FDA News

FDA committee unanimously recommends approval of teprotumumab for thyroid eye disease

The Dermatologic and Ophthalmic Drugs Advisory Committee of the FDA voted 12-0 Friday in favor of recommending approval of a biologics license application for teprotumumab, an experimental human monoclonal antibody shown to dramatically reduce the most debilitating symptoms of Graves’ orbitopathy.

Committee members expressed concern before casting votes about the small patient population studied — fewer than 90 adults treated with infusions of teprotumumab (Horizon Therapeutics) have been enrolled in controlled clinical trials — and several adverse events reported, among them hearing loss, muscle spasms, hyperglycemia and infections. In briefing materials, the FDA noted the population was considerably smaller than the common safety database of greater than 300 patients treated with a course of therapy. However, committee members ultimately agreed that the benefits of the drug outweighed any potential risks.

“I don’t say this about every disease, but I hate this disease,” James Chodosh, MD, MPH, D.G. Cogan professor of ophthalmology at Harvard Medical School, associate director of cornea service at Massachusetts Eye and Ear, and the committee chairperson, said before casting a vote in favor of approval. “It is a devastating problem for patients. This is a disease that we need to do something for. This is a bad disease, and it has a tremendous impact on people’s lives. Though the numbers were small, the data presented was quite remarkable for a clinical trial.”

Teprotumumab, an insulin-like growth factor-1 receptor inhibitor, is a fully human monoclonal antibody developed to address a significant unmet need for patients with thyroid eye disease, a condition most commonly associated with Graves’ hyperthyroidism. The drug blocks the inflammatory/autoimmune pathophysiology that underlies thyroid eye disease and, if approved, would be the first pharmacotherapy indicated for the treatment of thyroid eye disease.

Thyroid eye disease typically comes with a range of symptoms that can make everyday tasks challenging and quickly reduce quality of life. Within 18 months of a diagnosis of Graves’ disease, approximately 25% of patients will develop thyroid eye disease, with symptoms including proptosis, the main cause of morbidity, as well as eyelid retraction, strabismus and, occasionally, compressive optic neuropathy.

As Healio previously reported, phase 3 data from the OPTIC trial presented at the AACE Annual Scientific and Clinical Congress demonstrated that adults with active Graves’ orbitopathy treated with teprotumumab for 21 weeks experienced an average proptosis reduction of 2.82 mm at 24 weeks compared with an average of 0.54 mm for those assigned placebo, with between-group differences in proptosis reduction observed at all study time points. Other symptoms associated with the disease, including inflammation, pain, swelling and redness, were also reduced for patients assigned teprotumumab vs. placebo.

“In the oculoplastic and endocrine communities, we have been looking for something like this that will modify the disease course rather than treating the issues that develop from the disease,” David Yoo, MD, associate professor of ophthalmology and director of ophthalmic plastic, reconstructive and orbital surgery at Loyola University Medical Center in Maywood, Illinois, said during the meeting. “The benefits outweigh the risks.”

Adverse event concerns

The advisory committee discussed several questions before voting on whether to recommend approval of the drug, including the expected onset and duration of effect and whether there is a potential safety concern with repeated courses of treatment.

“I was so struck, as I think many of us were, by how well this drug works,” Cecilia C. Low Wang, MD, professor of medicine at the University of Colorado Anschutz School of Medicine and director of the glucose management team at University of Colorado Hospital in Aurora, said during a committee discussion. “The safety database is incredibly limited. There is so much we don’t know about the safety of this drug. We don’t know how this is going to change the path of the disease. The question about potential implications of disease course is important.”

The FDA also asked the committee to discuss its level of concern with reported episodes and frequency of muscle spasms, hypoacusis and diarrhea and associated infection rate. The agency stated in briefing documents that interpretability of adverse events was difficult due to the low number of participants enrolled in the clinical trials.

“There appear to be increased trends in the teprotumumab groups for gastrointestinal disorders, infections, muscle spasms, hyperglycemia, and reproductive system and breast disorders,” the agency wrote.

Committee members expressed particular concern about reports of hearing loss, and members debated whether or not it was useful to monitor hearing before and during treatment.

“[Hearing loss] was an adverse effect I really noted,” Christina Y. Weng, MD, MBA, associate professor of ophthalmology in the department of ophthalmology at Baylor College of Medicine in Houston, said during committee discussion. “It’s much more specific than other adverse events, like fatigue. You really can’t ignore that. Plus, there was a proportion of patients that did not recover. If there is a potential for irreversible change in one sense, I don’t want to trade one sense for another sense, especially one that is so valuable for so many people.”

The committee also discussed the need for glucose monitoring after initiation of teprotumumab, with several members recommending periodic fasting glucose and HbA1c measurements for any person prescribed the drug. In briefing documents, the FDA noted teprotumumab has the potential to interfere with glucose regulation, particularly among individuals with diabetes. Some patients who received teprotumumab required additional amounts of insulin to maintain glycemic control, according to FDA.

“At a minimum, we need fasting glucose and HbA1c [measurements],” Wang said. “There are patients with no [diabetes] history who developed hyperglycemia. We need baseline testing and periodic monitoring after that.”

In a statement released after the vote, Timothy Walbert, chairman, president and chief executive officer, Horizon, said the committee’s decision marks a significant step toward the first FDA-approved treatment for patients with thyroid eye disease.

“Our comprehensive set of data presented today on teprotumumab’s efficacy and safety is a testament to the extraordinary efforts of the physicians who partnered with us on the clinical development program, the TED patients who enrolled in our studies, and Horizon’s research and development team,” Walbert said in the release. “We believe that teprotumumab has the potential to address a significant unmet need for these patients and we look forward to working with the FDA as it completes its review of our application.”

Teprotumumab is one of less than five medicines ever to receive priority review, orphan drug, fast track and breakthrough therapy designations from the FDA, according to Horizon. The Prescription Drug User Fee Act (PDUFA) action date is March 8, 2020. The advisory panel’s recommendations are nonbinding, although the FDA often follows its suggestions.by Regina Schaffer

Disclosures: Chodosh, Low Wang, Weng and Yoo are members of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee.

The Dermatologic and Ophthalmic Drugs Advisory Committee of the FDA voted 12-0 Friday in favor of recommending approval of a biologics license application for teprotumumab, an experimental human monoclonal antibody shown to dramatically reduce the most debilitating symptoms of Graves’ orbitopathy.

Committee members expressed concern before casting votes about the small patient population studied — fewer than 90 adults treated with infusions of teprotumumab (Horizon Therapeutics) have been enrolled in controlled clinical trials — and several adverse events reported, among them hearing loss, muscle spasms, hyperglycemia and infections. In briefing materials, the FDA noted the population was considerably smaller than the common safety database of greater than 300 patients treated with a course of therapy. However, committee members ultimately agreed that the benefits of the drug outweighed any potential risks.

“I don’t say this about every disease, but I hate this disease,” James Chodosh, MD, MPH, D.G. Cogan professor of ophthalmology at Harvard Medical School, associate director of cornea service at Massachusetts Eye and Ear, and the committee chairperson, said before casting a vote in favor of approval. “It is a devastating problem for patients. This is a disease that we need to do something for. This is a bad disease, and it has a tremendous impact on people’s lives. Though the numbers were small, the data presented was quite remarkable for a clinical trial.”

Teprotumumab, an insulin-like growth factor-1 receptor inhibitor, is a fully human monoclonal antibody developed to address a significant unmet need for patients with thyroid eye disease, a condition most commonly associated with Graves’ hyperthyroidism. The drug blocks the inflammatory/autoimmune pathophysiology that underlies thyroid eye disease and, if approved, would be the first pharmacotherapy indicated for the treatment of thyroid eye disease.

Thyroid eye disease typically comes with a range of symptoms that can make everyday tasks challenging and quickly reduce quality of life. Within 18 months of a diagnosis of Graves’ disease, approximately 25% of patients will develop thyroid eye disease, with symptoms including proptosis, the main cause of morbidity, as well as eyelid retraction, strabismus and, occasionally, compressive optic neuropathy.

As Healio previously reported, phase 3 data from the OPTIC trial presented at the AACE Annual Scientific and Clinical Congress demonstrated that adults with active Graves’ orbitopathy treated with teprotumumab for 21 weeks experienced an average proptosis reduction of 2.82 mm at 24 weeks compared with an average of 0.54 mm for those assigned placebo, with between-group differences in proptosis reduction observed at all study time points. Other symptoms associated with the disease, including inflammation, pain, swelling and redness, were also reduced for patients assigned teprotumumab vs. placebo.

“In the oculoplastic and endocrine communities, we have been looking for something like this that will modify the disease course rather than treating the issues that develop from the disease,” David Yoo, MD, associate professor of ophthalmology and director of ophthalmic plastic, reconstructive and orbital surgery at Loyola University Medical Center in Maywood, Illinois, said during the meeting. “The benefits outweigh the risks.”

Adverse event concerns

The advisory committee discussed several questions before voting on whether to recommend approval of the drug, including the expected onset and duration of effect and whether there is a potential safety concern with repeated courses of treatment.

“I was so struck, as I think many of us were, by how well this drug works,” Cecilia C. Low Wang, MD, professor of medicine at the University of Colorado Anschutz School of Medicine and director of the glucose management team at University of Colorado Hospital in Aurora, said during a committee discussion. “The safety database is incredibly limited. There is so much we don’t know about the safety of this drug. We don’t know how this is going to change the path of the disease. The question about potential implications of disease course is important.”

The FDA also asked the committee to discuss its level of concern with reported episodes and frequency of muscle spasms, hypoacusis and diarrhea and associated infection rate. The agency stated in briefing documents that interpretability of adverse events was difficult due to the low number of participants enrolled in the clinical trials.

“There appear to be increased trends in the teprotumumab groups for gastrointestinal disorders, infections, muscle spasms, hyperglycemia, and reproductive system and breast disorders,” the agency wrote.

Committee members expressed particular concern about reports of hearing loss, and members debated whether or not it was useful to monitor hearing before and during treatment.

“[Hearing loss] was an adverse effect I really noted,” Christina Y. Weng, MD, MBA, associate professor of ophthalmology in the department of ophthalmology at Baylor College of Medicine in Houston, said during committee discussion. “It’s much more specific than other adverse events, like fatigue. You really can’t ignore that. Plus, there was a proportion of patients that did not recover. If there is a potential for irreversible change in one sense, I don’t want to trade one sense for another sense, especially one that is so valuable for so many people.”

The committee also discussed the need for glucose monitoring after initiation of teprotumumab, with several members recommending periodic fasting glucose and HbA1c measurements for any person prescribed the drug. In briefing documents, the FDA noted teprotumumab has the potential to interfere with glucose regulation, particularly among individuals with diabetes. Some patients who received teprotumumab required additional amounts of insulin to maintain glycemic control, according to FDA.

“At a minimum, we need fasting glucose and HbA1c [measurements],” Wang said. “There are patients with no [diabetes] history who developed hyperglycemia. We need baseline testing and periodic monitoring after that.”

In a statement released after the vote, Timothy Walbert, chairman, president and chief executive officer, Horizon, said the committee’s decision marks a significant step toward the first FDA-approved treatment for patients with thyroid eye disease.

“Our comprehensive set of data presented today on teprotumumab’s efficacy and safety is a testament to the extraordinary efforts of the physicians who partnered with us on the clinical development program, the TED patients who enrolled in our studies, and Horizon’s research and development team,” Walbert said in the release. “We believe that teprotumumab has the potential to address a significant unmet need for these patients and we look forward to working with the FDA as it completes its review of our application.”

Teprotumumab is one of less than five medicines ever to receive priority review, orphan drug, fast track and breakthrough therapy designations from the FDA, according to Horizon. The Prescription Drug User Fee Act (PDUFA) action date is March 8, 2020. The advisory panel’s recommendations are nonbinding, although the FDA often follows its suggestions.by Regina Schaffer

Disclosures: Chodosh, Low Wang, Weng and Yoo are members of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee.