Remibrutinib safe, effective for chronic spontaneous urticaria over 52 weeks
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Key takeaways:
- There was a –28.8 mean change from baseline in weekly Urticaria Activity Scores at week 52.
- 55.8% of patients had a weekly Urticaria Activity Score of 0 at week 52.
Patients with chronic spontaneous urticaria showed rapid symptom improvement with a favorable safety profile over 52 weeks of treatment with remibrutinib, according to a study published in The Journal of Allergy and Clinical Immunology.
Patients who do not respond to other therapies may be able to use remibrutinib (LOU064, Novartis), Vipul Jain, MBBS, FRCPC, assistant professor in the division of clinical immunology and allergy of the department of medicine at McMaster University, and colleagues wrote.
The drug’s mechanism
By blocking the Burton tyrosine kinase (BTK) cascade, Jain told Healio, remibrutinib prevents the release of multiple inflammatory mediators, including histamine, which causes itch, hives and wheals, and swelling.
When remibrutinib is used alongside standard-dose antihistamines, Jain continued, it results in a “two-pronged approach,” where two parts of the pathway are targeted by inhibiting both histamine release and histamine receptors, reducing symptoms of chronic spontaneous urticaria (CSU).
“H1 antihistamines are the first line-treatment in CSU. However, over 50% of patients are inadequately controlled with antihistamines alone,” Jain said.
International guidelines recommend increasing the approved dose by a factor of four, he continued, but some people can still have uncontrolled symptoms, even at high doses. “While injectable biologic therapies are an option for those whose CSU is uncontrolled by antihistamines, less than 20% of eligible patients worldwide are treated with them,” Jain said. “Therefore, a significant unmet medical need exists for new effective options for the treatment of CSU inadequately controlled by antihistamines.”
A previous core 12-week phase 2b study showed remibrutinib to be highly effective, with a favorable safety profile at all doses tested, ranging from 10 mg once daily to 100 mg twice daily, Jain said. Next, the researchers launched a 52-week extension study of adults with CSU.
“In the extension study, we wanted to assess whether patients with an inadequate response during the core study, or after the core study in case symptoms reappear, would benefit from longer exposure to remibrutinib,” Jain said.
Study design, results
The study included 194 patients (mean age, 45.5 years; 71.6% women; 78.4% white) with inadequate control of their CSU despite treatment with second-generation H1 antihistamines. At baseline, their CSU was moderate to severe with a mean weekly Urticaria Activity Score (UAS7) of 27.9.
Patients took two 50 mg capsules of remibrutinib in the morning and two more in the evening at 12-hour intervals at approximately the same time each day for up to 52 weeks, along with a second-generation H1 antihistamine if needed. Median duration of exposure was 52.1 weeks for 170.5 patient-years of exposure.
Overall, 139 (71.6%) patients experienced at least one treatment-emergent adverse event, including 68 (35.1%) with at least one mild or moderate treatment-emergent adverse event and eight (4.1%) with severe events.
Eleven (5.7%) patients discontinued treatment because of treatment-emergent adverse events or severe adverse events. Overall, 23 (11.9%) patients had at least one treatment-emergent adverse event that the researchers said could have been related to the remibrutinib, all of which were individual events in up to two patients.
The most common treatment-emergent adverse events included infections and infestations, occurring in 60 (30.9%) patients, followed by skin and subcutaneous tissue disorders in 52 (26.8%) patients and gastrointestinal disorders reported by 32 (16.5%) patients.
Individual treatment-emergent adverse events occurring in 5% or more of patients included CSU (n = 22; 11.3%), COVID-19 (n = 16; 8.2%), headache (n = 13; 6.7%) and eczema (n = 10; 5.2%). The most common infections were upper respiratory tract infections such as COVID-19 (8.2%) and nasopharyngitis (4.1%).
CSU events were the most common skin disorders, with 76% of them reported during the treatment-free follow-up period. Twelve (6.2%) patients reported minor and mild to moderate bleeding events that primarily were cutaneous. The single cases of lymphopenia and neutropenia that were reported were not associated with infection.
Six (3.1%) patients had seven treatment-emergent serious adverse events, but the researchers did not consider any of them related to the remibrutinib, and all of them resolved during the study. One patient discontinued treatment due to a moderate melena from bariatric surgery, and another discontinued because of severe COVID-19 pneumonia. There were no deaths.
Researchers observed a 140 µg/L decrease in mean IgE from a baseline of 839.47 µg/L, a 0.534 g/L decrease in IgG levels from a baseline of 11.043 g/L, and IgM levels fell 0.13 g/L from their 1.047 g/L baseline. There was no change in total serum levels of IgA from the baseline of 2.266 g/L.
By week 4, UAS7 scores had a –17.6 mean change from baseline without any background H1 antihistamine medication, which was not allowed for this portion of the treatment period. The researchers called this clinical improvement rapid, with a –14.8 mean change observed at week 1. Improvements persisted, the researchers continued, with mean changes of –19.4 at week 12 and –21.8 at week 52.
Further, 27.3% (90% CI, 22.2%-33.1%) of the patients achieved complete response as indicated by UAS7 scores of 0 based on nonresponder imputation. Observed complete responses included 28.2% at week 4, 43.4% at week 12 and 55.8% at week 52.
Based on UAS7 scores of 6 or lower, 51% (90% CI, 44.9%-57.1%) of patients achieved well-controlled disease at week 4. Observed UAS7 scores of 6 or lower included 56.6% at week 12 and 68% at week 52.
Conclusions, next steps
These findings indicate that patients with CSU who have had inadequate control with H1 antihistamines can achieve rapid control of their disease with a favorable safety profile via long-term remibrutinib treatment.
“In this long-term phase 2b study, treatment with remibrutinib resulted in a fast, marked and sustained reduction in signs and symptoms of CSU, with complete responses achieved in a considerable proportion of patients,” Jain said.
These findings could be significant for millions who suffer the debilitating symptoms of CSU, which can adversely affect daily activities, work productivity, sleep and, ultimately, quality of life, Jain said.
“While antihistamines and injectable biologics are available, an innovative efficacious oral treatment that is highly selective, with a novel mode of action and favorable safety profile, would offer another option,” he said.
The researchers expect to present phase 3 data at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting in Anaheim, California, later this month, along with a final 52-week readout and filing in 2024, Jain said.
Perspective
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There is a high unmet need for treatments for CSU, as approximately 50% of patients have uncontrolled or partially controlled hives regardless of existing treatments, including omalizumab (Xolair; Genentech, Novartis), which is a monoclonal antibody.
As the global prevalence is up to 1.5% of the general population and CSU is a chronic relapsing and unpredictable disease with a significant impact on the quality of life of patients, clearly, there is an unmet need for developing additional drugs.This study’s findings are not surprising, as the core phase 2b study demonstrated a rapid effect on CSU, and this long-term extension study further supports the safety and durability of this treatment.
These also are very promising studies and suggest that remibrutinib, which is a BTK inhibitor for CSU, will be an excellent addition to our treatment regimen. Research should continue developing drugs that target mast cell degranulation, as CSU is not just mediated by IgE but also by non-IgE-dependent pathways. Studies using dupilumab (Dupixent; Regeneron, Sanofi), which is an IL-4 receptor antibody already on the market for atopic dermatitis, asthma and allergic diseases, to target type 2 inflammation that contributes to both pathways are also very promising, as well as phase 2 trials using barzolvolimab (Celldex Therapeutics) and drugs targeting Siglec and MRGPRx2, which are important receptors in mast cell activity.
All are promising, and more drugs are in development in this field. I foresee a bright future for miserable CSU patients who, until a few years ago, had only used antihistamines and one targeted biologic, omalizumab.
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