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

Mark Toshner,James Liley,William C Nichols,Amit Arora,Louise Harlow,Paul A Corris,Katie A Lutz,Emily Knightbridge,Nicholas W Morrell,Ken Batai,Jay Suntharalingam,Martin R Wilkins,Colin Church,Ankit A Desai,Lars Harbaum,Michael W Pauciulo,Florent Soubrier,J Simon R Gibbs,Marc Humbert,David G Kiely,Brian Lam,Stefan Gräf,D Gor ,Richard Trembath ,Tae‐Hwi Schwantes‐An ,J Gerry Coghlan ,Christopher J Rhodes ,Jason H Karnes ,Stephen J Wort ,Luke Howard ,Seán Gaine ,Ray V H Jones ,Jules Hernández-Sánchez ,Joanna Pepke‐Zaba ,Rick A Kittles ,Sofia S Villar Moreschi

doi:10.1183/13993003.02463-2020

Abstract

BackgroundInflammation 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.MethodsWe 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.ResultsWe 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 Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab.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).ConclusionAdverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Highlights

Pulmonary arterial hypertension (PAH) is a rare and often fatal disease characterised by profound remodeling of small pulmonary arteries leading to an increased pulmonary vascular resistance (PVR) and right heart failure [1]
We present data on modified intention to treat; defined as the set of patients who have had at least one dose of Tocilizumab and at least one post-baseline result and ITT analysis as a sensitivity analysis, i.e. to assess the existence of potential bias and that it did not differ from the mITT
Genotype at IL-6 receptor (IL6R) SNP rs7529229 was not associated with all-cause mortality in the NIHRBR study cohort. This proof-of-concept open-label clinical trial demonstrated no significant effect of tocilizumab in prevalent group 1 PAH

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a rare and often fatal disease characterised by profound remodeling of small pulmonary arteries leading to an increased pulmonary vascular resistance (PVR) and right heart failure [1]. Much interest has focused on the association of PAH with dysregulated immunity, infection and inflammation [2]. Auto-immune diseases are causative in PAH, most commonly scleroderma and systemic lupus erythematosus. Inflammatory/ infectious processes such as HIV infection and schistosomiasis are associated with PAH [3]. Idiopathic and heritable forms of PAH are associated with auto-immune thyroid disease, HLA subtypes, and the presence of autoantibodies has been noted in up to 93% of patients [4]. It has been proposed that idiopathic PAH might be an auto-immune disease [2]

Methods

Results

Conclusion