KV Kishore Babu MD, DM
Senior Consultant Rheumatologist, Anvi Hospital, Nellore, Andhra Pradesh, India
Pulmonary arterial hypertension (PAH) is a serious complication of various connective tissue diseases (CTD), with significant morbidity and mortality. Although new drugs have been added to the treatment regimen, the survival rate has not improved significantly. Different therapeutic targets are being evaluated in clinical trials.
Sotatercept is a newly approved drug targeting TGF-β signalling. It is a fusion protein composed of the human IgG Fc domain linked to the extracellular domain of human activin receptor type IIa. It acts as a ligand trap for activin A, activin B, growth differentiation factor 8, and 11, inhibiting their function and restoring pulmonary vascular homeostasis by increasing growth-inhibitory and proapoptotic signalling. The Phase III STELLAR study showed promising results over placebo. The interim results of the Phase III SOTERIA study showed favourable results of add-on Sotatercept in adults with PAH. HYPERION, ZENITH, and CADENCE trials are ongoing.
Chloroquine and hydroxychloroquine have been tried for their potential role in PAH due to their anti-inflammatory and anti-proliferative properties. In animal models of PAH, chloroquine prevented loss of BMPR2 protein, thereby reducing BMP signalling, inhibiting autophagy pathways, and increasing apoptosis of pulmonary artery smooth muscle cells. The STRATOSPHERE 2 study is a randomised, placebo-controlled, phase II trial that will evaluate hydroxychloroquine and phenylbutyrate in patients with idiopathic or hereditary PAH caused by BMPR2 mutations, in WHO functional class I-IV, who are on stable PAH therapy.
Imatinib, a multi-target tyrosine kinase inhibitor used in chronic myeloid leukaemia, also targets platelet-derived growth factor (PDGF) and the stem cell factor receptor (c-Kit). Oral Imatinib has shown significant improvement in hemodynamics but is associated with a high frequency of severe adverse events. So inhaled Imatinib is currently being tested in a phase IIb/IIIa clinical trial. Seralutinib targets the same receptors as Imatinib. Inhaled Seralutinib has a 10-fold greater potency for PDGFα/β inhibition. Phase II trial, TORREY, evaluated the efficacy, safety, and tolerability of inhaled Seralutinib; the phase 3 study, PROSERA, is ongoing.
A phase 2 open-label trial evaluated the safety and efficacy of the IL-6 receptor antagonist Tocilizumab in PAH patients over 6 months; no significant improvement was observed. SATISFY-JP is an ongoing trial assessing the effectiveness of Tocilizumab in group 1 PAH patients with elevated IL-6 levels. A prospective, multi-centre, phase 2 randomised trial assessed the safety and efficacy of Rituximab in patients with systemic sclerosis-associated PAH without severe interstitial lung disease, and there was no significant improvement. An ongoing trial is evaluating the safety and efficacy of Rituximab in patients with PAH associated with SLE.
Several drugs targeting other pathways are currently in clinical trials. Oral Ifetroban, a selective thromboxane receptor antagonist, is currently being tested in a phase II multicentre, randomised, placebo-controlled trial on diffuse cutaneous SSc or SSc-PAH. ELEVATE-2 trial is a phase 2b, double-blind, multicentre trial evaluating the safety and efficacy of Rodatristal ethyl (an antagonist of tryptophan hydroxylase, a key enzyme in serotonin synthesis) versus placebo in patients with PAH. Oestrogen modulators, Anastrozole (an aromatase inhibitor) and Tamoxifen (an oestrogen receptor antagonist), are being tested in phase 2 trials. Bardoxolone methyl is an oral activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which showed significant functional improvement in the CTD-PAH subset in a phase 2 trial. Further studies are warranted. With more drugs targeting different pathways in the pathogenesis, the management of CTD-PAH will have more options and potentially better outcomes.
