Positioning Imatinib for Pulmonary Arterial Hypertension: A Dose-Finding Phase 2 Study

Abstract

Rationale: Imatinib, 400 mg daily, reduces pulmonary vascular resistance and improves exercise capacity in patients with pulmonary arterial hypertension. Concerns about safety and tolerability limit its use. Objectives: We sought to identify a safe and tolerated dose of oral imatinib between 100 mg and 400 mg daily and evaluate its efficacy. Methods: Oral imatinib was added to the background therapy of 17 patients with pulmonary arterial hypertension, including 13 who were implanted with devices that provide daily measurements of cardiopulmonary hemodynamics and physical activity. The first patient was started on 100 mg daily. The next 12 patients, recruited serially, were started on 200 mg, 300 mg, or 400 mg daily, following a continuous reassessment dose-finding model. An extension cohort (Patients 14-17) received 100 mg or 200 mg daily. Measurements and Main Results: The continuous reassessment model recommended starting dose was 200 mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (-6.5 mm Hg; 95% confidence interval [CI] = -2.4 to -10.6; P < 0.01) and total pulmonary resistance (-2.8 Wood units; 95% CI = -1.5 to -4.2; P < 0.001), with no significant change in cardiac output. The reduction in total pulmonary resistance was dose and exposure dependent; the reduction from baseline with imatinib, at 200 mg daily, was -20.3% (95% CI = -14.3 to -26.3%). Total pulmonary resistance and night heart rate declined steadily over the first 28 days of treatment and remained below baseline up to 40 days after imatinib withdrawal. Conclusions: Oral imatinib, 200 mg daily, is well tolerated as an add-on treatment for pulmonary arterial hypertension. A delay in the return of cardiopulmonary hemodynamics to baseline was observed after imatinib was stopped.

Keywords: adaptive trial design; implanted hemodynamic sensors; remote monitoring.

Figure 1.

Continuous reassessment model (CRM) method. Trajectory of dose and tolerability data at 4 weeks during recruitment using the CRM (Patients 1–13) in the trial protocol and the 4-patient extension (Patients 14–17; shaded area). Red symbols represent dose-limiting adverse events; cross symbols represent patients with implanted devices.

Figure 2.

Change in total pulmonary resistance (TPR), resting heart rate, and physical activity. (A) Change in TPR from baseline to end of treatment with imatinib (n = 16). Circles represent CardioMEMS data; squares represent right heart catheter data; box and whiskers represent median and interquartile range. (B–D) Time course of change in (B) TPR (dark blue) and total systemic resistance (red), (C) night heart rate (light blue), and (D) physical activity (mauve) from baseline (period before drug administration) starting at Day 0, plotted as a rolling 3-day average in all patients with implanted devices (n = 13; all doses grouped response, mean ± 95% confidence interval). (E) Percent change in TPR from baseline at 60 days in relation to plasma level (area under the curve in μg · h/L) of imatinib at steady state. Red represents100 mg once daily (q.d.), orange represents 200 mg q.d., cyan represents 300 mg q.d., and blue represents 400 mg q.d. (F) Percent change in TPR 60 days after imatinib withdrawal in patients with devices (n = 12; one patient withdrew before plasma levels were obtained). TPR in patients represented by the green shaded area had not returned to baseline 60 days after stopping imatinib.

Figure 3.

Remote evaluation of physiological effect of imatinib in a patient with pulmonary arterial hypertension. A female in her 40s was established on dual oral therapy with a pulmonary artery pressure monitor and insertable cardiac monitor implanted 8.6 months before enrollment. Initiation of imatinib at 300 mg q.d. was followed by an improvement in World Health Organization (WHO) functional class, EmPHasis-10 questionnaire score, N-terminal pro–B-type natriuretic peptide (NTproBNP), and Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 2.0 risk score (change from intermediate–high risk, marked by an orange vertical strip, to low risk, marked by a green strip) and a reduction in total pulmonary resistance and night heart rate. Per-protocol withdrawal resulted in a decline in WHO functional class, EmPHasis-10 score, NTproBNP, and COMPERA 2.0 risk score (second orange vertical strip) and an increase in total pulmonary resistance and night heart rate (black) with maintenance of day heart rate (green). After approval was granted by the Sheffield Teaching Hospitals NHS Foundation Trust Medicines Safety Committee, imatinib was reintroduced off-label at 200 mg q.d., which led to an improvement in WHO functional class, EmPHasis-10, NTproBNP, and COMPERA 2.0 risk score (second green vertical strip) and a reduction in total pulmonary resistance and night heart rate.