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.

Informations de copyright

© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: [e-mail].

Déclaration de conflit d'intérêts

Conflicts of interest: All authors have completed the International Committee of Medical Journal Editors (ICMJE) uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare the following: F.S. was or currently is a speaker and/or advisor and has received honoraria and/or funding for research from Allakos, Blueprint, Celldex, Cogent, Genentech, Novartis, Sanofi/Regeneron and Uriach. S.A. is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, AstraZeneca, CSL Behring, Moxie, Novartis, Sanofi, Takeda and Thermo Fisher. M.M. is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Aralez, AstraZeneca, FAES, Genentech, Menarini, Moxie, MSD, Novartis, Roche, Sanofi, UCB and Uriach. H.S.R. and B.S. were employees of Allakos, Inc. at the time of the study, own stocks and stock options and are named on patents for the company. A.M.K. was an employee of Allakos Inc., and owned stock and stock options at the time of the study. A.T.C. and B.A.Y. are employees of Allakos, Inc. and own stock options in the company. H.B. has received honoraria from Novartis for participation on an advisory board and as a speaker. T.H. is or recently was a speaker for Moxie. M.H. and E.G.M. declare no conflicts of interest.