TY - JOUR
T1 - Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension
AU - the Uniphy Clinical Trials Network
AU - Toshner, Mark
AU - Church, Colin
AU - Harbaum, Lars
AU - Rhodes, Christopher
AU - Villar Moreschi, Sofia S.
AU - Liley, James
AU - Jones, Rowena
AU - Arora, Amit
AU - Batai, Ken
AU - Desai, Ankit A.
AU - Coghlan, John G.
AU - Gibbs, Simon J.R.
AU - Gor, Dee
AU - Gräf, Stefan
AU - Harlow, Louise
AU - Hernandez-Sanchez, Jules
AU - Howard, Luke S.
AU - Humbert, Marc
AU - Karnes, Jason
AU - Kiely, David G.
AU - Kittles, Rick
AU - Knightbridge, Emily
AU - Lam, Brian
AU - Lutz, Katie A.
AU - Nichols, William C.
AU - Pauciulo, Michael W.
AU - Pepke-Zaba, Joanna
AU - Suntharalingam, Jay
AU - Soubrier, Florent
AU - Trembath, Richard C.
AU - Schwantes-An, Tae Hwi L.
AU - John Wort, S.
AU - Wilkins, Martin R.
AU - Gaine, Sean
AU - Morrell, Nicholas W.
AU - Corris, Paul A.
N1 - Publisher Copyright:
© 2022 European Respiratory Society. All rights reserved.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Background Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. Methods We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg−1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11744 individuals with European ancestry including 2085 patients with idiopathic/ heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. Results We recruited 29 patients (male/female 10/19; mean±SD age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). Conclusion Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
AB - Background Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. Methods We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg−1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11744 individuals with European ancestry including 2085 patients with idiopathic/ heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. Results We recruited 29 patients (male/female 10/19; mean±SD age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). Conclusion Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
UR - http://www.scopus.com/inward/record.url?scp=85122269281&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122269281&partnerID=8YFLogxK
U2 - 10.1183/13993003.02463-2020
DO - 10.1183/13993003.02463-2020
M3 - Article
C2 - 34588193
AN - SCOPUS:85122269281
SN - 0903-1936
VL - 59
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 3
M1 - 2002463
ER -