Teprotumumab Eases Thyroid Eye Disease in All, Including Smokers

Miriam E. Tucker

April 22, 2020

Teprotumumab (Tepezza, Horizon Therapeutics), the first-ever medication approved specifically to treat thyroid eye disease, works in patients regardless of age, gender, and smoking status, new research finds.

The data were presented on March 31 by Raymond S. Douglas, MD, PhD, director of the thyroid eye disease program at Cedars-Sinai Medical Center, Los Angeles, California, during an Endocrine Society virtual press briefing convened following cancellation of ENDO 2020 in San Francisco because of the COVID-19 pandemic.

Thyroid eye disease occurs in up to 50% of people with Graves disease, causing a variety of symptoms, such as eye pain, double vision, light sensitivity or difficulty closing the eye, as well as proptosis or bulging of the eye, and vision-threatening complications. It affects more women than men, and the symptoms can lead to the progressive inability to perform important daily activities, such as driving or working.

Teprotumumab is a fully human monoclonal antibody inhibitor of the insulin-like growth factor-1 (IGF-1) receptor, and was approved by the US Food and Drug Administration in January 2020. Prior to that, therapy typically involved steroids or, in severe cases, surgery.

Blocking the IGF-1 receptor leads to reduced inflammation and reversal of retro-orbital tissue expansion and hyaluronan production in the eye orbit. Teprotumumab is given as an infusion once every 3 weeks for a total of eight infusions.

"Exciting to Have Agent That Reduces Proptosis to This Degree"

Previously reported pooled phase 2 and phase 3 data from the randomized, placebo-controlled OPTIC trial involving 171 patients showed significantly greater reductions in proptosis, as well as diplopia, and clinical symptoms of inflammation with teprotumumab versus placebo.

"This has really been unheralded in comparison to other medical therapies previously offered," Douglas said during the briefing.

Now, the new analysis shows that the drug works across patient subgroups, he added, highlighting in particular the fact that the agent seems to work equally well in smokers compared with nonsmokers. Smoking leads to a worse prognosis in thyroid eye disease.

Asked to comment, endocrinologist David C. Lieb, MD, associate professor of medicine at Eastern Virginia Medical School in Norfolk, told Medscape Medical News, "It's reassuring that this drug appears to have benefits in reducing proptosis across multiple age groups, in both genders, and that there are also benefits seen in patients who smoke and who don't."

So far Lieb has two patients who have been prescribed teprotumumab by their ophthalmologists, but it's too soon to know how they'll respond.

"I have no first-hand experience yet, but it's very exciting to have something to offer patients with active Graves eye disease, which causes a lot of disability for people. It makes work difficult and driving difficult. It's exciting to have an agent that reduces proptosis to the degree that this one does, because we haven't had anything like this before," he said.

All Patient Subgroups Benefited in Combined Analysis

A total of 79 patients completed phase 2 and 76 patients completed phase 3 of the OPTIC trial.  

Overall, the proportions achieving proptosis reductions of at least 2 mm without deterioration in the fellow eye at week 24 were 77.4% with teprotumumab versus 14.9% with placebo in the intention-to-treat analysis (P < .001) and 84.8% versus 17.1%, respectively, in the per-protocol analysis (P < .001). The number needed to treat was 1.6.

Similar results were achieved across all subgroups of patients: those aged 65 and older versus younger than aged 65; male versus female; tobacco user versus nonuser; and US versus EU study centers (all P < .001). 

Overall, the average decrease in proptosis was 3.1 mm compared to just 0.4 mm with placebo (P < .001). By subgroup, those reductions ranged from 3.55 mm for those aged 65 and older to 2.93 mm for the US group.

The average proptosis reductions with teprotumumab were 2.99 mm among smokers versus 3.20 mm in nonsmokers, but responses in both groups were significant compared with placebo.

Smoking contributes to the severity of thyroid eye disease and is associated with more optic neuropathy, poorer response to anti-inflammatory treatment, and worse outcomes, Douglas said.

"Smoking appears to preferentially cause fibroblasts in the orbit to increase proinflammatory cytokines...It’s reassuring that this medicine does work in smokers, since most other medications are much less effective in reducing inflammatory signs in smoking versus nonsmoking patients," he said.

Most Adverse Reactions Disappeared After Infusion Stopped

In the pooled studies overall there were no deaths, but there were seven severe adverse events in the teprotumumab group versus one in the placebo group. Two adverse events in the teprotumumab group — diarrhea and infusion-related reaction — were considered treatment-related and led to drug discontinuation. Another adverse event, Hashimoto's encephalopathy, was deemed possibly related to the drug and also led to discontinuation.

Treatment-emergent adverse events occurred in 79.8% of patients treated with teprotumumab versus 69.8% with placebo. Those occurring in 5% or more of patients included muscle spasms (25% vs 7%), nausea (17% vs 9%), alopecia (13% vs 8%), and diarrhea (12% vs 8%). Most were well-tolerated and tended to resolve after the infusions ended, Douglas noted, adding muscle spasms tended to occur at night, improved with massage, and were not accompanied by electrolyte abnormalities.

Antidrug antibodies were detected in two teprotumumab-treated patients, one at study day 1 and another at week 3 during the 24-week treatment period. The patient with antibodies at day 1 also tested positive at week 72. "[Antidrug] antibodies appeared to be very uncommon," Douglas noted.

The trial was sponsored by Horizon Therapeutics. Douglas is a consultant for Horizon Therapeutics and Immunovant. Lieb has reported no relevant financial relationships.

ENDO 2020. Presented March 31, 2020, during an Endocrine Society virtual press briefing. Abstract OR18-01.

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