Dichloroacetate (DCA) for the Treatment of Pulmonary Arterial Hypertension

Overview

Hypothesis: The small molecule and metabolic modulator Dichloroacetate (DCA) is safe, tolerated as a potential therapy in patients with moderate or severe Pulmonary Arterial Hypertension (PAH). This is a Phase I, two centre study in subjects with PAH WHO functional class III-IV whose symptoms have been clinically stable on their prescribed medical treatment (which includes endothelin and/or phosphodiesterase type 5 inhibitors) for 8 weeks prior to enrollment. Such patients will be given either DCA 3.0 mg/kg BID (group I), 6.25 mg/kg BID (group II) or 12.5 mg/kg BID (group III) as an additional treatment for 16 weeks. The design is open-label with the subjects acting as their own controls. Primary endpoint is the safety and tolerability of DCA. Secondary end points include: a) functional capacity including a change in the 6 minute walk form baseline, b) change in pulmonary vascular resistance (measured by right heart catheterization), c) right ventricular volumes and mass (measured by MRI), d) NT-proBNP levels changed from baseline, e) change in FDG-glucose uptake in the lung and right ventricle (measured by PET) and f) change in quality of life indices. 15 evaluable patients in each site are expected to be included.

The vascular remodeling in PAH is a state of apoptosis-resistance. As in cancer, a switch from the anti-apoptotic glycolytic metabolism towards the pro-apoptotic oxidative phosphorylation metabolism, has been shown to cause regression of vascular remodeling and PAH in several animal models. This has been achieved with the small molecular DCA, an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase kinase. DCA has been used in humans for over 30 years, mostly in the treatment of inherited mitochondrial disorders and is also currently being evaluated as a potential therapy in cancer. This is a first-in-humans, Phase I, two centre study (University of Alberta and Imperial College) in subjects with advanced PAH, whose symptoms have been clinically stable on their prescribed medical treatment for 8 weeks prior to enrollment. These treatments include standard (eg diuretics, warfarin) or specific PAH therapies (eg endothelin or phosphodiesterase type 5 inhibitors). From the known metabolism of the drugs involved, no pharmacokinetic interaction is anticipated. In line with most safety and efficacy studies, the design is open-label with the subjects acting as their own controls. Patients with PAH who have been stable on their current therapy for the preceding 2 months will be given either DCA 3.0 mg/kg BID (group I), 6.25 mg/kg BID (group II) or 12.5 mg/kg BID (group III) as an additional treatment for 16 weeks. Following the baseline visit, the patients will be followed every week for the first month, and then at weeks 6, 8 10, 12 and 16. In weeks 1, 3, 6 and 10, the patients' status will be assessed by telephone interview. At all the other visits: medical history and physical examination will be performed. With the exception of week 2 (unless clinically indicated), this will be combined with routine hematology and biochemistry and an assessment of functional capacity (6 minute walk test). Serum lactate and NT-pro-BNP levels will be measured and PDH activity assay will be performed. Urine will be obtained for DCA metabolite studies. At baseline and 16 weeks: A cardiac catheterization to assess change in pulmonary hemodynamics; a routine cardiac MR (RV mass/volumes, MR angiography); FDG-PET to examine for an effect on regional lung or RV glucose uptake. If tolerated well, the subjects will continue with their medication and return for follow-up assessments at Weeks 20, 24 and 28. At each follow-up visit, a physical examination will be performed and functional capacity will be assessed (6 minute walk test). At the Week 28 visit a routine cardiac MR will also be performed. Enrollment will continue until 30 evaluable subjects (15 in each site) are included.