Title: Positioning Imatinib for Pulmonary Arterial Hypertension
Funder: Medical Research Council

Abstract: This project re-visits the use of Imatinib, a drug used for some blood cancers, as a treatment for pulmonary arterial hypertension (PAH). PAH is a rare condition in which a narrowing of blood vessels carrying blood through the lungs puts an increased pressure load on the heart. Patients die prematurely of heart failure. While current treatments relieve some of the symptoms, they do not stop or reverse the disease in the affected blood vessels. Imatinib has been shown to have beneficial effects on exercise capacity and blood flow through the lungs in patients with PAH, even when added to existing treatments, but there are some serious concerns about its safety and tolerability in PAH. This includes a risk of blood clots on the brain, particularly when the drug is used in association with warfarin. Nonetheless, Imatinib continues to be prescribed occasionally on compassionate grounds, usually when other treatment options have been exhausted, and there are a number of reports of very successful outcomes. This project will investigate the safety and tolerability of doses of Imatinib lower than the dose commonly used in previous studies and asks whether there is a particular group of patients with PAH that benefit from it._x000D_ _x000D_ The study will be conducted in patients with idiopathic or heritable PAH recruited to the UK PAH Cohort study; patients in this study have had their DNA sequenced and consented to recall for research. No patient will be talking warfarin and all will be invited to have a brain scan before entry. Part 1 of the project seeks to identify a safe and tolerated dose. Patients will receive 100mg, 200mg, 300mg or 400mg daily for 4 weeks and their symptoms recorded. This dose range covers the doses used on compassionate grounds and explores the lower range used in clinical trials. A Safety Committee will review the data as each patient is recruited and decide the best tolerated dose. Part 2 will measure the effect of 6 months treatment with Imatinib, at a dose selected from Part 1, on blood flow through the lung (measured by a heart catheter) and exercise capacity. The results will be analysed for the patient group overall but also according to a variant in a gene (PDGFRB) that affects levels of a protein through which Imatinib may act. Changes in circulating levels of key proteins in the blood in the first 4 weeks of treatment will be analysed to see if they predict longer term clinical response to the drug. _x000D_ _x000D_ Finding a lower dose of Imatinib that is better tolerated and identifying a subgroup of patients with PAH most likely to benefit, either on the basis of their genotype or an early change in plasma proteins after starting the drug, would improve the benefit-harm profile of the drug in PAH and inform how it might be used and further studies. The results will be published on ClinicalTrials.gov and in academic journals, and shared at local, national and international meetings.

Lay abstract: Research Question: We hypothesise that there is a safe dose of Imatinib that will benefit a subset of patients with pulmonary arterial hypertension (PAH), identifiable by their genotype at a protein quantitative trait locus (pQTL) for platelet-derived growth factor receptor beta (PDGFRB) expression and/or plasma levels of a panel of circulating proteins. _x000D_ _x000D_ Background: PAH is a rare condition characterised by vascular remodelling of pulmonary arterioles, leading to obstruction of blood flow through the lung, and is an unmet clinical need. The use of Imatinib as a treatment is frequently debated at international meetings. A phase 3 study (IMPRES) reported marked haemodynamic and functional improvement in patients on established treatments but did not define the lowest efficacious dose and raised serious concerns about its safety and tolerability in PAH. Compassionate use of Imatinib suggests doses lower than those used in IMPRES may be effective. A common polymorphism in the gene, PDGFRB, with a large effect on the expression of PDGFRB, a major protein target for Imatinib in PAH, and a small panel of proteins (c-Kit, RET, JNK2 and ErbB3), where plasma levels appear to associate with clinical response, may identify patients most likely to benefit from Imatinib._x000D_ _x000D_ Aims and objectives: Part 1 will investigate the safety and tolerability of Imatinib 100 to 400mg daily in PAH. In Part 2 we will investigate the clinical response to the selected dose from Part 1 and analyse that response according to genotype and candidate plasma markers. _x000D_ _x000D_ Methods: Patients will be recruited from the UK PAH Cohort Study through one of 7 regional NHS designated pulmonary hypertension centres. Part 1 will use the Bayesian continual reassessment method to identify a maximum tolerated dose (MTD) of imatinib in 10 patients. We will investigate 100mg, 200mg, 300mg and 400mg once daily on a 1 patient cohort basis. Target toxicity is defined as discontinuation of treatment for more than 3 days due to gastrointestinal symptoms, peripheral oedema unresponsive to an increase in diuretics or peri-orbital oedema and the MTD will be the dose which leads to withdrawal on any of these criteria closest to a 30% probability._x000D_ _x000D_ Part 2 will use Simon’s 2-stage design to investigate the effect of the MTD of Imatinib (from stage 1) on pulmonary vascular resistance (PVR) at 6 months. The primary endpoint is an absolute reduction in PVR of =300 dynes (or =30% when baseline PVR is = 1000 dynes) at 24 weeks. Seventeen patients homozygous for the T allele and 17 for the C allele at rs3816018 for the PDGFRB pQTL will be recruited (all patients in the UK Cohort Study have been genotyped and have consented to recall). If there are 1 or fewer responses in the first 13 patients (equally split across subtypes), the study will be stopped early on grounds of futility. The response by genotype and relationship of plasma candidate proteins to change in PVR will be secondary analyses. _x000D_ _x000D_ Timelines: Part 1 will be completed in 18 months. Part 2 will follow on and be completed by the end of year 4._x000D_ _x000D_ Impact: The results would be widely anticipated by the pulmonary hypertension community and inform the utility of a large international study.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR