LOS ANGELES — An experimental human monoclonal antibody dramatically reduced the most debilitating symptoms of Graves’ orbitopathy, including proptosis and double vision, giving new hope to patients that a treatment for thyroid eye disease may finally be within reach, according to a speaker at the AACE Annual Scientific and Clinical Congress.
According to new phase 3 data from the OPTIC trial presented here, adults with active Graves’ orbitopathy treated with teprotumumab (Horizon Pharma) for 21 weeks experienced an average proptosis reduction of 2.82 mm at 24 weeks compared with an average of 0.54 mm for those assigned to placebo, with between-group differences in proptosis reduction observed at all study time points, according to Raymond Douglas, MD, PhD, director of the orbital and thyroid eye disease program at Cedars-Sinai Medical Center. Other symptoms associated with the disease, including inflammation, pain, swelling and redness, were also reduced for patients assigned teprotumumab vs. placebo, he said. Proptosis is the main cause of morbidity in thyroid eye disease; there are currently no FDA-approved treatments.
“I often speak about thyroid eye disease is something where you watch and wait,” Douglas told Endocrine Today. “You have an active phase, and you have an inactive phase, but really, what you do is watch these people with an ongoing, debilitating disease and you cannot do anything about it. This is the first time, and the first hope, that there will be an indication for a drug that will change that whole paradigm.”
Thyroid eye disease is most commonly associated with Graves’ hypothyroidism, but can also be associated with Hashimoto’s thyroiditis, Douglas said during his presentation. Within 18 months of a diagnosis of Graves’ disease, approximately 80% of patients will develop thyroid eye disease, he said, typically leading to a range of symptoms, including proptosis, eyelid retraction, strabismus, compressive optic neuropathy and overall poor quality of life.
“This gives us an enormous opportunity as a window to work together, as oculoplastic surgeons and as endocrinologists, for identifying these patients and potentially moving them toward early treatment,” Douglas said.
Douglas, a co-principal investigator for the OPTIC trial, and colleagues analyzed data from 83 patients with active Graves’ orbitopathy randomly assigned to one IV infusion of teprotumumab, a targeted inhibitor of insulin-like growth factor I receptor (n = 41; mean age, 52 years; 70.7% women; 85.4% white), or placebo (n = 42; mean age, 49 years; 73.8% women; 88.1% white) every 3 weeks for 21 weeks. The median time since Graves’ disease diagnosis was 1.04 years for the teprotumumab group and 0.9 years for the placebo group; 78% and 81%, respectively, were nonsmokers in each group. Primary endpoint was a 2-mm or more reduction of proptosis in the study eye, without deterioration in the fellow eye, at week 24.
“The primary endpoint is critical because this is where this study differs from others you have heard about,” Douglas said. “The primary endpoint is actually proptosis. It is actually modifying disease.”
As Endocrine Today previously reported in March, top-line results showed that 82.9% of patients assigned teprotumumab and 9.5% patients assigned placebo were proptosis responders at week 24 (P < .001). In newly presented data, Douglas said there was a between-group difference in proptosis reduction from baseline at week 6 (mean, –2 mm vs. –0.38 mm), week 12 (mean, –2.7 mm vs. –0.64 mm), week 18 (mean, –3.26 mm vs. –0.59 mm) and week 24 (mean, –3.32 mm vs. –0.53 mm).
Patients treated with teprotumumab had an overall responder rate of 78% compared with 7.1% in the placebo group at week 24 (P < .001), Douglas said, with a greater overall response rate observed for teprotumumab at all study time points.
One of the more exciting findings, Douglas said, was the observed effect was stronger in patients with more severe disease.
“This drug marks a defining line in how we will move forward with the treatment of this disease in the future,” Douglas said in an interview.
The safety profile of teprotumumab in the phase 3 study was similar to what was observed during the phase 2 trial, Douglas said. Muscle spasms were the most commonly reported adverse event (31.7%), followed by potential infusion-related reactions (14.6%), diarrhea (9.8%) and hearing impairment (9.8%), all considered mild to moderate.
“This pivotal, phase 3, placebo-controlled study demonstrates there is a significant reduction in proptosis, confirming phase 2 results almost as a mirror,” Douglas said. “Targeting the IGF-I receptor is critical for the treatment of thyroid eye disease. This appears to be a highly effective drug for reducing the proptosis and likely improving double vision and quality of life.”
Douglas said the therapy, if approved, could potentially replace surgery for many patients, including those with more advanced disease.
“Not all surgery for thyroid eye disease is created equal,” Douglas said. “The more surgery you do, the more risk you take for causing double vision. These patients often have five to seven surgeries to improve this disease. If you could diminish that in a large number of these patients to zero or a couple, that would be revolutionary. We will have to see how that plays out.”
Teprotumumab has received breakthrough therapy, orphan drug and fast track designations from the FDA. Horizon expects to submit a biologics license application to the FDA in mid-2019, according to a company press release. – by Regina Schaffer
Douglas RS. Late breaking oral session. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles.
Disclosure: Douglas reports he serves as a consultant for Horizon Pharma.