麻豆传媒

SILVER SPRING, Md. -- An on Friday overwhelmingly recommended the first non-surgical treatment for thyroid eye disease, teprotumumab, for approval.

In a 12-0 vote, members of the Dermatologic and Ophthalmic Drugs Advisory Committee felt the benefits far outweighed the potential risks of Horizon Therapeutics's drug delivered via eight intravenous infusions.

"I welcome the addition of this drug to our armamentarium to treat this horrible, horrible disease. This is really maybe the only arrow in our quiver," said panel member John Stamler, MD, PhD, of the University of Iowa in Iowa City.

Erica Brittain, PhD, of the National Institutes of Health in Bethesda, Maryland, agreed, calling the decision a "pretty easy vote -- easier than they usually are."

"This is going to be a life changer [for the patient community]. And it offers hope to conditions that were so hard to treat before," added patient representative Jennifer Schwartzott, MS.

Horizon was seeking an indication for the treatment of active thyroid eye disease, otherwise known as Graves' orbitopathy. Currently there are no other medical treatments indicated for this rare but potentially blinding condition besides surgery. Other medical managements include immunosuppressants, high-dose glucocorticoids, and eye drops.

When thyroid eye disease is considered "active," patients may suffer from a myriad of debilitating symptoms including pain, periorbital edema and erythema, conjunctival redness, eyelid retraction, proptosis, strabismus -- or misalignment of the eyes -- as well as diplopia. However, patients also may suffer chronically from some persistent symptoms even when their disease is considered to be in an "inactive" phase.

Teprotumumab, an investigational fully human monoclonal antibody, acts as an insulin-like growth factor-1 receptor inhibitor to reduce proptosis, or the bulging of the eyes.

The agent demonstrated efficacy in two clinical studies. With the findings appearing in the , the phase II double-blind, placebo-controlled study included 88 patients with active thyroid eye disease. In the half who received teprotumumab, the drug was administered once every 3 weeks, totaling eight infusions. The first infusion included 10 mg/kg of the drug, while all subsequent infusions had a target dose of 20 mg/kg.

After 24 weeks, teprotumumab patients were significantly more likely to achieve a proptosis reduction of at least 2 mm from baseline in the study eye compared with placebo (OR 8.86, 95% CI 3.29-23.8).

And in results presented earlier this year at the American Association of Clinical Endocrinologists (AACE) annual meeting, a total of 83% of adult patients treated with teprotumumab in the 83-patient phase III clinical study achieved a reduction of 2 mm or more in proptosis compared with only 9.5% who received placebo (difference 73.45 percentage points, 95% CI 58.89-88.01) -- meeting the study's primary endpoint.

"I think one of the exciting aspects is that [with] this drug, the effect is relatively similar to what I'm achieving with surgery," the second study's lead investigator, Raymond Douglas, MD, PhD, of Cedars Sinai Medical Center in Los Angeles, previously told 麻豆传媒, calling the benefit "really significant, and clinically significant."

There's also a third, open-label clinical study currently underway, called , which is enrolling patients from the second study who were considered "non-responders" at week 24, or who were responders and then lost response, who will undergo eight infusions of teprotumumab.

In the clinical program, all patients had thyroid eye disease for fewer than 9 months, with a clinical diagnosis of Graves' disease with active thyroid eye disease of a clinical activity score of 4 or greater in the most severely afflicted eye.

The most common treatment-emergent adverse event was muscle spasms, experienced by 25% of patients in the teprotumumab group in the phase II and III studies. Muscle spasms most commonly affected the lower extremities, including the legs, calves, feet, and toes. Spasms also afflicted the hands, back, cheek, and side of the body. However, noted that the underlying mechanism causing these spasms is unknown.

Another more concerning adverse event included hearing impairment with the teprotumumab, as five patients reported hypoacusis -- or loss of hearing -- while more reported tinnitus. Nausea and diarrhea were also seen in about 12% of patients on the study drug, and two patients had an exacerbation of pre-existing inflammatory bowel disease.

After data presentations, the panel heard an hour-long public hearing session, which included several patient testimonials of individuals suffering from thyroid eye disease who have endured loss of autonomy, income, and a decline in quality of life due to their condition. One patient representative even struggled to read her own speech off of her paper. Nearly all panel members highlighted how personally moved they were by these testimonials.

But in panel discussions following, several voting members raised their concerns over the small sample sizes of the clinical studies, questioning potential unseen safety concerns. The applicant representatives, however, responded that this was simply due to the rareness of the condition. Other questions the panel members raised included whether or not eight infusions was the magic number, or if fewer -- or a greater -- number of infusions would deliver a better risk/benefit profile. The question of whether these patients would require re-treatment in a year, or several years after initial treatment, was also a topic of discussion.

Prior to the vote, some panel members suggested Horizon implement longer-term, post-marketing observational studies involving a greater number of patients, particularly to monitor hearing loss and metabolic safety like blood glucose with the drug.

Nonetheless, the panel as a whole were in consensus, agreeing that the risks were generally manageable in nature.

"I thought the data for the benefits were really, really striking, especially the difference between placebo and the drug," said Cecilia Low Wang, MD, of the University of Colorado in Aurora. "I think there are risks and there's limited safety data, but I think they're manageable and hopefully we can get more data to support the safety."

Also singing the praises of teprotumumab, Kenneth Burman, MD, of Medstar Washington Hospital Center in Washington, D.C., said: "This agent apparently provides benefits for the thyroid eye patients not demonstrated by any previous treatment modality."

"The seminal question to me, in addition, is whether the indications for treatment should mirror the study inclusion criteria or whether the indication should be slightly broader based on clinical and physician experience," Burman continued, suggesting that the indications should be broader than the study inclusion, particularly expanding the duration of thyroid eye disease beyond 9 months, and to instead include those with an onset of the past 12 to 18 months.

Although the FDA is not required to follow its advisory committees' recommendations, it typically does.

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