutic benefit with minimal toxicity," Ryder said.

The research was supported by grants from River Vision USA and Horizon Pharma. Ryder has reported no relevant financial relationships.

2018 Annual Meeting of the American Thyroid Association. October 4, 2018; Washington, DC. Abstract 2.

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