Pulmonary Arterial Hypertension

PHACeT: Pulmonary Hypertension: Assessment of Cell Therapy

A single centre, Phase IIa clinical trial to establish the safety of autologous cell-based gene transfer of human eNOS (heNOS) in patients with refractory Pulmonary Arterial Hypertension (PAH) that have failed all conventional treatments.

A total of up to 18 patients will be enrolled in this study using an open label, dose escalating protocol. The target population includes patients with Idiopathic PAH (IPAH) who have failed conventional therapy and are awaiting lung transplantation.

PAH is a progressive disease, which in its most severe form, IPAH, which includes Familial PAH (FPAH), has a prognosis that is as poor as many malignancies. IPAH is characterized by marked increases in pulmonary vascular resistance (PVR) and is associated with profound perturbations in pulmonary vascular endothelial function, including an imbalance in the production of endothelium-derived vasoconstrictor and vasodilator factors. In particular, decreased nitric oxide (NO) production may result in narrowing of small muscular arteries in the lung which may increase the resistance for blood flow, ultimately leading to pulmonary hypertension and heart failure.

We are using a novel “cell-based gene therapy” approach that allows for a selective gene transfer to the pulmonary circulation with the hope of repairing the damaged lung vasculature. This method involves the isolation of the patient’s own peripheral blood mononuclear cells (PBMNCs), further growth of these cells outside the body under strict conditions that will allow differentiation into an endothelial lineage (EPC), followed by insertion of the therapeutic gene (heNOS) into the cells and re-introduction into the pulmonary circulation allowing the genetically modified cells to engraft into the lung. These cells are efficiently filtered by the pulmonary circulation and lodge at the pre-capillary level, rapidly engrafting the perivascular tissue. In this location, these cells produce their therapeutic gene products which then can act on the pulmonary microcirculation. Secondary objectives will be to determine the efficacy of these genetically-modified EPCs on pulmonary hemodynamics, patient-perceived quality of life and exercise capacity. This cell type is believed to play a critical role in the repair and regeneration of vascular endothelium throughout the body. Since it is a progenitor rather than a true stem cell, its ability to differentiate is limited mainly to the endothelial cell lineage.

Pulmonary Arterial Hypertension Market Opportunity: Addressing an Unmet Clinical Need.

Recent market estimates have forecast 2005 worldwide sales for the treatment of PAH to reach more than US$700 million, and to double within the next 4-5 years, with approximately 16,000 to 18,000 currently treated patients.* A number of estimates have predicted the patient population in the US and Europe to be roughly 100,000 in each market, as the advent of new therapies has led to increased awareness and diagnosis of the disease.

At present, PAH represents a serious medical condition which is nearly universally fatal and despite new pharmacological approaches, most patients continue to progress with an expected survival of only 3 to 5 years after the first diagnosis. The currently available therapies utilized to treat PAH are not without their limitations, the approved oral agents have shown diminished efficacy over time as PAH is a progressive disease, as well as the potential for liver toxicity; while the prostanoids require either a cumbersome and time consuming inhalation delivery device or infusion systems which carry associated risks such as sepsis and intolerable infusion site pain.

Lung transplantation is the final resort for some patients, however a relatively low number of patients ultimately receive a transplant. As well, this procedure carries with it a substantial initial mortality, and its long-term success is hampered by chronic rejection such that five-year survival is less than 50%. Thus, there is an urgent unmet need for new therapies that can restore the pulmonary vascular structure and function and improve pulmonary hemodynamics in advanced PAH.

* WACHOVIA CAPITAL MARKETS, Breathe Easy: PAH Therapeutic Overview And ATS Preview, May 5, 2005.