Tepezza—A Breakthrough, Non-Surgical Treatment for Thyroid Eye Disease

Teprotumumab (Tepezza) approved by FDA to make this first and only vision-preserving, pain-reducing treatment available to patients with Graves eye disease.

with Terry J Smith, MD, and Raymond Douglas, MD

The Food and Drug Administration (FDA) has approved teprotumumab—to be marketed as Tepezza (Horizon Therapeutics)— as the first and only therapeutic available for early management of Graves-associated opthalmopathy.1  

The FDA decision was arrived at following a fast-tracked, priority review, with a breakthrough therapy designation as well as an orphan drug designation. According to the FDA,1 development of this drug was also supported by the FDA Orphan Products grant program, which provides clinical trial funding to assess safety and efficacy of therapeutics aimed at rare diseases and conditions. 

In announcing its decision, the FDA described this action as a "milestone for the treatment of thyroid eye disease" as this biologic offers patients a signficiant, improved course of the disease, likely sparing them from progressive disfigurement, pain, and vision loss with only the prospect of repeated surgeries for any relief.1

In addition, results of the OPTIC phase 3 trial data—upon which the FDA new drug application was based—have been published in the New England Journal of Medicine.2

Terry J. Smith, MD, the Frederick GL Huetwell Professor in Ophthalmology and Visual Sciences at WK Kellogg Eye Center at the University of Michigan Medical School in Ann Arbor, spoke with EndocrineWeb about the strength of the clinical data supporting the biologic application for teprotumumab during a break in sessions at the American Thyroid Association Annual Meeting.

Monoclonal Antibody Angles to be 1st Treatment for TED

By way of background—Research conducted in Dr. Smith’s laboratory led to the identification of unique molecular attributes in the tissue surrounding the eye, which helped to explain the increased susceptibility to inflammation in patients with Graves' disease.

Dr. Smith described a novel autoantibody that binds to and may activate a specific receptor that leading to an exaggerated autoimmune response. This work led to the identification of potential therapeutic targets that, when distrupted, may halt progression of the thyroid eye disease process.

It was this pioneering work that was the basis for development of teprotumumab, the first pharmacological therapy to alter the severity of symptom relief for this disfiguring, painful and potentially blinding thyroid-related eye disease.

Until now, orbital decompression surgery has been the only treatment for the 30-50% of individuals with Graves’ disease that also resulted in thyroid eye disease.3

Now there there is the prospect of treatment—teprotumumab is a fully human monoclonal antibody that functions as an insulin-like growth factor-1 (IGF-1R) inhibitor— acting to interrupt autoimmune activity and the inflammatory response, which offers a favorable risk/benefit profile for Graves' orbitopathy,4 Dr. Smith said.

FDA Advisory Committee Endorsed First-Ever Treatment for TED  

The Food and Drug Administration (FDA) Advisory Committee on Dermatologic and Ophthalmic Drugs reviewed the biological license application for teprotumumab solution for intravenous application as a viable first and only treatment for emergent thyroid eye disease (TED),4  indicating favorable approval for this drug. Teprotumumab was viewed as a breakthrough therapeutic for patients who develop this Graves' disease-related condition, receiving unanimous (12-0) support.

“FDA approval of teprotumumab would make this the first medication to gain approval to treat TED, and is posed to become the standard of care,” said Dr. Smith, which would be a game-charger for patients since surgery has been the only option until now, and often was reserved for only very severe cases.

Before Treatment for TED Can be Effective, Timely Diagnosis is Needed
“Patients typically were told that they must wait several years—during the active phase of TED—for their symptoms to dissapate. However, some damage to vision occuring during this waiting period was irreversible,” said Dr. Smith.

Figure 1. Examples of TED Signs and Symptoms

Progression of Graves eye disease can lead to permanent vision damage if not treated early.

To recognize thyroid eye disease, the most common signs are:

  • Inflammation of orbital soft tissues (et, caruncle or plica) causing pain, erythema, swelling and foreign object sensation in the eyes
  • Eyelid retraction with increased eyelid aperture
  • Proptosis (eye bulging), due to expansion of the soft tissues of the orbit forcing eyes to prortrude from their sockets
  • Strabismus (misalignment of the eyes) with compromised eye motility
  • Diplopia (double vision), due to incorrect orientation of the eyes
  • Corneal ulceration because patients cannot fully close their eyelids
  • Optic neuropathy arising from rigid orbital walls and tissue enlargement putting undue pressure on the optic nerve 

These signs and symptoms often progress, particularly in moderate to severe cases of TED.

Efficacy and Safety Data on Teprotumumab for Graves Eye Disease

Data from the phase 3 OPTIC trial—Treatment of Graves’ Orbitopathy to Reduce Proptosis with teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study—demonstrated significantly more patients (82.9%) achieving consequential improvement in the primary study endpoint, proptosis among those receiving teprotumumab compared to placebo (9.5%, P ˂ 0.001).2,5

While the data appear clinically significant, members of the advsory committee were said to have deliberated over the relative risks of the reported adverse effects given that one in four individuals who received teprotumumab reported muscle spams, the most common emergent adverse event.2,5

Another side effect under consideration was hyperglycemia, experienced in 7% of patients receiving treatment, was discussed but not considered of sufficient concern given the overriding benefits.

The committee members also evaluated the risk associated with an apparent worsening of inflammatory bowel disease observed in two treated patients. Other frequently cited complaints were nausea, alopecia, diarrhea, fatigue, dyspepsia, headache, and dry skin.5

The two completed clinical trials offer sufficient favorable evidence of the safety and efficacy of teprotumumab in achieving a reduction in proptosis, diplopia, and inflammation in patients with active thyroid eye disease.5,7  

"The muscle spasms were clinically similar to cramps and were well-controlled with massage and fluids. In most cases, these side effects were not severe and patients did not want to stop the drug, and there appeared no increase with continuing treatment," Dr. Douglas told EndocrineWeb

"The initial data show that the previously thought irreversible aspects of the disease can now be reversed and improved," said Raymond Douglas, MD, director of the Orbital and Thyroid Eye Disease program at Cedars-Sinai Medical Center in Los Angeles, California, asked to comment on the overriding benefit of this drug for patients with even moderate thyroid eye disease to receive treatment upon diagnosis. 

The proposed treatment will entail eight intravenous infusions of teprotumumab, administered every three weeks, for a total treatment period of 24 weeks to achieve a reduction in proptosis of at least 2 mm, the level,2,5 according to co-principal investigator, Raymond Douglas, MD, PhD, professor of medicine, and ocuplastic surgeon at the Cedars Sinai Medical Center in Los Angeles, California.

The [Phase 3 OPTIC] confirmatory trial  was conducted at 23 leading centers across the United States, Germany, and Italy,2 with co-principal investigator George Kahaly, MD. PhD, professor of medicine, and of endocrinology and metabolism at Johannes Gutenberg University Medical Center in Mainz, Germany.

“The pooled data just presented [at the American Thyroid Association], reflects combined results from both the phase 2 trial, completed in 2016, and the phase 3 OPTIC Trial.2,5 The outcomes unambiguously demonstrate that both primary and secondary endpoints were met in the majority of patients treated with teprotumumab over a 24-week treatment period who responding favorably,” said Dr. Smith.

“Patients can expect a reduction in proptosis in the more affected eye of at least 2 mm and a reduction in clinical activity score, in the same eye, of greater than or equal to three points on a CAS scale. The patients also demonstrated remarkable improvement in double vision or diplopia and enhanced quality of life, as assessed by a fully-validated quality of life assessment,” Dr. Smith told EndocrineWeb.

Clinicians should let patients know that there may be side effects, and while we have very little data in patients with IBD taking teprotumumab, it is prudent at this stage to be cautious and ask patients about their GI history, said Dr. Douglas.

Diagnose & Initiate Medication Early in Active Phase 

“Thyroid eye disease typically follows a clinical course where the disease begins with, what we call, the ‘active’ phase—dominated by symptoms and signs of inflammation and congestion or swelling around the eye or upper face. This active phase, which has, as its underpinnings, a pathological activity of the immune system, involves the trafficking to the orbit of professional immune cells,” Dr. Smith said.

“The active phase typically lasts two to three years and gives way to the ‘stable’ or chronic phase. However, some of our patients actually experience disease activity considerably longer, sometimes many years in duration,” he said.

Need to identify TED early in the active phase. A delay in treatment may diminish the potential of teprotumumab to lessen adverse vision changes, and preventing permanant eye damage, according to Dr. Smith. To aid clinicians in identifying Graves’ eye disease early on, there are several established protocols and tools available to clinicians to assist in identifying thyroid eye disease.

One reliable diagnostic tool, Dr. Smith said, is the Clinical Activity Score (CAS), a seven-point scale to detect signs and symptoms of active TED, with a score of 3 or more indicating active disease, which was used in the clinical trials.

Once the stable or chronic phase has been reached, the patient’s eye manifestations largely stop changing, and many of the superficial inflammatory signs disappear but the patient may then be left with the consequences of the disease, which can be viewed as endpoints of severity, such as proptosis and double vision. 

In its most severe forms, Graves eye disease can result in loss of vision, usually occurring as a consequence of either compression of the optic nerves, or deterioration in the interior surface of the eye itself, he said.

“Given our understanding of the disease process, we believe early identification of disease onset will most likely to yield optimal clinical response to medication and thus we’re stressing the importance of recognizing the disease in the active phase and initiating therapy when there is the best chance to change the ultimate course of disease,” said Dr. Smith.

What Is the Extended Durability of Teprotumumab?

“We have some initial insights into the intermediate durability of the therapy in that 48-week data from the clinical study suggests that the majority of responders (ie, those who responded well to the intravenous treatments with teprotumumab), remained inactive and showed no progression. This was an additional 24 weeks beyond the therapeutic phase of the trial,” Dr. Smith said.

However, there is no information yet on long-term outcomes in patients treated for 24 weeks but certainly this reamins a critical question, said Dr. Smith. Just such a study has already begun recruitment.8

Horizon has initiated the OPTIC‐X open label phase 3 extension trial to continue to gather data on the long-term efficacy and safety of teprotumumab in patients (n=50) who completed the 24-week course of therapy and who met the criteria for relapse. They were eligible to enroll to receive eight additional infusions over a second Graves’ eye disease; the expected study completion is March 2022.8

Teprotumumab product has been designated for priority review given its potential as a significance advance in the here to for lack of therapeutic treatment for thyroid eye disease. The manufacturer has indicated a Prescription Drug User Fee Act (PDUFA) goal date of early March 2020.

"Once this drug is available, patients who have moderate to severe thyroid eye disease will be able to receive treatment immediately, which means they will not be required to wait years [to gain symptom relief]," Dr. Douglas told EndocrineWeb, as has been the circumstance until now.

NOTE: When Horizon gains final FDA approval for their biologic to treat thyroid eye disease, this article will be updated to reflect additional clinically beneficial information made available.

Continue Reading:
Factors Predicting Relapse of Graves’ Disease
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