Lebrikizumab
Lebrikizumab is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds to interleukin-13 and inhibits its function.[169]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.[169]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
[170]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.[169]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
[170]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.[171]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.[172]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 ages 12-17 years showed promising efficacy results but was prematurely terminated.[173]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 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.[155]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 Feb 5 [Epub ahead of print].
https://www.doi.org/10.1016/j.jaip.2022.01.040
http://www.ncbi.nlm.nih.gov/pubmed/35131510?tool=bestpractice.com
[174]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.[175]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.[176]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
Vitamin D
Administration of vitamin D is associated with decreased rates of asthma exacerbations with very minimal adverse effects.[133]Wang M, Liu M, Wang C, et al. Association between vitamin D status and asthma control: a meta-analysis of randomized trials. Respir Med. 2019 Apr;150:85-94.
https://www.resmedjournal.com/article/S0954-6111(19)30061-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/30961957?tool=bestpractice.com
[177]Chen Z, Peng C, Mei J, et al. Vitamin D can safely reduce asthma exacerbations among corticosteroid-using children and adults with asthma: a systematic review and meta-analysis of randomized controlled trials. Nutr Res. 2021 Aug;92:49-61.
http://www.ncbi.nlm.nih.gov/pubmed/34274554?tool=bestpractice.com
A randomized controlled trial (RCT) of adults with asthma and vitamin D deficiency showed that supplementation with weekly oral calcifediol compared with placebo improved asthma control test scores and quality of life over 6 months.[178]Andújar-Espinosa R, Salinero-González L, Illán-Gómez F, et al. Effect of vitamin D supplementation on asthma control in patients with vitamin D deficiency: the ACVID randomised clinical trial. Thorax. 2021 Feb;76(2):126-33.
https://www.doi.org/10.1136/thoraxjnl-2019-213936
http://www.ncbi.nlm.nih.gov/pubmed/33154023?tool=bestpractice.com
Despite these data, there is no clear consensus on how and when to supplement with vitamin D and which patients with asthma are most likely to benefit. It is currently not part of any of the major guidelines at this time but remains an active area for further investigation.[179]Martineau AR, Cates CJ, Urashima M, et al. Vitamin D for the management of asthma. Cochrane Database Syst Rev. 2016 Sep 5;(9):CD011511.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011511.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/27595415?tool=bestpractice.com
[180]Jolliffe DA, Greenberg L, Hooper RL, et al. Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respir Med. 2017 Nov;5(11):881-90.
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30306-5/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/28986128?tool=bestpractice.com
Guidelines indicate that correction of vitamin D deficiency in women with asthma who are pregnant, or planning pregnancy, may reduce the risk of wheezing episodes in their child's early life.[52]Global Initiative for Asthma. 2024 global strategy for asthma management and prevention. May 2024 [internet publication].
https://ginasthma.org/wp-content/uploads/2024/05/GINA-2024-Strategy-Report-24_05_22_WMS.pdf
However, follow-up data from the Vitamin D Antenatal Asthma Reduction Trial (VDAART) showed that prenatal supplementation failed to reduce incidence of asthma or recurrent wheeze in at-risk children at 6 years.[181]Litonjua AA, Carey VJ, Laranjo N, et al. Six-year follow-up of a trial of antenatal vitamin D for asthma reduction. N Engl J Med. 2020 Feb 6;382(6):525-33.
https://www.doi.org/10.1056/NEJMoa1906137
http://www.ncbi.nlm.nih.gov/pubmed/32023372?tool=bestpractice.com
An RCT of vitamin D supplementation in children ages 6-16 years with persistent asthma and low vitamin D levels also failed to show improvement in severe exacerbations versus placebo.[182]Forno E, Bacharier LB, Phipatanakul W, et al. Effect of vitamin D3 supplementation on severe asthma exacerbations in children with asthma and low vitamin D levels: the VDKA randomized clinical trial. JAMA. 2020 Aug 25;324(8):752-60.
https://www.doi.org/10.1001/jama.2020.12384
http://www.ncbi.nlm.nih.gov/pubmed/32840597?tool=bestpractice.com