Phase 3 Study Supports Use of Teprotumumab for Thyroid Eye Disease

Results of a phase 3 study presented at the American Academy of Ophthalmology (AAO) 2019 Annual Meeting in San Francisco is giving new hope that an approved treatment for thyroid eye disease—also known as Graves Eye Disease—may be a reality in the near future.

Investigators presented positive results from the trial examining teprotumumab, a fully human monoclonal antibody inhibitor of IGF-1R, including the treatment’s ability to reduce proptosis compared with placebo.

In an effort to further evaluate teprotumumab’s ability to serve as a treatment for thyroid eye disease, investigators designed and conducted the Treatment of Graves’ Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical(OPTIC) study in a cohort of 83 individuals. Upon enrollment in the trial, patients were randomized to receive either placebo or teprotumumab—42 patients were randomized to placebo and the remaining 41 received teprotumumab.

The 24-week randomized, double-masked, placebo-controlled trial included adults between the ages of 18 and 80 years old, with less than 9 months since active thyroid eye disease onset with no prior treatment, a clinical activity score of 4 or more, and free triiodothyronine(FT3) and free thyroxine(FT4) more than 50% above or below normal limits. Additionally, steroid use needed to be limited to low doses with no use at least 4 weeks prior to study entry.

Patients included in the study received 8 intravenous infusions every three weeks for 21 weeks. Investigators noted the first injection was 10 mg/kg followed by 20mg/kg for the remaining seven infusions.

The primary endpoint of the study was the proportion of patients with a 2 mm or greater reduction in proptosis from baseline. Secondary outcome measures of the study included overall responder rate at week 24, proportion of patients was a clinical activity score value of 0 or 1 at week 24, proportion of patients with a change from baseline of at least 1 grade in diplopia, mean change in proptosis from baseline, and mean change in Graves’ Ophthalmology Quality of Life score from baseline.

At the end of the 24-week study period, 40 patients had completed treatment in the placebo group and 39 completed from the teprotumumab. The overall responder rate at week 25 in patients in the teprotumumab group was 78% compared to 7.1% in the placebo group(P<0.001)—representing a difference of 70.82%(95% CI 55.89%, 85.75%).

In regard to proptosis, 82.9% of patients receiving teprotumumab experienced a reduction of 2 mm or more versus 9.5% in the placebo group. Investigators noted difference between groups was 73.45% (95% CI 58.89%, 88.01%) the number needed to treat was 1.36. Investigators noted all secondary endpoints of the study were also met(P≤0.001).

To learn about the impact of teprotumumab and what it would mean if the potential treatment were to receive approval—a PDUFA date is set for March 8, 2020&mdash;MD Magazine sat down with investigator Raymond Douglas, MD, PhD, professor of ophthalmology and director of the Orbit and Thyroid Eye Disease Center at Cedars-Sinai, for more on his clinical perspective.

MD Mag: What were the results of the phase 3 OPTIC study examining teprotumumab for active thyroid eye disease?

Douglas: So, the phase three OPTIC study was designed to test whether the drug teprotumumab, which blocks the IGF-1 receptor, can actually then diminish the signs of thyroid eye disease—namely proptosis, double vision, improving quality of life. What the study was designed to do was to take a placebo arm and a treatment arm, subject them to 8 infusions of teprotumumab, which blocks the IGF-1 receptor, and then measure whether that had an effect upon proptosis, strabismus, and quality of life.

What we found was a dramatic improvement of proptosis or reduction of proptosis reversal of this disease process and what we've found is that this was diminished by approximately 3 millimeters, which is rather equivalent to what would be considered for an average orbital decompression. In addition, we found a substantial improvement in the double-vision of these patients, which continued to improve over the course of the study. Moreover, the quality of life was also improved dramatically—both in their visual function and in their facial appearance overall&mdash;implying the teprotumumab really does appear to be a pivotal drug in the potential in their use for thyroid eye disease.

MD Mag: What would an FDA approval for teprotumumab mean for the current disease state of thyroid eye disease?

Douglas: I personally think this will be a landmark step in the treatment of thyroid eye disease. I think that there will be a time where we thought of treating this disease teprotumumab and a time after because this really does apply to the large majority of patients who get thyroid eye disease and are subjected to this really horrible disease process—and it reverses each aspect of the disease. So, it really adds up to a dramatic improvement in that patient’s quality of life.