Safety and efficacy of lirentelimab in patients with refractory indolent systemic mastocytosis: a first-in-human clinical trial.

Background: Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell accumulation and mast cell-driven signs and symptoms. Currently used therapies are not approved and have limited efficacy. Lirentelimab (AK002) is a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8 that inhibits mast cell activation.
Objective: To determine the safety, tolerability, and efficacy of lirentelimab in reducing ISM symptoms.
Methods: At a specialty center for mastocytosis in Germany, we conducted a phase 1, first-in-human, single-ascending dose and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had WHO-confirmed ISM and unsatisfactory response to available treatment. In Part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01, or 0.03 mg/kg; in Part B, patients received 1 lirentelimab dose of 0.3 mg/kg or 1.0 mg/kg; and in Part C, patients received either 1.0 mg/kg lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one 1-mg/kg dose followed by five 3- to 10-mg/kg doses every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS), and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose.
Results: Across 25 patients with ISM (n=13 Part A+B, n=12 Part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events were feeling hot (76%) and headache (48%). No serious adverse events occurred. Part C median MSQ and MAS symptom severity scores improved across all symptoms (MSQ: skin [38%-56% improvement vs baseline], gastrointestinal [49%-60%], neurologic [47%-59%], musculoskeletal [26%-27%]; MAS: skin [53%-59%], gastrointestinal [72%-85%], neurologic [20%-57%], musculoskeletal [25%]). Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%), and skin (44%).
Conclusions: Lirentelimab was generally well tolerated and improved symptoms and QoL in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM.
Trial Registration: ClinicalTrials.gov number, NCT02808793.
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