The Safety and Efficacy of Macitentan for Treatment of Pulmonary Hypertension in Sickle Cell Disease

Background and Rationale:

Sickle cell disease (SCD) affects 250,000 births per year worldwide, with 70-80,000 patients currently residing in the US. Although classically thought of as a genetic hemoglobinopathy, most of the clinical complications are vascular in etiology and pulmonary manifestations are the primary cause of morbidity and mortality. Pulmonary hypertension (PH), one such pulmonary complication, occurs in 6-10.5% of SCD adults and is associated with a 60% four-year survival. No specific therapy for PH in SCD exists representing an area of intense clinical need in this field.

Clinical trials of pulmonary vasodilator medications in PH of SCD have been problematic. There have been no randomized placebo controlled trials of any traditional pulmonary arterial hypertension (PAH) medication completed in this population to date. Three randomized placebo-controlled trials have been undertaken previously. Two compared treatment with bosentan to placebo in SCD patients with right heart catheterization (RHC) -defined elevated pulmonary vascular resistance (PVR) with a normal pulmonary capillary wedge pressure (PCWP) (the ASSET-1 trial) or pulmonary venous hypertension (PVH) with a PVR > 100 dynes.sec/cm5 (the ASSET-2 trial). After the randomization of only 14 subjects in ASSET-1 and 12 patients in ASSET-2, the trials were prematurely terminated due to slow patient enrollment. Although very few patients were enrolled, there were no apparent toxicity issues. The third trial, Walk-PHaSST (Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy), compared the safety and efficacy of sildenafil to placebo in SCD patients with a TRV ≥2.7m/s. After 74 (of a targeted 132) subjects were enrolled, the study was prematurely discontinued due to an increase in serious adverse events in the sildenafil group, primarily hospitalization for pain.

There are a number of possible explanations for these failed trials:

1. The hemodynamics of PH in SCD reflect a spectrum of abnormalities. Approximately 40-50% of PH in SCD patients have hemodynamics similar to other forms of PAH; a mean pulmonary arterial pressure >25 mmHg, normal left-sided filling pressures (PCWP or left ventricular end diastolic pressure <15 mmHg) and an elevated PVR. But at least 50% of PH in SCD patients have at least some degree of PVH usually due to diastolic dysfunction of the left ventricle. How an elevated PVR is defined in PH of SCD is controversial. While typically in other forms of PAH, it is defined as 3 Wood units or 240 dynes.sec/cm5, this is reflective of a normal PVR of 120-160 dynes.sec/cm5. In SCD, the anemia-induced elevations in cardiac output observed in these patients produce a baseline PVR of 60-100 dynes.sec/cm5 suggesting that a PVR of 160 dynes.sec/cm5 or 2 Wood units may be a more appropriate value.
2. SCD is considered to be a rare disease in the US according to the NIH. As PAH of SCD probably only occurs in 2-4% of HbSS adults, many centers in the US will only have a few (<10) eligible patients for enrollment even under the best circumstances. SCD patients often have co-morbidities limiting their participation in clinical trials, which often decreases this number even further.
3. The epidemiology of PH in SCD has been evolving over the past 10-15 years. Numerous studies demonstrated an elevated pulmonary artery systolic pressure (PASP) by echocardiography reflected by an elevated tricuspid regurgitant jet velocity (TRV) was present in 1/3 of HbSS and 10-28% of HbSC adults. However, an elevated TRV only has approximately a 25% positive predictive value for PH in SCD. The need for a right heart catheterization to confirm a diagnosis of PH in SCD has only been gaining clinical acceptance over the past few years and when the prior clinical trials were conducted, this was not a standard part of the PH workup in these patients.