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 (MC) accumulation and MC-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 MC activation. Objectives To determine the safety, tolerability and efficacy of lirentelimab in reducing the symptoms of ISM. Methods At a specialty centre for mastocytosis in Germany, we conducted a phase I first-in-human single-ascending and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had World Health Organization-confirmed ISM and an 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(-1); in part B, patients received one lirentelimab dose of 0.3 mg kg(-1) or 1.0 mg kg(-1); and in part C, patients received either 1.0 mg kg(-1) lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one dose of 1 mg kg(-1) followed by five doses of 3-10 mg kg(-1) 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 In 25 patients with ISM (13 in parts A + B and 12 in part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events (AEs) were feeling hot (76%) and experiencing a headache (48%). No serious AEs occurred. Median MSQ and MAS symptom severity scores in part C improved (vs. baseline) across all symptoms [MSQ: skin (38-56%), gastrointestinal (49-60%), neurological (47-59%), musculoskeletal (26-27%); MAS: skin (53-59%), gastrointestinal (72-85%), neurological (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 quality of life in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM. Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell accumulation and mast cell-driven signs and symptoms. Here, the safety and efficacy of lirentelimab, a monoclonal antibody against Siglec-8 that selectively inhibits mast cells, was assessed in 25 adults with ISM. Lirentelimab was generally well tolerated and improved symptoms and quality of life, suggesting its therapeutic potential for mast cell-driven diseases such as ISM.