Lirentelimab shows efficacy for antihistamine-refractory chronic urticaria

Lirentelimab improved disease control among patients with antihistamine-refractory chronic urticaria, according to results of an open-label, proof-of-concept study published in The Journal of Allergy and Clinical Immunology.

Sabine Altrichter, MD, a dermatologist and allergist from the Berlin Institute of Health in Germany, and colleagues wrote that the treatment goal of chronic urticaria is to achieve complete control and normal quality of life. Current guidelines recommend first-line therapy using nonsedating H1-antihistamines, possibly up to four times the standard dose in refractory cases.

However, some patients with chronic spontaneous urticaria (CSU) do not respond or become refractory to this treatment, and there are no currently approved therapies for chronic inducible urticaria beyond oral antihistamines.

To determine the potential safety and efficacy of lirentelimab (AK002, Allakos), an investigational anti-sialic-acid-binding immunoglobulin-like lectin-8 monoclonal antibody that selectively inhibits mast cells and depletes eosinophils, Altrichter and colleagues evaluated 47 patients (median age, 42 years; age range, 18 to 75 years; 74% women; 98% white; median disease duration, 6 years; disease duration range, 1-58 years) with chronic urticaria from the U.S. and Germany. All patients had uncontrolled disease that was refractory to antihistamine treatment.

Patients received up to six monthly IV doses of lirentelimab starting at 0.3 mg/kg. If well-tolerated, the second and third doses were increased to 1 mg/kg and increased again up to 3 mg/kg for the remaining doses.

Two patients were excluded due to having no post-baseline efficacy data. The remaining 45 patients had omalizumab (Xolair; Genentech, Novartis)-naive CSU (n = 13), omalizumab-refractory CSU (n = 11), cholinergic urticaria (n = 11) or symptomatic dermographism (n = 10).

Treatment with lirentelimab led to the primary efficacy endpoint of Urticaria Control Test score improvement from baseline for all cohort patients, including mean increases of 11.1 (95% CI, 8.6-13.5) for patients with omalizumab-naive CSU, 4.8 (95% CI, 0.1-9.5) for patients with omalizumab-refractory CSU, 6.5 (95% CI, 2.3-10.6) for those with cholinergic urticaria and 3.4 (95% CI, 0.5-6.3) for those with symptomatic dermographism.

Among patients with CSU, 92% (95% CI, 64-100) of those who were omalizumab-naive and 36% (95% CI, 11-69) of those who were refractory to omalizumab achieved a complete response at week 22. Complete response rates reached 82% (95% CI, 48-98) for those with cholinergic urticaria and 40% (95% CI, 12-74) for those with symptomatic dermographism.

Researchers observed decreases in disease activity at week 22 as measured by mean changes on the Urticaria Activity Score 7 scale of –73% for omalizumab-naive and –47% for omalizumab-refractory patients with CSU.

Of patients with symptomatic dermographism, 50% had complete itch resolution and 40% had complete hive resolution according to the FricTest, and all evaluable patients with cholinergic urticaria demonstrated negative responses to a pulse-controlled ergometry exercise.

Symptom severity decreased in all four cohorts at the end of treatment according to both physicians and patients.

The most common adverse events were infusion-related reactions (43%), nasopharyngitis (21%) and headache (19%).

The researchers noted that limitations included a modest sample size and the open-label design. However, they wrote that even with the small number of patients, the impact of lirentelimab on disease activity and symptom control was consistent across all cohorts and substantially larger than what may be considered a placebo effect.

“Lirentelimab has been previously shown to inhibit mast cell activity, a known pathogenic driver of [chronic urticaria] symptoms; the clinical activity of lirentelimab demonstrated in omalizumab-refractory patients possibly reflects the direct targeted mechanism of action of lirentelimab against mast cells,” Altrichter and colleagues wrote.