A US Food and Drug Administration (FDA) advisory panel has unanimously recommended approval of teprotumumab solution for intravenous use (Horizon Pharma Ireland, Ltd) for the treatment of active thyroid eye disease (TED).
TED is a rare autoimmune disease that causes the eyes to bulge (proptosis) and can lead to blindness. It is also known as thyroid-associated ophthalmopathy, Graves' ophthalmopathy, and Graves' orbitopathy. Current treatment is aimed at relief of symptoms and includes corticosteroids and orbital decompression.
"TED can affect patients both physically and emotionally, limiting their ability to perform everyday activities like driving, working, reading, sleeping, and participating in social activities," Jeff Todd, president and chief executive officer, Prevent Blindness, said in a news release.
"As an organization dedicated to helping patients with vision impairment and those who are at significant risk, we are extremely encouraged by today's vote and hopeful this will change the future of TED treatment by giving patients an option that has been shown to improve the painful and vision-threatening aspects of the disease," Todd said.
Teprotumumab was granted fast-track status in April 2015 and breakthrough therapy designation in July 2016. It received orphan drug designation on June 19, 2019. If approved, it would be the first approved treatment for this indication.
All 12 member of the Dermatologic and Ophthalmic Drugs Advisory Committee of the FDA voted on Friday to recommend approval of teprotumumab.
"It's clearly a pleasure to participate in seeing a drug being designed and moving forward in a clinical trial for a disease that really has not been treatable for us in the past," said voting committee member Timothy Murray, MD, MBA, FACS, of the Bascom Palmer Eye Institute, Miami, Florida.
Efficacy Demonstrated in Two Clinical Trials
The FDA advisory committee considered data from two randomized, double-masked, placebo-controlled, parallel-group studies that were similar in design and that demonstrated efficacy.
The studies included a total of 171 patients, fewer than 90 of whom were treated with teprotumumab, the FDA explained in a briefing document. "This is a considerably smaller database than the common safety database of greater than 300 patients treated with a course of therapy," it observed.
The study required that patients have proptosis but did not require that they have "progressive forward motion of the globe," the FDA noted.
The primary objective ― ≥2 mm reduction in proptosis ― was met in 82% of patients who received teprotumumab, compared with 16% of those who received placebo.
As previously reported by Medscape Medical News, review study #1 (TED01RV) was a phase 2 study, and review study #2 (OPTIC) was a phase 3 study.
Both trials included a 24-week treatment period during which participants received teprotumumab or placebo intravenously every 3 weeks for a total of eight doses. Patients in both studies underwent a follow-up period during which they received no further treatment.
Some patients experienced a reduction in proptosis as early as 6 weeks after they received the first infusion. In an extension of review study #1, that reduction extended for at least 4 weeks after the last infusion. For approximately 60% of responders, no relapse had occurred by week 72. The extension of review study #2 and an open-label treatment period for those with no response to placebo or teprotumumab are ongoing.
"I welcome the addition of this drug to our armamentarium to treat this horrible, horrible disease," said temporary voting committee member John F. Stamler, MD, PhD, clinical instructor, ophthalmology and visual sciences, University of Iowa, Iowa City.
Adverse Events: Potential for Hyperglycemia, Hearing Loss
Teprotumumab inhibits the insulinlike growth factor–1 receptor, which can interfere with the body's ability to regulate glucose, particularly in patients with diabetes. In the study, some patients with diabetes required additional insulin for glycemic control.
In three study participants whose baseline fasting blood glucose levels were normal, blood glucose levels were found to be elevated at one or more visits during the treatment period. None had a history of diabetes mellitus, but for two, baseline A1c levels were elevated.
Five or more patients reported loss of hearing (hypoacusis), and others reported tinnitus. One of them experienced a spontaneous return of hearing the day after the hypoacusis developed, whereas for others, hearing did not return until after teprotumumab treatment was completed. The mechanism of action for hearing loss is unclear.
Panel members felt the potential for hearing loss is important and that patients should receive some type of monitoring, but they did not all agree on when that testing should occur or who should be responsible for getting it done.
"It strikes me that if this drug were approved, there would be centers that would be interested in undertaking independent studies of hearing loss in treated patients, and that that could be done outside the sponsor's responsibility and probably would be of interest to independent investigators," noted committee chairperson James Chodosh, MD, MPH, of Massachusetts Eye and Ear and Harvard Medical School, Boston.
Benefits of Teprotumumab Outweigh Risks
More than one third of patients (36%) experienced gastrointestinal complaints such as nausea and diarrhea (12% each) and abdominal pain (5%). None of the cases caused any patient to discontinue the study drug.
The overall incidence of muscle spasms was more than three times higher in the teprotumumab group (32%) than in the placebo group (9.5%).
One patient stopped taking teprotumumab after being hospitalized for E coli sepsis and dehydration, and another participant stopped after experiencing an episode of inflammatory bowel disease. It's not clear whether there is a causal association between teprotumumab and inflammatory bowel disease.
No study participants died.
Panel members expressed concern about safety in the longer term or in patients who receive multiple courses of teprotumumab, but they felt the potential benefits from teprotumumab outweigh the risks. The committee also wanted more information about the effects of teprotumumab with respect to glucose control, hearing loss, and other outcomes that are very important to patients, such as alopecia.
The panel favored including diarrhea in the list of adverse events in the label and felt that there should be a warning about inflammatory bowel disease.
"I think we're finally going to be able to get a lot of people some help," concluded voting committee member Sidney Gicheru, MD, LaserCare Eye Center, Irving, Texas.
Medscape Medical News © 2019
Cite this: FDA Panel Thumbs Up for Teprotumumab for Thyroid Eye Disease - Medscape - Dec 16, 2019.