Lebrikizumab
Lebrikizumab is a humanised immunoglobulin G4 (IgG4) monoclonal antibody that binds to interleukin-13 and inhibits its function.[128]Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011 Sep 22;365(12):1088-98.
https://www.nejm.org/doi/full/10.1056/NEJMoa1106469
http://www.ncbi.nlm.nih.gov/pubmed/21812663?tool=bestpractice.com
In phase 2 clinical trials, lebrikizumab reduced exacerbation rates and improved lung function in patients with uncontrolled asthma.[128]Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011 Sep 22;365(12):1088-98.
https://www.nejm.org/doi/full/10.1056/NEJMoa1106469
http://www.ncbi.nlm.nih.gov/pubmed/21812663?tool=bestpractice.com
[129]Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015 Aug;70(8):748-56.
https://www.doi.org/10.1136/thoraxjnl-2014-206719
http://www.ncbi.nlm.nih.gov/pubmed/26001563?tool=bestpractice.com
Efficacy was most pronounced in patients with high levels of blood eosinophils and periostin, both markers of type 2 inflammation.[128]Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011 Sep 22;365(12):1088-98.
https://www.nejm.org/doi/full/10.1056/NEJMoa1106469
http://www.ncbi.nlm.nih.gov/pubmed/21812663?tool=bestpractice.com
[129]Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015 Aug;70(8):748-56.
https://www.doi.org/10.1136/thoraxjnl-2014-206719
http://www.ncbi.nlm.nih.gov/pubmed/26001563?tool=bestpractice.com
Lebrikizumab subsequently failed to demonstrate consistent efficacy in biomarker-high patients in its pivotal phase 3 studies, and its development in asthma was discontinued in 2016.[130]Hanania NA, Korenblat P, Chapman KR, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med. 2016 Oct;4(10):781-96.
http://www.ncbi.nlm.nih.gov/pubmed/27616196?tool=bestpractice.com
However, in 2021, authors of a post-hoc analysis of the phase 3 data found that patients enrolled in the trials may have been underdosed, opening up the possibility of new trials at higher doses.[131]Korenblat P, Sher E, Berman G, et al. P069 effect of lebrikizumab on lung function in patients with severe eosinophilic asthma. Ann Allergy Asthma Immunol. 2021 Nov 1;127(5):S34.
https://doi.org/10.1016/j.anai.2021.08.098
One study of lebrikizumab in adolescent patients aged 12-17 years showed promising efficacy results but was prematurely terminated.[132]Szefler SJ, Roberts G, Rubin AS, et al. Efficacy, safety, and tolerability of lebrikizumab in adolescent patients with uncontrolled asthma (ACOUSTICS). Clin Transl Allergy. 2022 Jul;12(7):e12176.
https://onlinelibrary.wiley.com/doi/10.1002/clt2.12176
http://www.ncbi.nlm.nih.gov/pubmed/35846226?tool=bestpractice.com
Meanwhile, the US Food and Drug Administration has granted fast-track designation for lebrikizumab for the treatment of moderate-to-severe atopic dermatitis.
Itepekimab
Itepekimab is a human IgG4 monoclonal antibody directed against interleukin-33, an upstream epithelial alarmin involved in airway inflammation.[133]Chan R, Stewart K, Misirovs R, et al. Targeting downstream type 2 cytokines or upstream epithelial alarmins for severe asthma. J Allergy Clin Immunol Pract. 2022 Jun;10(6):1497-505.
https://www.doi.org/10.1016/j.jaip.2022.01.040
http://www.ncbi.nlm.nih.gov/pubmed/35131510?tool=bestpractice.com
[134]Kosloski MP, Kalliolias GD, Xu CR, et al. Pharmacokinetics and pharmacodynamics of itepekimab in healthy adults and patients with asthma: Phase I first-in-human and first-in-patient trials. Clin Transl Sci. 2022 Feb;15(2):384-95.
https://www.doi.org/10.1111/cts.13157
http://www.ncbi.nlm.nih.gov/pubmed/34523807?tool=bestpractice.com
In a phase 2 study of patients with moderate-to-severe asthma, itepekimab monotherapy was associated with fewer loss-of-control asthma events than dupilumab monotherapy, dupilumab plus itepekimab, or placebo.[135]Wechsler ME, Ruddy MK, Pavord ID, et al. Efficacy and safety of itepekimab in patients with moderate-to-severe asthma. N Engl J Med. 2021 Oct 28;385(18):1656-68.
https://www.doi.org/10.1056/NEJMoa2024257
http://www.ncbi.nlm.nih.gov/pubmed/34706171?tool=bestpractice.com
Itepekimab is also under clinical investigation in patients with chronic obstructive pulmonary disease.[136]Rabe KF, Celli BR, Wechsler ME, et al. Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial. Lancet Respir Med. 2021 Nov;9(11):1288-98.
http://www.ncbi.nlm.nih.gov/pubmed/34302758?tool=bestpractice.com