PMID- 37290787
OWN - NLM
STAT- MEDLINE
DCOM- 20231102
LR  - 20231102
IS  - 1365-2133 (Electronic)
IS  - 0007-0963 (Linking)
VI  - 189
IP  - 5
DP  - 2023 Oct 25
TI  - Safety and efficacy of lirentelimab in patients with refractory indolent systemic 
      mastocytosis: a first-in-human clinical trial.
PG  - 511-519
LID - 10.1093/bjd/ljad191 [doi]
AB  - 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.
CI  - (c) The Author(s) 2023. Published by Oxford University Press on behalf of British 
      Association of Dermatologists. All rights reserved. For permissions, please 
      e-mail: journals.permissions@oup.com.
FAU - Siebenhaar, Frank
AU  - Siebenhaar F
AD  - Institute of Allergology.
AD  - Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology 
      and Allergology IA, Berlin, Germany.
FAU - Altrichter, Sabine
AU  - Altrichter S
AD  - Institute of Allergology.
AD  - Department of Dermatology and Venerology, Kepler University Hospital, Linz, 
      Austria.
FAU - Bonnekoh, Hanna
AU  - Bonnekoh H
AD  - Institute of Allergology.
AD  - Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology 
      and Allergology IA, Berlin, Germany.
FAU - Hawro, Tomasz
AU  - Hawro T
AD  - Institute of Allergology.
FAU - Hawro, Marlena
AU  - Hawro M
AD  - Institute of Allergology.
FAU - Michaelis, Edward G
AU  - Michaelis EG
AD  - Institute of Allergology.
AD  - Institute of Pathology, Charite-Universitatsmedizin Berlin, Berlin, Germany 
      (corporate member or Freie Universitat Berlin, Humboldt-Universitat zu Berlin, 
      Berlin, Germany, and Berlin Institute of Health, Berlin, Germany).
FAU - Kantor, Andrea M
AU  - Kantor AM
AD  - Allakos, San Carlos, CA, USA.
FAU - Chang, Alan T
AU  - Chang AT
AD  - Allakos, San Carlos, CA, USA.
FAU - Youngblood, Bradford A
AU  - Youngblood BA
AD  - Allakos, San Carlos, CA, USA.
FAU - Singh, Bhupinder
AU  - Singh B
AD  - Allakos, San Carlos, CA, USA.
FAU - Rasmussen, Henrik S
AU  - Rasmussen HS
AD  - Allakos, San Carlos, CA, USA.
FAU - Maurer, Marcus
AU  - Maurer M
AD  - Institute of Allergology.
AD  - Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology 
      and Allergology IA, Berlin, Germany.
LA  - eng
GR  - Allakos, Inc/
PT  - Clinical Trial, Phase I
PT  - Journal Article
PL  - England
TA  - Br J Dermatol
JT  - The British journal of dermatology
JID - 0004041
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antineoplastic Agents)
SB  - IM
CIN - Br J Dermatol. 2023 Oct 25;189(5):503-504. PMID: 37403635
CIN - Br J Dermatol. 2023 Oct 25;189(5):e88. PMID: 37879742
MH  - Adult
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Antibodies, Monoclonal/therapeutic use
MH  - *Antineoplastic Agents/therapeutic use
MH  - Mast Cells
MH  - *Mastocytosis/diagnosis
MH  - *Mastocytosis, Systemic/drug therapy/complications
MH  - Quality of Life
COIS- 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.
EDAT- 2023/06/09 01:09
MHDA- 2023/10/27 06:42
CRDT- 2023/06/08 20:43
PHST- 2023/02/02 00:00 [received]
PHST- 2023/05/12 00:00 [revised]
PHST- 2023/06/02 00:00 [accepted]
PHST- 2023/10/27 06:42 [medline]
PHST- 2023/06/09 01:09 [pubmed]
PHST- 2023/06/08 20:43 [entrez]
AID - 7192419 [pii]
AID - 10.1093/bjd/ljad191 [doi]
PST - ppublish
SO  - Br J Dermatol. 2023 Oct 25;189(5):511-519. doi: 10.1093/bjd/ljad191.