Positioning Imatinib for Pulmonary Arterial Hypertension (PIPAH) study

Abstract Introduction Pulmonary arterial hypertension (PAH) is characterised by pre-capillary pulmonary vascular remodelling. Imatinib, a tyrosine kinase inhibitor, was the first treatment investigated in PAH patients with the primary aim of targeting vascular remodelling. A Phase 3 study showed that imatinib 400mg daily reduces pulmonary vascular resistance and increases exercise capacity but only 43% of patients continued the drug for 6 months. Concerns about safety prevented regulatory approval. Purpose To identify a safe and tolerated dose of oral Imatinib and evaluate efficacy in the dose range 100-400mg daily. Methods Oral Imatinib was added to the background therapy of 17 patients with PAH; prior intracranial haemorrhage was excluded by cross sectional imaging and none were receiving an anticoagulant. The first patient started on 100mg daily. The next 12 patients were recruited serially at a minimum of 4 week intervals and started on 200mg, 300mg or 400mg, according to a Bayesian adaptive design (Continuous Reassessment Method, CRM). Patients 14-17 were recruited as an extension cohort to better understand the safety and tolerability of the 100mg and 200mg doses. The primary endpoint was safety and tolerability at 4 weeks. Imatinib was continued for up to 24 weeks. Thirteen patients had implanted devices that provided remote daily measurements of cardiopulmonary haemodynamics and heart rate and rhythm and physical activity. Non-invasive measures of systemic blood pressure, weight and oxygen saturations were made remotely. We compared the time-haemodynamic response relationship with that produced by licensed treatments in a similar patient cohort. Results The recommended starting dose from the CRM was 200mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (P<0.01), increased cardiac output (P=0.08) and reduced total pulmonary resistance (TPR, P<0.001, Figure). There was a clear dose-TPR response relationship (r2=0.52, p<0.01). A reduction in TPR was evident within the first week and plateaued at 4-5 weeks. Withdrawal of Imatinib led to an increase to baseline in TPR over 4-5 weeks. This contrasts with a sharp fall in TPR with licensed therapy and rapid increase on treatment withdrawal. There was a small reduction in systemic vascular resistance (P<0.05) with Imatinib that reached plateau before TPR. Conclusions Oral Imatinib 200mg daily is well tolerated and effective as an add-on treatment in PAH. The time course of the initial haemodynamic response and the gradual return to baseline on withdrawal distinguishes Imatinib from licensed treatments and is supportive of a mechanism of action beyond reliance on vasodilation. Remote monitoring enables the safe evaluation of the withdrawal of an investigational drug in patients established on best medical therapy.Figure 1.