Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.

BACKGROUND

Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies.

METHODS

PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete.

FINDINGS

Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab.

INTERPRETATION

In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies.

FUNDING

Novartis Pharma.

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests MM is or recently was a speaker, an adviser for, or has received research funding from Amgen, Allakos, Aralez, AstraZeneca, Celldex, FAES, Genentech, GI Innovation, Kyowa Kirin, Leo Pharma, Menarini, Novartis, Moxie, MSD, Roche, Sanofi, Third Harmonic, UCB, and Uriach. LFE is or recently was a speaker or adviser for Novartis, Sanofi, and AbbVie, and has received research support from Novartis and Sanofi. AMG-A reports roles as a medical adviser for Uriach Pharma, Sanofi, Genentech, Novartis, FAES, GSK, AMGEN, Thermo Fisher, and has received research grants supported by Uriach Pharma, Novartis, and Instituto Carlos III- FEDER; she also participates in educational activities for Uriach Pharma, Novartis, Genentech, Menarini, LEO-PHARMA, GSK, MSD, Almirall, AVENE, and Sanofi. GS has received research support from Aimmune, Amgen, AstraZeneca, DBV technologies, Genentech, Kedrion, Leo Pharma, Novartis, Nuvo Pharmaceuticals, Sanofi, Stallergenes, Merck, and Schering-Plough; and is a medical adviser or has received payment for lectures from Merck, Novartis, CSL Behring, Pfizer, Anaphylaxis Canada, the Allergy Asthma and Immunology Society of Ontario, and the Canadian Hereditary Angioedema Network. MH has received lecture or consultation fees from TAIHO Pharmaceutical, Novartis, MSD, Teikoku Seiyaku, Mitsubishi Tanabe Pharma, Kaken Pharmaceutical, Kyorin Pharmaceutical, Uriach, Sanofi, and Kyowa-Kirin and GI Innovation. SS received grant, research, or clinical trial support from the National Institutes of Health, ITN, Novartis, Regeneron, and is a consultant or advisery board member for Genentech, Novartis, Medimmune, AstraZeneca, Pfizer, Allakos, Eli Lily, and Gossamer Bio. CG has recently been an adviser for Celltrion and has participated in an advisery board for Sanofi. DF is, or recently was, a speaker or adviser for Novartis, Sanofi, AbbVie, Takeda, AstraZeneca, CSL Behring, and Roche. DR received fees as lecturer and advisery board member for Novartis, Leo, Lilly, MSD, UCB, Janssen, Sanofi, Menarini, Genesis pharma, and AbbVie. FB has received payment or honoraria as speaker fees from Novartis. GWC reports having received research grants, as well as being a lecturer or having received advisery board fees, from Menarini, Alk-Abello', Allergy Therapeutics, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Genentech, Guidotti-Malesci, GSK, Hal Allergy, Mylan, Merck, Merck Sharp & Dome, Mundipharma, Novartis, Regeneron, Roche, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer, UCB Pharma, Uriach Pharma, Valeas, and Vibor-Pharma. HR reports receiving speaker's fees, advisery board fees or funds for research to the institution from Novartis Pharma, Pharming, Sanofi-Genzyme, Third Harmonic, and Leo Pharma. CI reports having received research or clinical trial support, or fees for lectures from Novartis, Sanofi, AstraZeneca, Takeda, and Stallergenes Greer. JCS reports receiving fees for being consultant or advisery board member for Leo Pharma, Novartis, Pfizer, Sanofi-Genzyme, Trevi, UCB, and Vifor; for being speaker for AbbVie, Almirall, Alvotech, Janssen-Cilag, Eli-Lilly, Leo Pharma, Novartis, Pfizer, and Sanofi-Genzyme; for being the investigator in clinical trials for AbbVie, Almirall, Amgen, AnaptysBio, BMS, Boehringer Ingelheim, Celtrion, Galderma, Galapagos, Helm, Kliniksa, Incyte, InfraRX, Janssen-Cilag, Leo Pharma, Medimmune, Menlo Therapeutics, Merck, Novartis, Pfizer, Regeneron, UCB, Teva, and Trevi. JAB reports grants and personal fees from Novartis, AstraZeneca, Allakos, Amgen, Celldex, Genentech, and Sanofi Regeneron outside the submitted work. JGP has received travel support, speakers' honoraria, and educational grants from Novartis, Sanofi Regeneron, Takeda, Pharming, and CSL Behring. KK is or recently was a speaker or adviser for Novartis, Sanofi, Takeda, and A Menarini, and has received research grants from Novartis. LA is or recently was a speaker, adviser, or has received research funding from AstraZeneca, GSK, Novartis, OM-Pharma, Regeneron, Shire, Takeda, and Sanofi-Genzyme. PS is or recently was a speaker, adviser, or has received research funding from AbbVie, Allergika, Almirall, Amgen, Beiersdorf, Biocryst, Biogen, BMS, Boehringer-Ingelheim, Celgene, CSL-Behring, Eli-Lilly, Galderma, Hexal, Janssen, Klinge, Klosterfrau, LEO-Pharma, LETI-Pharma, L'Oreal, Medice, Novartis, Octapharma, Pfizer, Pflüger, Pharming, Pierre Fabre, Regeneron, Shire, Takeda, Regeneron, Sanofi-Genzyme, und UCB Pharma. RS is Director and Founder of Samson Medical Pty, and serves on the pharmaceutical advisery board of Eli Lilly, Pfizer, Leo Pharmaceutical, and reports being on the speaker bureau of Pfizer, AbbVie, and Novartis. He has also been principal investigator in clinical trials for AbbVie, Aerotech, Akesobio, Amgen, Arcutis, Arena, Ascend AstraZeneca, Bayer, Biotherapeutics Boehringer Ingelheim, Bristol Myer Squibb, Celgene, Coherus BioSciences, Connect, Demira, Eli Lilly, Galderma, GSK, F. Hoffman–La Roche, Janssen, MedImmune, Merck, Merck Sharpe & Dohme, Novartis, Oncobiologics, Pfizer, Principia, Regeneron, Roche, Reistone Biopharma, Samson Clinical, Sanofi-Genzyme, Sun Pharma UCB, Valeant, and Zai Labs. He is President of the Australasian Hair and Wool Research Society, Vice President of the International Society of Dermatology, and The International Academy of Dermatology. SG has consulted or advised for Novartis and IgGenix. SFT is or recently was a speaker, adviser for, or has received research funding from AbbVie, Almirall, Boehringer Ingelheim, CSL, Eli Lilly, Janssen, Leo Pharma, Novartis, Sanofi, Pfizer, UCB, and Union Therapeutics. TT received clinical trial support from Novartis, AstraZeneca, Celldex Therapeutics, Genentech, and GSK. YMY has received research or clinical trial support from Novartis, Amgen, Yuhan, Takeda, and Daewoong ABa, DM, and ES are employees of Novartis Pharmaceuticals, East Hanover, New Jersey, NJ, USA. EH is an employee of Novartis Institutes for Biomedical Research, China. VV is an employee of Novartis Healthcare Private, Hyderabad, India. ABu, KL, MP, and TS are employees of Novartis Pharma, Basel, Switzerland. KG, JL, and OU report no conflicts of interest.