As expected, Horizon Pharma plc sailed through the meeting of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee regarding the BLA for teprotumumab in thyroid eye disease (TED) with few surprises but much discussion.

During the open public hearing part of the session, Terry Smith, professor of ophthalmology in the department of internal medicine at the University of Michigan Kellogg Eye Center in Ann Arbor, Mich., told the panel that the “molecular and cellular rationale” for teprotumumab was born in his laboratory. “My professional journey with [TED] began as a medical student when I first encountered this disorder,” and his subsequent experience with patients “played a large part in my choice of clinical sub-specialties.” High-dose corticosteroids, which doctors use for TED now, “fail to alter disease severity, its natural course, or the necessity for surgical intervention once the disease has stabilized,” he noted, urging the committee to recommend Horizon’s candidate for approval. 

They did. The single voting question was, “Do the potential benefits of using teprotumumab as recommended outweigh the potential risks associated with the use of the drug product for the intended population?” Panelists balloted 12 yes and 0 no, with none abstaining.

The teprotumumab BLA includes data from two randomized controlled studies, TED01RV and Optic. Both included a 24-week treatment period and a follow-up period with no additional study treatment. The follow-up period of Optic was ongoing, and safety data through Feb. 19, 2019, were included in the BLA. Safety data from an ongoing open-label extension study called Optic X through Feb. 27, 2019, were also included in the submission.

Discussion points for panelists included onset and duration, as well as “any safety limitations or safety labeling that should result from the relatively small database of patients in this orphan indication,” plus “whether the term ‘active’ as used in the proposed indication is informative to clinicians and patients considering use of the product.” They were also asked to mull the need for glucose monitoring after the start of treatment, along with their level of concern with episodes and frequency of such side effects as muscle spasms, loss of hearing, and gastrointestinal problems. Infection and alopecia episodes came up, too. Committee members were asked for label recommendations.

Tonya King, professor of biostatistics at Pennsylvania State University College of Medicine in Hershey, Pa., said that “based on the stories of the patients, even the potential side effects of therapy that we’ve learned about don’t compare to living with the disease,” though ongoing research will find out more. The company proposed a registry to track patients, and the FDA might ask for post-marketing studies.

Cecilia Low Wang, professor of medicine from the University of Colorado in Aurora, Colo., said that she was “struck by how well this drug works” but called the safety database “incredibly limited. There’s so much we don’t know about the safety of this drug.” She also noted that in both trials, patients had been diagnosed with TED in the past nine months before enrolling. “We’re thinking that this [drug] is probably modifying inflammation” but “we don’t know at what point it’s become irreversible,” so doctors should have not only a diagnosis of TED but an understanding of how long the condition had been present.

Mild snags arose in briefing documents with regard to the clinical activity score (CAS) as calculated by the Dublin-based company, and details emerged about hyperglycemia seen with the compound, not unanticipated by clinicians given teprotumumab’s mechanism of action as an inhibitor of the insulin-like growth factor-1 receptor. The agent has received breakthrough therapy, orphan drug, and fast track designations from the FDA.

Mary Hartnett, professor of ophthalmology at the University of Utah in Salt Lake City said the FDA should require “pregnancy tests before each infusion and maybe glucose monitoring after each infusion.” Others noted that anyone with underlying inflammatory bowel disease or colitis should avoid the treatment. On the topic of CAS, Kenneth Burman, chief of the endocrine section at Medstar Washington Hospital Center in Washington, D.C., said, “Despite the fact that it’s not a perfect tool, I couldn’t think of a better tool to use.”

Specifically, Horizon used the seven-item European Group on Graves’ Ophthalmopathy amended CAS, as a secondary endpoint in the Optic study, where 82.9% of teprotumumab patients compared to 9.5% of placebo patients achieved a two millimeter reduction or more (p<0.001) in proptosis, or bulging of the eye – the primary endpoint.

Survey finds docs like efficacy vs. corticosteroids

TED, also known as Graves’ orbitopathy or ophthalmopathy, is a condition in which the eye muscles, eyelids, tear glands and fatty tissues behind the eye become inflamed, which can cause the eyes and eyelids to redden, swell, and bulge. Stiffness of the muscles that move the eyes may follow so that they no longer move in line with each other, which can lead to double vision, as emotional testimony from patients at the committee meeting confirmed.

“I hate this disease,” said chairperson James Chodos, professor of ophthalmology at Harvard Medical School in Boston, adding that he could not say the same about every corneal condition that comes to his practice. Timothy Murray, director of Florida’s Miami Ocular Oncology and Retina, called the data package “outstanding. This is one of the more remarkable drugs coming available to treat unmet need in a rare disease.”

Randall Rutta, president and CEO of the nonprofit American Autoimmune Related Diseases Association, said his group “encourages the FDA to expedite” the BLA for teprotumumab. “Every day matters for tens of thousands of people struggling” with TED, he said, calling the disease a “soul crusher” and “chilling” in its effects on patients. He said teprotumumab is “more than life-changing. I believe it truly is life-saving,” and experts need to create more awareness of the compound if it becomes available. “You do not want this tree to fall silently in the forest,” he said. “For a treatment like this, we don’t have time to waste.”

In an August report, Piper Jaffray analyst David Amsellem described a brief survey his firm conducted among 27 doctors who manage TED patients, in which 70% noted that they use corticosteroids in anywhere from 41% to all of their patients with moderate-to-severe active disease. “That the footprint of corticosteroids isn't wider is not surprising, given that treatment requires a fairly long course (often six to 12 months) and given their obvious tolerability issues (some patients opt for no pharmacologic treatment at all),” he wrote. “Though a majority of respondents believe that corticosteroids are a viable option for at least a slight majority of their TED patients, 70% of respondents also cited an efficacy profile for teprotumumab that is significantly better than that of corticosteroids.” Seventy-one percent of respondents said they plan to use teprotumumab ahead of corticosteroids in “at least a slight majority” of their moderate-to-severe patients.

Wainwright analyst Raghuram Selvaraju forecast peak global sales of $800 million for teprotumumab, with Denmark, Copenhagen-based Genmab A/S collecting a 7% royalty on sales generated by its licensee Horizon, he noted in a report. Trading of Horizon shares (NASDAQ:HZNP) was halted during the adcom.

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