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LOS ANGELES -- The investigational agent teprotumumab was effective for reducing proptosis associated with thyroid eye disease, according to late-breaking phase III data presented here.

Patients with active thyroid eye disease treated with 24 weeks of teprotumumab infusions saw an average 2.82 mm reduction in proptosis (bulging of the eyes) that was significantly greater than the 0.54 mm reduction seen in the placebo group (difference -2.79, 95% CI -3.40 to -2.17), reported Raymond Douglas, MD, PhD, of Cedars Sinai Medical Center in Los Angeles, and colleagues.

Significantly more patients met the OPTIC study's primary endpoint of response to teprotumumab treatment -- defined as a proptosis reduction of ≥2 mm -- versus placebo after 24 weeks (82.9% vs 9.5%, difference 73.45%, 95% CI 58.89%-88.01%), they said at the American Association of Clinical Endocrinologists (AACE) annual meeting.

"I think it's kind of a watershed moment in how we'll look at the treatment of this disease -- before and after the advent of teprotumumab," Douglas told 番茄社区app. "I think one of the exciting aspects is that, this drug, the effect, is relatively similar to what I'm achieving with surgery. And so I think that kind of the ultimate underlying and main message is that the result that you're seeing here is really significant, and clinically significant. That's the exciting part for both patients and treating physicians because that's never been seen in any other drug."

Teprotumumab is a fully human monoclonal antibody inhibitor of IGF-1R that blocks autoantibodies from attacking orbital cells and reducing inflammation. In a , the agent was more effective than placebo in reducing proptosis and Clinical Activity Score (CAS) in patients with active ophthalmopathy. Currently, there are no FDA approved therapies for thyroid eye disease, and surgery is the only option.

Douglas added that "a lot of these other drugs have efficacy, but it's just efficacy of reducing the swelling and I still have to operate on [patients] ... [teprotumumab] is reducing their bulging and double-vision similar to what I can achieve with an operation. That's really exciting and a differentiator."

The authors also reported that a significant proportion of patients on teprotumumab had a reduction of ≥2 mm in proptosis after 6 weeks of treatment (56.1% vs 7.1% placebo).

Similar findings were seen among responders who saw a reduction of ≥2 mm in proptosis and an improvement of ≥2 points in CAS (78% vs 71%, difference of 70.82%, 95% CI 55.89%-85.75%).

The study also met all secondary endpoints, with a significant overall responder rate after 24 weeks of treatment, a greater percentage of participants with a CAS between 0-1, a greater percentage of patients with at least a one grade improvement in double vision, greater average change in proptosis from baseline, and greater mean change in Graves' Ophthalmopathy Quality of Life score after 24 weeks.

For OPTIC, 83 adult patients with active thyroid eye disease were randomized to receive either eight teprotumumab infusions over the 24-week treatment phase, or placebo infusions. All individuals had a 7-item CAS ≥4, FT4, and FT3 levels less than 50% above or below the normal limits, and <9 months since the onset of active thyroid eye disease onset without any prior treatment.

"The therapy is administered right after the patient is examined, making sure there's no contraindications to having that therapy today. Then it's administered via intravenous therapy, usually over 30-60 minutes. There's been really no anaphylactic reactions during the infusions. There's been really very little premedication required -- in fact, really no premedication required for the majority of patients. After the infusion, the patients are free to resume their normal activities. Usually [patients are] out in about an hour." Douglas explained.

"Endocrinologists and oculoplastic surgeons both follow these patients and probably co-manage them," he added. "And so I think in those management paradigms, between those two groups, one will probably take the lead as far as [administering] the infusion or work with the infusion centers. But given the low toxicity and low complication rate during infusion, it may turn out to be an in-office procedure or it may turn out to be a procedure delivered somewhere else."

According to the phase II findings, maintenance of this proptosis response held consistent, with the majority of responders maintaining their response after a year of being off treatment (61.3% of patients who were responders at week 28).

Douglas's group reported that more patients experienced treatment-emergent adverse events with teprotumumab (85.4% vs 69%). The majority of these were due to muscle spasm (31.7% of teprotumumab adverse events), followed by alopecia (19.5%), nausea (14.6%), and fatigue (12.2%).

The agent has been granted FDA Breakthrough Therapy, Orphan Drug, and Fast Track designations, according to developer Horizon Pharma. The company said it a Biologics License Application to the FDA in mid-2019, and the to monitor long-term safety and efficacy is underway.

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