Treatment with tocilizumab, an interleukin-6 (IL-6) receptor (IL6R) antagonist, caused no change in pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) in an open-label phase 2 clinical trial. Results were published in the European Respiratory Journal.
“In summary, treatment with tocilizumab is feasible in PAH but demonstrated no significant effects on hemodynamics or exploratory secondary endpoints in heritable or idiopathic PAH,” the authors concluded.
While no change in PVR was observed, there was evidence of IL6R inhibition, with IL-6 levels increasing (median, 9.5 pg/mL) and C-reactive protein levels decreasing (median, -1.2 mg/mL) in plasma. This indicated that tocilizumab was engaging with IL6R. No significant changes in the populations of B or T cells were observed either.
These results are in contrast to extensive preclinical work that showed IL-6 levels are an independent marker of prognosis, and overexpression of IL-6 can lead to pulmonary hypertension. Preclinical work has also shown that increased levels of IL-6 and certain IL6R mutations are associated with some connective tissue disorders that are known to cause pulmonary hypertension.
In a separate Mendelian randomization study, no significant association was found between the risk of PAH and the rs7529229 mutation of the IL6R gene (odds ratio, .99; 95% CI, .9-1.09; P =.88), known to increase circulating levels of IL6R. A small subset of patients with connective tissue disease (CTD)-associated PAH (4 out of 6) had a 15% or greater reduction in PVR. The authors noted that further investigation into immunosuppression of this subset of PAH patients may be warranted.
Secondary endpoints of the study including N-terminal pro-brain natriuretic peptide levels and World Health Organization functional class did not support a treatment effect, as well as the 6-Minute Walk Test and Cambridge Pulmonary Hypertension Outcome Review assessments.
The safety and effectiveness of tocilizumab have previously been established in rheumatoid arthritis and some evidence of treatment has been shown in scleroderma. Inhibition of IL-6 signaling is believed to have effects on immunomodulation and vascular remodeling, the authors said.
A total of 19 patients with PAH (13 with idiopathic or heritable PAH and 6 with CTD-associated PAH) completed the 6-month clinical trial. Patients received IV doses of tocilizumab on day 1, and weeks 4, 8, 12, 16, and 20.
Toshner M, Church C, Harbaum L, et al. Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH. Eur Respir J. Published online September 29, 2021. doi:10.1183/13993003.02463-2020