Former Cancer Drug Very Promising for Graves' Ophthalmopathy

Norra MacReady

May 04, 2017

A drug originally investigated as a cancer therapy has shown great promise in the treatment of thyroid eye disease, also known as Graves' orbitopathy or ophthalmopathy, in a new study published in the May 4 issue of the New England Journal of Medicine.

Teprotumumab, a fully human monoclonal antibody that inhibits insulinlike growth factor 1 (IGF-1) receptor, was significantly more effective than placebo at reducing proptosis (eye bulging) and clinical activity scores among patients with this condition.

And some experienced a clinical benefit within as little as 6 weeks, which is an extraordinary response, say the researchers.

The findings offer hope to patients with a condition that currently has no good treatments, lead researcher Terry J Smith, MD, an endocrinologist and Huetwell Professor of Ophthalmology and Visual Sciences at the University of Michigan Kellogg Eye Center, Ann Arbor, told Medscape Medical News.

"This treatment represents an unheralded advance" and is the result of more than 20 years of research," added Raymond S Douglas, MD, PhD, the study's senior author and professor of ophthalmology and visual sciences at the University of Michigan and director of the orbital and thyroid eye disease program at Cedars-Sinai Hospital, Los Angeles, California.

In 2016, following a review of this current trial, the US Food and Drug Administration designated teprotumumab a "breakthrough drug." The study is one of two pivotal clinical trials needed to achieve registration of teprotumumab as the first approved therapy to prevent thyroid eye disease symptoms, according to River Vision Development, which is now developing it.

Targeting Autoantibodies and Repurposing a Cancer Drug

Thyroid eye disease is a condition associated with Graves' disease, an autoimmune disorder that causes hyperthyroidism. Symptoms include swelling of the eyelids, constant stare, bulging eyes, eyelid retraction, optic neuropathy, and double vision. Up to 50% of patients with Graves' disease will develop ophthalmopathy, mostly women, and around a million Americans are affected by it.

Safe and effective therapies for thyroid eye disease have proven elusive, due mainly to an incomplete understanding of its pathogenesis and difficulty in developing good animal models, Dr Smith explained.

A major advance came through research conducted by Drs Smith and Douglas and colleagues, first at the University of California, Los Angeles, and later at the University of Michigan.

They found that there is an unusually high presence of IGF-1 receptors in the tissues surrounding the eye in Graves' ophthalmopathy and that the immune response appeared to be mediated through IGF-1 receptors.

So they set out to see if this could be attenuated by inhibiting the activity of IGF-1 receptors. They originally studied another molecule as a potential IGF-1–receptor inhibitor, until they learned about teprotumumab, an IGF-1–receptor blocker developed by Genmab and Roche as a possible treatment for breast cancer, lung cancer, lymphoma, and other malignancies.

Citing other business priorities, those companies ultimately ended their investigation of teprotumumab for cancer, but it "was exactly what we were designing and seemed a perfect fit" as an agent for treating thyroid eye disease, said Dr Douglas.

In 2012, River Vision Development licensed teprotumumab to further investigate the ophthalmic indications, and the company has a manufacturing agreement with CMC Biologics in Copenhagen, Denmark.

A Multicenter Trial in Four Countries

Patients for the current study were recruited between July 2, 2013, and September 23, 2015, at 15 sites across the United States, Germany, Italy, and the United Kingdom. To be eligible for inclusion, they had to be 18 to 75 years of age, with ophthalmopathy diagnosed no more than 9 months after symptom onset.

In addition, the patients had to have a clinical activity score of at least 4 on a 7-point scale, with a score of 3 or more indicating active thyroid-associated ophthalmopathy, and no previous treatment other than oral glucocorticoids.

Exclusion criteria included optic neuropathy, severe ocular surface damage, or an improved clinical activity score of 2 or more points between the screening and baseline visits.

The final intention-to-treat population included 45 patients in the placebo group and 42 in the treatment group. After a baseline assessment, teprotumumab was administered every 3 weeks for 24 weeks in a dose of 10 to 20 mg/kg body weight, delivered via intravenous infusion. Patients in the placebo group received infusions of saline on the same schedule. Treatment efficacy was assessed at weeks 6, 12, 18, and 24.

The composite primary end point was a reduction of 2 or more points in the clinical activity score and a reduction in proptosis in the study eye of at least 2 mm, with no worsening of symptoms in the other eye.

Proptosis and the clinical activity score, measured as continuous variables over time, were secondary end points, along with changes in quality of life as measured on the Graves's Ophthalmopathy-Quality of Life (GO-QoL) questionnaire.

A total of 37 patients in the teprotumumab group (88%) and 39 (87%) in the placebo group completed the trial. At baseline, measures of proptosis, clinical activity scores, and scores on the GO-QoL were "nearly identical" between the two groups. Diplopia was more prevalent among patients in the teprotumumab group.

However, 41% of the patients in the placebo group were smokers, compared with 26% of the teprotumumab patients, a finding the authors accounted for by adjusting for smoking as a covariate.

A Clear Response

In the intention-to-treat analysis, 29 of the 42 patients (69%) in the teprotumumab group achieved the primary end point, compared with nine of 45 patients (20%) in the placebo group (adjusted odds ratio [AOR], 8.86; P < .001).

In a per-protocol analysis, 26 of 33 patients who received teprotumumab (79%) had a response at week 24, compared with eight of 36 patients in the placebo group (22%) (AOR, 12.73; < .001).

Similarly, in an analysis of the secondary end points, patients who received teprotumumab showed significantly greater reductions in proptosis than patients in the placebo group at all time points.

"At week 24, a total of 17 of 42 patients (40%) who received teprotumumab had a reduction of 4 mm in proptosis, compared with 0% of patients who received placebo," the authors write.

Patients in both the treatment and placebo groups experienced a progressive reduction in clinical activity scores at all time points, but the changes were significantly greater for patients in the teprotumumab group.

On the GO-QoL, patients who received teprotumumab showed a significant improvement on the visual-functioning subscale at week 24, compared with the placebo group (= .009). Their scores on the appearance subscale also improved but did not attain statistical significance.

However, when the two subscales were combined, teprotumumab was associated with significant improvements at weeks 6 (= .003), 12 (= .007), and 24 (= .012) compared with placebo.

Adverse events occurred more frequently among patients in the teprotumumab group. The most common were nausea, muscle spasms, diarrhea, and hyperglycemia. Of those, only hyperglycemia was clearly identified as being related to teprotumumab and was managed through careful monitoring of blood glucose levels and medication adjustment for people with diabetes. The other adverse events were mild and self-limited.

"Remarkable" Results

Many patients in the teprotumumab group experienced a rapid clinical response, the authors note: by the second infusion at just 6 weeks, the clinical response was observed in 43% of patients in the treatment group, compared with 4% in the placebo group.

And the reduction seen in proptosis "is similar to that reported after decompression surgery," they write.

"The impact of even one infusion on the disease is remarkable," Dr Douglas told Medscape Medical News.

In designating teprotumumab as a breakthrough drug, the FDA acknowledges this is a product "intended to treat a serious or life-threatening disease or condition where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies," according to a press release from River Vision Development.

A follow-up clinical trial of teprotumumab is scheduled for 2018, Dr Smith said.

In addition, the drug is now being considered as a possible treatment for other autoimmune conditions, including rheumatoid arthritis and type 1 diabetes, as well as other ophthalmic conditions such as macular edema.

The study was supported by River Vision Development and grants from the Office of Orphan Products Development, Food and Drug Administration, National Institutes of Health, the Center for Vision, the National Eye Institute, Research to Prevent Blindness, the Bell Charitable Foundation, and the Department of Health's National Institute for Health Research Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and University College London Institute of Ophthalmology. Dr Smith reports grant support from River Vision Development during the conduct of the study and other support from River Vision Development outside the submitted work; and patents related to the detection of antibody mediated inflammatory autoimmune disorders, to the diagnosis and therapy of antibody-mediated inflammatory autoimmune disorders, and to diagnostic methods relating to Graves' disease and other autoimmune disorders. Dr Douglas reports grant support from the River Vision Development during the conduct of the study. Disclosures for the coauthors are listed on the journal website.

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N Engl J Med. 2017;376:1748-1761. Abstract

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