OPTIC Confirms Teprotumumab Benefit in Thyroid Eye Disease

Miriam E. Tucker

April 27, 2019

LOS ANGELES — New phase 3 data confirm the benefits of the investigational monoclonal antibody teprotumumab in reducing proptosis and related eye problems in patients with thyroid-associated ophthalmopathy. 

Results from the confirmatory multinational OPTIC trial were presented April 26 here at the American Association of Clinical Endocrinologists (AACE) 2019 Annual Scientific & Clinical Congress by oculoplastic surgeon Raymond S. Douglas, MD, PhD, director of the thyroid eye disease program at Cedars-Sinai Hospital, Los Angeles, California, who led the study.

In a special hour-long late-breaker presentation, Douglas compared the new data with those from a phase 2 trial that also showed significant reduction in proptosis (eye bulging) with teprotumumab. Those findings were published in the New England Journal of Medicine in May 2017. Improvements in proptosis response (reduction of ≥ 2 mm) and clinical activity scores (CAS) were similar in both studies, he said.

In the United States, about 15,000 to 20,000 people annually are believed to have active thyroid eye disease. The condition is usually associated with Graves' disease and occasionally Hashimoto thyroiditis. But it evolves through a distinct process in which autoantibodies activate an insulin-like growth factor 1 receptor (IGF-1R)-mediated signaling complex on cells within the eye orbit. Teprotumumab inhibits that receptor, Douglas explained. 

Currently, there is no medical treatment for the condition other than steroids, and surgery can't be done during the active phase, which can last up to 3 years and during which patients can experience eye swelling, bulging, irritation, pain, and double vision. 

Horizon Pharma intends to apply for US approval of teprotumumab this year.

Practice Changing...But Currently for Severe Eye Disease Only

In a company press release, Douglas said: "Currently, patients with active thyroid eye disease suffer through life-altering symptoms and — once the active phase of disease ends — are often left with permanent damage. The results of this confirmatory study...suggest that teprotumumab may help reduce proptosis and alleviate the inflammatory symptoms...potentially avoiding the need for multiple complex surgeries."

Expanding on this in an interview with Medscape Medical News, Douglas characterized teprotumumab as practice changing, noting that currently thyroid eye disease is "where you watch these patients who have a debilitating eye disease that's ongoing and progressive, and you can't do anything about it.

"Now, it's the first hope that we have a...drug that will change that whole paradigm...These data really mark a defining line in how we'll move forward with the treatment of this disease in the future."

However, endocrinologist and Graves' ophthalmopathy expert Marius N. Stan, MD, of the Mayo Clinic, Rochester, Minnesota, expressed caution about the patient population for whom teprotumumab should be used, at least initially, noting that the trial participants all had moderate-to-severe active disease, and so only represent a small percentage of those with thyroid eye disease. 

"One needs to be able to identify that particular group of patients. Knowing what is active disease and what is moderate to severe is essential in order to get the results this clinical trial has identified," Stan told Medscape Medical News.

In both the phase 2 and 3 trials, inclusion criteria were ophthalmopathy diagnosis no longer than 9 months after onset of symptoms, and a CAS of 4 or greater on a 7-point scale, with 3 or greater indicating active thyroid-associated ophthalmopathy in the more severely affected eye. CAS includes measures of orbital pain, eyelid swelling, and vision, among others. No previous treatment was allowed, except with oral glucocorticoids (cumulative dose ≤ 1 g of methylprednisolone or equivalent with a 6-week washout period).

"It might be that down the road this therapy will apply to a broader range of thyroid eye disease, but for now I think we need to be confident that we are identifying the same patients that were treated to get the results that we expect," Stan explained.

"Mild disease is not what was studied here. They had to have a certain severity to qualify for this trial. They represent about 5% of patients with thyroid eye disease. In the majority...the other 95%, it improves without systemic therapy," he commented.

Phase 3 Data Confirm Phase 2 Results

As in phase 2, in the phase 3 study teprotumumab or placebo was delivered by infusion every 3 weeks for 24 weeks for a total of eight infusions. Of the 83 patients randomized and who received study drug, 40 and 39 completed double-masked treatment with placebo or teprotumumab, respectively. The patients were a mean age of about 50 years, and nearly three quarters were women. 

The primary outcome, a reduction in proptosis of at least 2 mm at week 24, occurred in 82.9% of those receiving teprotumumab (34/41 in the intent-to-treat population), vs 9.5% with placebo (4/42), a significant difference (P < .001). (Those data were announced by Horizon in a press release in February 2019.)

All secondary outcomes were also met, including overall responder rate at week 24, percent of participants with a CAS of 0 or 1 at week 24, percentage of patients with a change from baseline of at least one grade in diplopia, mean change in proptosis from baseline through week 24 (2.82 mm with teprotumumab vs 0.54 mm with placebo), and mean change in Graves' Ophthalmopathy Quality of Life score from baseline to week 24 (all P ≤ .001).

The overall responder rate at week 24, defined as proptosis reduction of at least 2 mm plus improvement in CAS of at least 2 points, was achieved in 78% of patients with teprotumumab vs 7.1% with placebo (P < .001), and was significantly better at all timepoints (weeks 6, 12, 18, and 24), Douglas reported.

Although the study only lasted 24 weeks, Douglas noted a 72-week extension of the phase 2 study showed 53% of patients who responded at week 24 continued to maintain at least a 2-mm improvement compared with baseline.

Those findings were reported last October at the 2018 Annual Meeting of the American Thyroid Association.

Drug Well-Tolerated, Could Facilitate Earlier Referral to Ophthalmology

The safety profile in the phase 3 study was also similar to that seen in phase 2, with overall treatment-emergent adverse events occurring in 83.4% of the teprotumumab group vs 69.0% of the placebo group, and serious adverse events in 4.9% vs 2.4%, respectively. There were no deaths, and less than 5% of patients dropped out of either group. 

Adverse events more common with teprotumumab than placebo included muscle spasms (31.7% vs 9.5%), alopecia (19.5% vs 11.9%), hyperglycemia (4.9% vs 0%), potential infusion-related reaction (14.6% vs 9.5%), and hearing impairment (9.8% vs 0%). Most were mild to moderate and resolved by study end.     

During off-treatment follow-up, nine orbital surgeries were performed in five placebo patients, compared with three surgeries in two teprotumumab patients.

Horizon expects to submit a biologics license application to the US Food and Drug Administration for teprotumumab in mid-2019. The company is also conducting the OPTIC-X extension trial to gather further insight into the long-term efficacy and safety of the drug.

Douglas told Medscape Medical News that if teprotumumab is approved it could change referral patterns from endocrinologists to ophthalmologists.

"I think [the drug] will really push endocrinologists to refer sooner because now there is something for the first time that you can do...I think it will really garner much more collaboration between endocrinologists and ophthalmologists."

Stan advised: "Patients with risk factors for [thyroid eye disease] should be monitored closely, particularly if treated with [radioactive iodine]. If any eye changes develop then I see the benefit of ophthalmology evaluation in order to be able to avail the potential benefit of early therapy."

Overall, Stan said, "This has the potential to change the paradigm for the patients in most need of therapy. It's not for every patient with thyroid eye disease at this point. 

"Hopefully more studies will be done to see if it remains relatively innocuous and can improve even mild disease without causing any harm. That would be beautiful. For now, I think we should aim to stick with what we've seen — that it's beneficial where the benefit is high and the risk seems to be manageable."

The study was funded by Horizon Pharma. Douglas is a consultant for Horizon Pharma. Stan has reported no relevant financial relationships.

AACE 2019. Presented April 26, 2019.

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