Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension

Uniphy Clinical Trials Network

doi:10.1183/13993003.02463-2020

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension

Uniphy Clinical Trials Network

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Abstract

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 11 744 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 Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab.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.

Original language	English
Article number	2002463
Journal	The European respiratory journal
Volume	59
Issue number	3
Early online date	10 Mar 2022
DOIs	https://doi.org/10.1183/13993003.02463-2020
Publication status	E-pub ahead of print - 10 Mar 2022

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10.1183/13993003.02463-2020

Mendelian randomisation and experimental_TOSHNER_Published online 10 Mar 22_GOLD VoR (CC BY)Final published version, 922 KBLicence: CC BY

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@article{f9af1dadfb5e4352bd0676139e34250b,

title = "Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension",

abstract = "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 11 744 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.",

author = "{Uniphy Clinical Trials Network} and Mark Toshner and Colin Church and Lars Harbaum and Christopher Rhodes and {Villar Moreschi}, {Sofia S.} and James Liley and Rowena Jones and Amit Arora and Ken Batai and Desai, {Ankit A.} and Coghlan, {John G.} and Gibbs, {J. Simon R.} and Dee Gor and Stefan Gr{\"a}f and Louise Harlow and Jules Hernandez-Sanchez and Howard, {Luke S.} and Marc Humbert and Jason Karnes and Kiely, {David G.} and Rick Kittles and Emily Knightbridge and Brian Lam and Lutz, {Katie A.} and Nichols, {William C.} and Pauciulo, {Michael W.} and Joanna Pepke-Zaba and Jay Suntharalingam and Florent Soubrier and Trembath, {Richard C.} and Schwantes-An, {Tae Hwi L.} and Wort, {S. John} and Wilkins, {Martin R.} and Sean Gaine and Morrell, {Nicholas W.} and Corris, {Paul A.}",

note = "Funding Information: Conflict of interest: M. Toshner reports grants and personal fees from Bayer and Actelion, and personal fees from MSD and GSK, during the conduct of the study, and serves on the advisory board for MorphogenIX. C. Church has received travel grants and speaker fees from GSK, Actelion and Bayer. L. Harbaum has nothing to disclose. C. Rhodes reports personal fees for advisory board work from Actelion and United Therapeutics, outside the submitted work. S.S. Villar Moreschi has nothing to disclose. J. Liley has nothing to disclose. R. Jones has nothing to disclose. A. Arora has nothing to disclose. K. Batai has nothing to disclose. A.A. Desai has nothing to disclose. J.G. Coghlan reports research support, consultancy fees and speaker honoraria from Actelion. J.S.R. Gibbs reports personal fees from Acceleron, Arena, Bayer, Bellepheron, Complexa, Pfizer and United Therapeutics, grants and personal fees from Actelion, and personal fees and non-financial support from GSK, outside the submitted work. D. Gor was an employee of Roche, during the conduct of the study. S. Gr{\"a}f has nothing to disclose. L. Harlow has nothing to disclose. J. Hernandez-Sanchez is an employee of Roche but was not at the time of trial conduct. L.S. Howard has received personal fees and institutional grants/research support from Bayer and personal fees from MSD, Daichii Sayo and Pfizer. M. Humbert has received personal fees from Actelion, Merck and United Therapeutics, and grants and personal fees from Bayer and GSK. J. Karnes has nothing to disclose. D.G. Kiely reports grants and personal fees from Bayer and Actelion, and personal fees from GSK and MSD, during the conduct of the study. R. Kittles has nothing to disclose. E. Knightbridge has nothing to disclose. B. Lam has nothing to disclose. K.A. Lutz has nothing to disclose. W.C. Nichols has nothing to disclose. M.W. Pauciulo has nothing to disclose. J. Pepke-Zaba has served on advisory boards of and received personal fees and institutional grant/research support from Actelion, Bayer, MSD and GSK. J. Suntharalingam has nothing to disclose. F. Soubrier has nothing to disclose. R.C. Trembath has nothing to disclose. T-H.L. Schwantes-An has nothing to disclose. S.J. Wort reports grants and personal fees from Actelion and Bayer, and personal fees from GSK and MSD, outside the submitted work. M.R. Wilkins has nothing to disclose. S. Gaine has received honoraria from Actelion and United Therapeutics; has received travel grants from Actelion, Novartis and Menerini; and has performed drug safety board monitoring for United Therapeutics, GSK and Novartis. N.W. Morrell reports personal fees from MorphogenIX, during the conduct of the study. P.A. Corris has served on speakers{\textquoteright} bureau and advisory boards of Actelion, Bayer and MSD, and received institutional grant/research support from Actelion and Bayer. Funding Information: Support statement: This work was funded by a grant from the UK National Institute of Health Research Cambridge Biomedical Research Centre and Rare Diseases Translational Research Collaboration, in addition to an unrestricted grant from Roche Products Limited, Welwyn Garden City, UK. TRANSFORM-UK, ClinicalTrials.gov number NCT02676947. Funding information for this article has been deposited with the Crossref Funder Registry. Publisher Copyright: {\textcopyright} 2022 European Respiratory Society. All rights reserved.",

year = "2022",

month = mar,

day = "10",

doi = "10.1183/13993003.02463-2020",

language = "English",

volume = "59",

journal = "The European respiratory journal",

issn = "1399-3003",

publisher = "European Respiratory Society",

number = "3",

}

TY - JOUR

T1 - Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension

AU - 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, J. Simon 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 - Wort, S. John

AU - Wilkins, Martin R.

AU - Gaine, Sean

AU - Morrell, Nicholas W.

AU - Corris, Paul A.

N1 - Funding Information: Conflict of interest: M. Toshner reports grants and personal fees from Bayer and Actelion, and personal fees from MSD and GSK, during the conduct of the study, and serves on the advisory board for MorphogenIX. C. Church has received travel grants and speaker fees from GSK, Actelion and Bayer. L. Harbaum has nothing to disclose. C. Rhodes reports personal fees for advisory board work from Actelion and United Therapeutics, outside the submitted work. S.S. Villar Moreschi has nothing to disclose. J. Liley has nothing to disclose. R. Jones has nothing to disclose. A. Arora has nothing to disclose. K. Batai has nothing to disclose. A.A. Desai has nothing to disclose. J.G. Coghlan reports research support, consultancy fees and speaker honoraria from Actelion. J.S.R. Gibbs reports personal fees from Acceleron, Arena, Bayer, Bellepheron, Complexa, Pfizer and United Therapeutics, grants and personal fees from Actelion, and personal fees and non-financial support from GSK, outside the submitted work. D. Gor was an employee of Roche, during the conduct of the study. S. Gräf has nothing to disclose. L. Harlow has nothing to disclose. J. Hernandez-Sanchez is an employee of Roche but was not at the time of trial conduct. L.S. Howard has received personal fees and institutional grants/research support from Bayer and personal fees from MSD, Daichii Sayo and Pfizer. M. Humbert has received personal fees from Actelion, Merck and United Therapeutics, and grants and personal fees from Bayer and GSK. J. Karnes has nothing to disclose. D.G. Kiely reports grants and personal fees from Bayer and Actelion, and personal fees from GSK and MSD, during the conduct of the study. R. Kittles has nothing to disclose. E. Knightbridge has nothing to disclose. B. Lam has nothing to disclose. K.A. Lutz has nothing to disclose. W.C. Nichols has nothing to disclose. M.W. Pauciulo has nothing to disclose. J. Pepke-Zaba has served on advisory boards of and received personal fees and institutional grant/research support from Actelion, Bayer, MSD and GSK. J. Suntharalingam has nothing to disclose. F. Soubrier has nothing to disclose. R.C. Trembath has nothing to disclose. T-H.L. Schwantes-An has nothing to disclose. S.J. Wort reports grants and personal fees from Actelion and Bayer, and personal fees from GSK and MSD, outside the submitted work. M.R. Wilkins has nothing to disclose. S. Gaine has received honoraria from Actelion and United Therapeutics; has received travel grants from Actelion, Novartis and Menerini; and has performed drug safety board monitoring for United Therapeutics, GSK and Novartis. N.W. Morrell reports personal fees from MorphogenIX, during the conduct of the study. P.A. Corris has served on speakers’ bureau and advisory boards of Actelion, Bayer and MSD, and received institutional grant/research support from Actelion and Bayer. Funding Information: Support statement: This work was funded by a grant from the UK National Institute of Health Research Cambridge Biomedical Research Centre and Rare Diseases Translational Research Collaboration, in addition to an unrestricted grant from Roche Products Limited, Welwyn Garden City, UK. TRANSFORM-UK, ClinicalTrials.gov number NCT02676947. Funding information for this article has been deposited with the Crossref Funder Registry. Publisher Copyright: © 2022 European Respiratory Society. All rights reserved.

PY - 2022/3/10

Y1 - 2022/3/10

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 11 744 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 11 744 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

U2 - 10.1183/13993003.02463-2020

DO - 10.1183/13993003.02463-2020

M3 - Article

C2 - 34588193

AN - SCOPUS:85122269281

SN - 1399-3003

VL - 59

JO - The European respiratory journal

JF - The European respiratory journal

IS - 3

M1 - 2002463

ER -

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension

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