New Anti-Chemokine Oral Drug XC8 in the Treatment of Asthma Patients with Poor Response to Corticosteroids: Results of a Phase 2A Randomized Controlled Clinical Trial.
Asthma
Chemokine
Corticosteroid resistance
Eosinophils
Interferon-gamma
XC8
Journal
Pulmonary therapy
ISSN: 2364-1746
Titre abrégé: Pulm Ther
Pays: United States
ID NLM: 101687144
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
24
06
2020
accepted:
26
09
2020
pubmed:
24
10
2020
medline:
24
10
2020
entrez:
23
10
2020
Statut:
ppublish
Résumé
A significant number of patients with moderate asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS). These patients do not yet meet the criteria for oral corticosteroids (OCS) and monoclonal antibodies. The new anti-chemokine oral drug XC8 could represent an alternative treatment option for these patients. The objective of this trial was to evaluate the effect of different doses of the XC8 in patients with partly controlled asthma in a phase 2a clinical trial. A double-blind, parallel-group, randomized, multicenter, phase 2a trial was conducted at 12 sites in Russia. Patients with asthma were randomized into four groups (n = 30 each) to receive XC8 at 2 mg, 10 mg, 100 mg or placebo once-daily for 12 weeks in addition to low-dose ICS with or without LABA. Efficacy and safety parameters were evaluated at weeks 0, 2, 6, and 12. No statistically significant difference between the treatment arms in the number of patients with adverse events was observed. The primary endpoint, improvement of forced expiratory volume in 1 s (FEV Given the high safety, oral route of administration, and efficacy, XC8 may provide a promising treatment option for patients with mild-to-moderate asthma. 795-30/12/2015 (Ministry of Health Russian Federation), NCT03450434 (ClinicalTrials.gov).
Identifiants
pubmed: 33095411
doi: 10.1007/s41030-020-00134-5
pii: 10.1007/s41030-020-00134-5
pmc: PMC7671956
doi:
Banques de données
ClinicalTrials.gov
['NCT03450434']
Types de publication
Journal Article
Langues
eng
Pagination
351-369Subventions
Organisme : Ministry of Industry and Trade of the Russian Federation.
ID : contract No. 14411.2049999.19.031 from 8/4/2014
Références
Braman SS. The global burden of asthma. Chest. 2006;130(1 Suppl):4S–12S.
doi: 10.1378/chest.130.1_suppl.4S
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2015. www.ginasthma.org . Accessed 30 Dec 2015.
Lommatzsch M, Stoll P. Novel strategies for the treatment of asthma. Allergo J Int. 2016;25:11–7.
doi: 10.1007/s40629-016-0093-5
Akenroye A, McCormack M, Keet C. Severe Asthma in the US Population and Eligibility for Monoclonal Antibody Therapy. J Allergy Clin Immunol. 2020;145(4):1295–1297.e6.
doi: 10.1016/j.jaci.2019.12.009
Norman P. Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs. Expert Opin Investig Drugs. 2014;23(1):55–66.
doi: 10.1517/13543784.2013.839658
Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax. 2002;57(7):643–8.
doi: 10.1136/thorax.57.7.643
de Groot JC, Ten Brinke A, Bel EH. Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Res. 2015;1(1):1–11.
doi: 10.1183/23120541.00024-2015
Casciano J, Krishnan J, Dotiwala Z, Li C, Sun SX. Clinical and economic burden of elevated blood eosinophils in patients with and without uncontrolled asthma. J Manag Care Spec Pharm. 2017;23(1):85–91.
pubmed: 28025926
Zeiger RS, Schatz M, Li Q, Chen W, Khatry DB, Gossage D, et al. High blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma. J Allergy Clin Immunol Pract. 2014;2(6):741–50.
doi: 10.1016/j.jaip.2014.06.005
Lawrence MG, Steinke JW, Borish L. Cytokine-targeting biologics for allergic diseases. Ann Allergy Asthma Immunol. 2018;120(4):376–81.
doi: 10.1016/j.anai.2018.01.009
Ramonell RP, Iftikhar IH. Effect of Anti-IL5, Anti-IL5R, Anti-IL13 therapy on asthma exacerbations: a network meta-analysis. Lung. 2020;198:95–103.
doi: 10.1007/s00408-019-00310-8
Edris A, De Feyter S, Maes T, Joos G, Lahousse L. Monoclonal antibodies in type 2 asthma: a systematic review and network meta-analysis. Respir Res. 2019;20(1):179.
doi: 10.1186/s12931-019-1138-3
Park HS, Kim MK, Imai N, Nakanishi T, Adachi M, Ohta K, et al. A phase 2a study of benralizumab for patients with eosinophilic asthma in South Korea and Japan. Int Arch Allergy Immunol. 2016;169(3):135–45.
doi: 10.1159/000444799
Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5(5):390–400.
doi: 10.1016/S2213-2600(17)30125-X
Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–66.
doi: 10.1016/S2213-2600(15)00042-9
Yancey SW, Ortega HG, Keene ON, Mayer B, Gunsoy NB, Brightling CE, et al. Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma. J Allergy Clin Immunol. 2017;139(4):1167–75.
doi: 10.1016/j.jaci.2016.08.008
Rathinam KK, Abraham JJ, Vijayakumar TM. Dupilumab in the treatment of moderate to severe asthma: an evidence-based review. Curr Ther Res Clin Exp. 2019;91:45–51.
doi: 10.1016/j.curtheres.2019.100571
Skolnik NS, Carnahan SP. Primary care of asthma: new options for severe eosinophilic asthma. Curr Med Res Opin. 2019;35(7):1309–18.
doi: 10.1080/03007995.2019.1595966
Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475–85.
doi: 10.1056/NEJMoa1804093
Nebol'sin VE, Zheltukhina GA, Krzhechkovskaia VV, Kovaleva VL, Evstigneeva RP. The effect of gamma-L-glutamylhistamine analogues on the severity of experimental anaphylactic reaction, hormonal status and liver cytochrome P450 system. Vopr Med Khim. 2001;47(3):301–7.
pubmed: 11558312
Kovaleva VL, Nebol'sin VE, Makarova OV, Noseikina EM, Mikhailova LP. The effect of a potential drug ingamine on a model of noninfectious pneumonia. Eksp Klin Farmakol. 2004;67(4):30–4.
pubmed: 15500042
Kovaleva VL, Nebol'sin VE, Karabinenko AA, Zheltukhina GA, Uteshev DB. The protector properties of a pseudopeptide drug ingamine studied on a model of bronchospasm in guinea pigs. Eksp Klin Farmakol. 2005;68(2):21–4.
pubmed: 15934361
Ferko B, Romanova J, Rydlovskaya AV, Kromova TA, Proskurina OV, Amelina AN, et al. A novel oral glutarimide derivative XC8 suppresses Sephadex-induced lung inflammation in rats and ovalbumin-induced acute and chronic asthma in Guinea pigs. Curr Pharm Biotechnol. 2019;20(2):146–56.
doi: 10.2174/1389201020666190215103505
Proudfoot AE. Chemokine receptors: multifaceted therapeutic targets. Nat Rev Immunol. 2002;2(2):106–15.
doi: 10.1038/nri722
Dunzendorfer S, Kaneider NC, Kaser A, Woell E, Frade JM, Mellado M, et al. Functional expression of chemokine receptor 2 by normal human eosinophils. J Allergy Clin Immunol. 2001;108(4):581–7.
doi: 10.1067/mai.2001.118518
Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29(6):313–26.
doi: 10.1089/jir.2008.0027
Renner A, Romanova J, Ferko B, Schmutz H, Nebolsin V, Muller M, et al. Safety, pharmacokinetics and pharmacodynamics of a novel anti-asthmatic drug, XC8, in healthy probands. Pulm Pharmacol Ther. 2019;59:101852.
doi: 10.1016/j.pupt.2019.101852
Santanello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes for asthma measures in a clinical trial? Eur Respir J. 1999;14(1):23–7.
doi: 10.1034/j.1399-3003.1999.14a06.x
Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59–99.
doi: 10.1164/rccm.200801-060ST
Cynis H, Hoffmann T, Friedrich D, Kehlen A, Gans K, Kleinschmidt M, et al. The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions. EMBO Mol Med. 2011;3(9):545–58.
doi: 10.1002/emmm.201100158
Lee JS, Yang EJ, Kim IS. The roles of MCP-1 and protein kinase C delta activation in human eosinophilic leukemia EoL-1 cells. Cytokine. 2009;48(3):186–95.
doi: 10.1016/j.cyto.2009.07.008
Lloyd CM, Hessel EM. Functions of T cells in asthma: more than just T(H)2 cells. Nat Rev Immunol. 2010;10(12):838–48.
doi: 10.1038/nri2870
Hens G, Vanaudenaerde BM, Bullens DM, Piessens M, Decramer M, Dupont LJ, et al. Sinonasal pathology in nonallergic asthma and COPD: 'united airway disease' beyond the scope of allergy. Allergy. 2008;63(3):261–7.
doi: 10.1111/j.1398-9995.2007.01545.x
Magnan AO, Mely LG, Camilla CA, Badier MM, Montero-Julian FA, Guillot CM, et al. Assessment of the Th1/Th2 paradigm in whole blood in atopy and asthma Increased IFN-gamma-producing CD8(+) T cells in asthma. Am J Respir Crit Care Med. 2000;161(6):1790–6.
doi: 10.1164/ajrccm.161.6.9906130
Litonjua AA, Sparrow D, Guevarra L, O'Connor GT, Weiss ST, Tollerud DJ. Serum interferon-gamma is associated with longitudinal decline in lung function among asthmatic patients: the Normative Aging Study. Ann Allergy Asthma Immunol. 2003;90(4):422–8.
doi: 10.1016/S1081-1206(10)61827-3
Bentley AM, Hamid Q, Robinson DS, Schotman E, Meng Q, Assoufi B, et al. Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am J Respir Crit Care Med. 1996;153(2):551–6.
doi: 10.1164/ajrccm.153.2.8564096
Kaur M, Smyth LJ, Cadden P, Grundy S, Ray D, Plumb J, et al. T lymphocyte insensitivity to corticosteroids in chronic obstructive pulmonary disease. Respir Res. 2012;13:20.
doi: 10.1186/1465-9921-13-20
O'Connell D, Bouazza B, Kokalari B, Amrani Y, Khatib A, Ganther JD, et al. IFN-gamma-induced JAK/STAT, but not NF-kappaB, signaling pathway is insensitive to glucocorticoid in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2015;309(4):L348–L359359.
doi: 10.1152/ajplung.00099.2015
Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41(2):330–8.
doi: 10.1183/09031936.00223411
Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184(10):1125–32.
doi: 10.1164/rccm.201103-0396OC
Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973–84.
doi: 10.1056/NEJMoa0808991