Oral EP262 Fails to Beat Placebo in Urticaria Trial
A Phase II study of the oral MRGPRX2 blocker EP262 for chronic spontaneous urticaria did not show a significant advantage over placebo.
Updated on Nov. 8, 2026 in Allergies
In the Phase II CALM-CSU trial, 113 adults with chronic spontaneous urticaria received oral EP262 at 50 mg or 150 mg, or placebo, once daily for six weeks. Neither EP262 dose produced a statistically significant improvement over placebo on the primary endpoint, and a planned lower-dose study component was terminated.
Why it matters
Chronic spontaneous urticaria remains difficult to control in patients who do not respond to daily H1 antihistamines, so a new oral option would fill a clinical gap. The trial's failure to separate EP262 from placebo means this mechanism will need further evaluation before it can be considered a viable treatment.
The trial enrolled 113 adults, of whom 107 completed treatment, and reported a placebo-adjusted UAS7 difference of 1.99 points for the 50 mg dose and -1.53 points for the 150 mg dose. Neither difference reached statistical significance, and the study does not yet explain why the active arms failed to separate from placebo.
The players
EP262
An oral investigational compound designed to block the MRGPRX2 receptor on skin mast cells, a pathway being explored as a non-antihistamine approach to urticaria.
The details
The multicenter, double-blind study randomized patients aged 18 to 80 with CSU of at least six months and UAS7 of at least 16 despite stable daily H1 antihistamines to oral EP262 or placebo once daily. EP262 targets Mas-related G protein-coupled receptor X2 (MRGPRX2), a receptor found on skin mast cells, and weekly itch and hive severity scores improved across all groups without significant treatment differences.
Timeline
The primary endpoint was measured from baseline to Week 6 of treatment.
A planned lower-dose study component was terminated following the lack of efficacy.
Health Landscape
The MRGPRX2 pathway has been pursued as a route to treatments that work independently of H1 antihistamines, which remain the standard first-line therapy for chronic spontaneous urticaria. This Phase II outcome shows that targeting the receptor with EP262 did not outperform placebo in this trial, which constrains how quickly the approach can move toward patients who do not respond to antihistamines.
For people whose hives persist despite daily antihistamines, this result means EP262 is not yet an available option and current treatment choices remain unchanged. Patients should continue to discuss existing management strategies with their clinicians rather than waiting on this investigational compound.
The takeaway
A negative Phase II result does not rule out future development, but it signals that the MRGPRX2 approach must demonstrate efficacy before it can offer a practical alternative to antihistamines. Readers with chronic hives should rely on established treatments until new evidence emerges.
Further reading
For more on the immune conditions behind this research, see the site's Allergies section.
Source note: This article includes information reported by European Medical Journal.
