Drugs in Clinical Development for Pulmonary Hypertension: Summary and Table
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Drugs in Clinical Development for Pulmonary Hypertension: Summary and Table
Ó Springer International Publishing Switzerland 2015
Pulmonary hypertension is a rare form of high blood pressure that arises as a result of partial or complete blockage of the arteries in the lungs, as well as those in the right side of the heart, which eventually expands in size. Pathogenic changes within the venous part of the pulmonary circuit result in a variety of symptoms, including shortness of breath, fatigue, syncope, chest pain, edema, cyanosis and heart palpitations, all of which are associated with a profound reduction in quality of life and survival time. When an underlying cause for the condition cannot be identified, it is labelled as idiopathic pulmonary hypertension; however, the condition can also be secondary to other illnesses including pulmonary emboli, chronic obstructive pulmonary diseases such as emphysema, lung diseases such as pulmonary fibrosis, chronic liver disease, sickle cell anaemia, left-side heart failure and AIDS. The last 10 years have seen significant advances in our understanding of the pathophysiology of pulmonary hypertension. To date, a number of compounds, belonging to four distinct drug classes, have been approved for its treatment, including: prostacyclin analogues such as epoprostenol, treprostenil and iloprost, which act to dilate narrowed blood vessels; endothelin receptor antagonists such as bosentan, ambrisentan and macitentan, which reverse the narrowing effects of endothelin in the blood vessel walls; phosphodiesterase type 5 inhibitors such as sildenafil and tadalafil, which expand the bloods vessels in the lung to increase blood flow; and soluble guanylate cyclase stimulators, such as riociguat, which have
vasodilatory and anti-proliferative effects on blood vessels. These drugs target different signalling pathways implicated in the disease and their use has resulted in improved exercise tolerance for patients with the disease and delayed disease progression. Given the issues associated with intravenous administration of prostacyclins and the limitations of inhaled therapies, new oral prostacyclin analogues are being tested. The most advanced agent in the clinical development pipeline is the orally-available selective prostanoid selexipag, which is currently preregistration for pulmonary arterial hypertension in the EU and US. Selexipag targets the prostacyclin pathway but the structure of the molecule is quite different to the other prostanoids. According to data released in March, the reduction in the risk of a morbidity/mortality event for patients enrolled in the pivotal GRIPHON study, was consistent across key subgroups, independent of age, gender, disease etiology, baseline World Health Organisation (WHO) functional class and irrespective of background therapy, including patients receiving selexipag on top of a combination of both an endothelin receptor antagonist and a phosphodiesterase type 5 inhibitor. A decision on the authorisation of selexipag is expe
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