Remibrutinib safe, effective for chronic spontaneous urticaria over 52 weeks
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Key takeaways:
- Remibrutinib reduces histamine formation inside of cells.
- Improvements in itch and hives were seen as early as 1 week.
- Liver transaminase elevations in the treatment and placebo groups were balanced.
Patients with chronic spontaneous urticaria experienced early symptom improvements that were sustained through 52 weeks with remibrutinib, according to a presentation at the European Academy of Allergy & Clinical Immunology Congress.
The safety profile for the Bruton’s tyrosine kinase (BTK) inhibitor was favorable and consistent through 52 weeks as well, the researchers said.
“Everyone starts with nonsedating antihistamines,” Mark G. Lebwohl, MD, dean of clinical therapeutics and chair emeritus of the Kimberly and Eric J. Waldman Department of Dermatology at Icahn School of Medicine at Mount Sinai, told Healio. “If patients fail four nonsedating antihistamines daily, they are then moved to the next level of treatments. Currently, those are primarily biologics.”
Biologics target receptors on the surface of cells and block their activation, Lebwohl said. But even with biologics, he continued, many cases remain inadequately controlled.
“Having a new agent for those patients would be great,” Lebwohl said.
As a BTK inhibitor, Lebwohl said, remibrutinib (Novartis) reduces the formation of histamine, which causes CSU, inside the cell.
“They work by completely different mechanisms,” Lebwohl said.
Also unlike the biologics, which are injected, remibrutinib is an oral medication, which Lebwohl called another key difference and potential advantage.
Study design, results
The global, double-blind, placebo-controlled, phase 3 REMIX-1 and REMIX-2 studies explored the impact of 25 mg of remibrutinib or placebo twice a day on patients with CSU who remained symptomatic despite second-generation H1 antihistamine use over 52 weeks.
REMIX-1 had 313 patients on active treatment and 157 on placebo, and REMIX-2 had 300 active patients and 155 on placebo. Overall, Lebwohl said, average age was in the low to mid-40s, with an approximately two-to-one ratio of females to males.
“Which is not unexpected in an urticaria trial,” Lebwohl said.
Mean BMI was in the 27 kg/m2 to 28 kg/m2 range and “a little on the overweight side,” he continued, with higher numbers among patients from the United States.
“The drug is extremely fast. We’ve seen a response as early as 1 week,” Lebwohl said. “And you see a leveling off the response at week 4, but continued improvement through week 24 and even a little more improvement through week 52.”
At week 12, patients who used remibrutinib experienced significant improvements in weekly Urticaria Activity Score (UAS7), weekly Itch Severity Score (ISS7) and weekly Hive Severity Score (HSS7) that were confirmed at week 24, compared with placebo.
In fact, the authors said, improvements in UAS7 scores emerged as early as week 1.
Specific differences included an approximately 12-point reduction in the placebo group and a nearly 20-point reduction in the treatment group in average UAS7 scores at week 12, Lebwohl said.
“Then if you look at week 24, it’s a little over 20 in the active group and about 14 and a half in the placebo group,” he said. “So major, highly statistically significant differences.”
Similar patterns were seen among the ISS7 and HSS7 scores, he continued.
The patients in the placebo group then transitioned to treatment with remibrutinib at week 24 and experienced responses that emerged as early as the first week and were sustained for the next 28 weeks.
“So, 52-week results showed durability of response with no loss of efficacy,” Lebwohl said.
At week 52, nearly half of the patients achieved a UAS7 score of 0, indicating that they were completely free of itch and hives.
“It was actually a little better than it was at week 24,” Lebwohl said.
The safety profile through 52 weeks included balanced liver function tests compared with placebo. During the 24-week placebo-controlled period, the treatment and placebo groups had comparable adverse events, including serious adverse events and treatment discontinuations.
Exposure-adjusted rates of adverse events did not increase. Also, the elevations of liver transaminase in the treatment and placebo groups were balanced, and they all were asymptomatic, transient and reversible.
“We worry about liver effects,” Lebwohl said.
Major cardiovascular events and other side effects that have been reported with other BTK inhibitors were not reported in these patients either, he continued.
“There is no signal for any of those,” Lebwohl said.
“If you look at infections or headache, which were common side effects as they are in every study, the proportion in remibrutinib was not very different than placebo,” he added.
Next steps
Overall, Lebwohl said that these findings for remibrutinib were encouraging.
“This is not only effective, which is very clear from the results, it’s fast acting, it has a durable effect, and it is a safe, oral option that we did not have before,” he said.
Next, Novartis will seek approval from the FDA and other global health authorities beginning in the second half of 2024. Researchers also will continue to investigate remibrutinib’s use in multiple immune-mediated conditions.
“Over time, I’m sure we will be looking at durability of response beyond week 52. I think we’ll also look at emerging side effect profiles over years to make sure that we don’t see any unanticipated side effects,” Lebwohl said. “But I would say right now, the picture looks pretty good.”
Reference:
- Novartis phase III data confirm sustained efficacy and long-term safety of oral remibrutinib in chronic spontaneous urticaria. https://www.novartis.com/news/media-releases/novartis-phase-iii-data-confirm-sustained-efficacy-and-long-term-safety-oral-remibrutinib-chronic-spontaneous-urticaria. Published May 31, 2024. Accessed June 6, 2024.