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LOS ANGELES – New phase 3 data confirms the benefits of the investigational monoclonal antibody against teprotumumab in patients with thyroid-badociated ophthalmopathy.
Results from the international confirmatory OPTIC trial were presented April 26 here at the American Association of Clinical Endocrinologists (AACE) 2019 Annual Scientific & Clinical Congress by Oculoplastic Surgeon Raymond S. Douglas, MD, PhD, director of the thyroid eye disease program at Cedars- Sinai Hospital, Los Angeles, California, who led the study.
In a special hour-long late-breaker presentation, Douglas compared the new data with those in phase 2 that showed significant reduction in proptosis (eye bulging) with teprotumumab. Those findings were published in the New England Journal of Medicine in May 2017. Improvements in proptosis response (reduction of ≥ 2 mm) and clinical activity scores (CAS) were similar in both studies, he said.
In the United States, about 15,000 to 20,000 people are thought to have active thyroid eye disease. The condition is usually badociated with Graves' disease and occasionally Hashimoto thyroiditis. But it evolves through a distinct process in which autoantibodies activate an insulin-like growth factor receptor (IGF-1R) -mediated signaling complex on cells within the eye orbit. Teprotumumab inhibits that receptor, Douglas explained.
Currently, there is no need for the active phase, which can be used to swelling, bulging, irritation, pain, and double vision.
Horizon Pharma intends to apply for US approval of teprotumumab this year.
Practice Changing … But Currently for Severe Eye Disease Only
Douglas said: "Currently, patients with active thyroid eye disease suffer from life-altering symptoms and – the active phase of disease end suggest that teprotumumab may help reduce proptosis and alleviate the inflammatory symptoms … potentially avoiding the need for multiple complex surgeries. "
Expanding on this in an interview with Medscape Medical News, Douglas has a history of changing the world of depression, which is currently being debilitated.
"Now, it's the first hope that we'll have a change that's going to change that whole paradigm … These data really have a defining line in how we'll be moving forward with this treatment in the future."
However, Endocrinologist and Graves' ophthalmopathy expert Marius N. Stan, MD, of the Mayo Clinic, Rochester, Minnesota, expressed caution about the patient population for whom teprotumumab should be used, at least initially, noting that the trial participants all had moderate- to-severe active disease, and so on, with a small percentage of those with thyroid eye disease.
"Stanties are one of the most important causes of this disease." Knowing what is active disease and what is moderate to severe? Medscape Medical News.
In both the phase 2 and 3 trials, the inclusion of osteoporosis and osteoarthritis in patients with osteoarthritis and more severely affected eye. CAS includes measures of orbital bread, eyelid swelling, and vision, among others. No previous treatment was allowed, except with oral glucocorticoids (cumulative dose ≤1 g of methylprednisolone or equivalent with a 6-week washout period).
"It may be that we are going to have a more general perspective on this issue, but for now, we need to be confident that we are identifying patients" Stan explained.
They have to have a certain severity to qualify for this trial They represent about 5% of patients with thyroid eye disease In the majority … the other 95%, it improves without systemic therapy, "he commented.
Phase 3 Data Confirm Phase 2 Results
As in phase 2, in the phase 3 study, the placebo was delivered by infusion every 3 weeks for 24 weeks for a total of eight infusions. Of the 83 patients randomized and who received the drug study, 40 and 39 completed double-masked treatment with placebo or teprotumumab, respectively. The patients were a mean age of about 50 years, and nearly three quarters were women.
The primary outcome, a reduction in at least 2 mm at week 24, occurred in 82.9% of those receiving teprotumumab (34/41 in the intent-to-treat population), vs. 9.5% with placebo (4/42), a significant difference (P <.001). (These data are announced by Horizon in a press release in February 2019.)
All secondary outcomes were equal, with overall responder rate at week 24, percent of participants with a CAS of 0 or 1 at week 24, percentage of patients with a change of at least one grade in diplopia, mean change in proptosis from baseline through week 24 (2.82 mm with teprotumumab vs. 0.54 mm with placebo), and mean change in Graves' Ophthalmopathy Quality of Life score from baseline to week 24 (all P ≤ .001).
The overall responder rate at week 24, defined as at least 2 mm improvement in the case of at least 2 points, was achieved in 78% of patients with teprotumumab vs 7.1% with placebo (P <.001), and was significantly better at all timepoints (weeks 6, 12, 18, and 24), Douglas reported.
Although it was reported in the last two weeks, a 72-week extension of the phase 2 study showed that it was at least 2-mm improved compared with baseline.
These findings were reported last October at the 2018 Annual Meeting of the American Thyroid Association.
Drug Well-Tolerated, Could Facilitate Earlier Referral to Ophthalmology
The safety profile in the phase 3 was also similar to that seen in phase 2, with overall treatment-emergent adverse events in 83.4% of the teprotumumab group vs 69.0% of the placebo group, and serious adverse events in 4.9% vs 2.4 %, respectively. There were no deaths, and less than 5% of patients dropped out of either group.
Adverse events were more common with teprotumumab than placebo included muscle spasms (31.7% vs 9.5%), alopecia (19.5% vs 11.9%), hyperglycemia (4.9% vs 0%), potential infusion-related reaction (14.6% vs 9.5%), and hearing impairment (9.8% vs. 0%). Most were mild to moderate and resolved by study end.
During off-treatment follow-up, nine orbital surgeries were performed in five placebo patients, compared with three surgeries in two teprotumumab patients.
Horizon expects to submit a biologics license application to the US Food and Drug Administration for tprotumumab in mid-2019. The company is also conducting the OPTIC-X extension trial to gather further insight into the long-term efficacy and safety of the drug.
Douglas told Medscape Medical News that if teprotumumab is approved it could change referral patterns from endocrinologists to ophthalmologists.
"I think [the drug] will really push you endocrinologists because you can do … I think it will really garner much more collaboration between endocrinologists and ophthalmologists. "
Stan advised: "Patients with risk factors for [thyroid eye disease] should be closely monitored, particularly if treated with [radioactive iodine]. If any eye changes develop then the benefit of ophthalmology evaluation in order to be able to avail the potential benefit of early therapy.
Overall, Stan said, "This is the best way to change the paradigm for patients in this area.
"Hopefully more studies will be made to stay safe and harmless, and it would be nice to have a good time. where the benefit is high and the risk seems to be manageable. "
The study was funded by Horizon Pharma. Douglas is a consultant for Horizon Pharma. Stan has reported no relevant financial relationships.
AACE 2019. Presented April 26, 2019.
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