High Blood Pressure / Hypertension

Pulmonary Hypertension: Emerging Therapies

By Cardiologist on May 12th, 2011

R&D for pulmonary hypertension is currently limited to the development of agents for pulmonary arterial hypertension, thus leaving considerable untapped opportunity for the pharmaceutical industry with respect to investigation of potential therapies for other classifications of pulmonary hypertension. Not surprisingly, drug development pipelines for pulmonary arterial hypertension itself generally reflect this indication’s status as a rare disease. However, commercial interest in the disease has increased in the last year due to the presence of three compounds in late-stage development: sildenafil (Pfizer’s Revatio), sitaxsentan (Encysive’s Thelin), and Myogen’s ambrisentan.

New delivery methods for existing compounds — namely, treprostinil (United Therapeutics’ Remodulin), which has been plagued by problems associated with infusion-site pain — are also under development. Physicians and pulmonary arterial hypertension patients attending the Sixth Annual Conference of the Pulmonary Hypertension Association in Miami in June 2004 were very excited about the prospect of inhaled and even oral preparations of this agent.

Other compounds and treatment approaches for pulmonary arterial hypertension, including gene therapy, remain at early stages in the development process. For example, the exact role of serotonin (5-HT [5-hydroxytryptamine]) in the pathophysiology of pulmonary arterial hypertension is a matter of debate; however, elevated 5-HT — as seen in pulmonary arterial hypertension patients — has been associated with vasoconstriction and mitogenesis. The receptors involved in the actions of 5-HT in this disease remain to be determined, although 5-HTib, 5-HT2A, and 5-HT2B have all been implicated. Two companies are investigating compounds that target the 5-HT2B receptor. Biofrontera’s BF1 is a 5-HT2B receptor antagonist in preclinical development; studies in mice demonstrated the agent has a good pharmacokinetic profile and is not associated with any notable side effects, including sedation. Predix Pharmaceuticals has a similar R&D program.

TABLE . Emerging Therapies in Development for Pulmonary Arterial Hypertension

PC = Preclinical (including discovery). PR = Preregistered.

Atrial natriuretic peptide (ANP) clearance receptor antagonists are an avenue of preclinical research that AstraZeneca is pursuing for this indication. Produced endogenously, ANPs are important vasodilators; preventing their clearance may have therapeutic implications by increasing their availability. Meanwhile, Australia-based Cytopia and U.S.-based Myomatrix have signed a collaborative agreement to evaluate the therapeutic potential of several kinase targets for cardiovascular diseases, including pulmonary hypertension.

Therapeutic avenues for this indication being pursued in an academic, rather than commercial, setting include L-arginine supplementation. Inhaled nitric oxide (nitric oxide) is an effective treatment for acute pulmonary hypertension and can improve exercise capacity in patients with the chronic condition; unfortunately, continuous treatment requires constant use of an inhalation device and so is very inconvenient. Researchers therefore investigated supplementation with L-arginine, the amino acid from which nitric oxide is synthesized. In one study, intravenous (IV) L-arginine reduced pulmonary vascular resistance and increased endogenous nitric oxide production, but these results could not be reproduced. In another investigation, supplementation of pulmonary arterial hypertension patients for one week with oral L-arginine improved exercise capacity and hemodynamics. Some researchers propose that a possible alternative to L-arginine supplementation, in terms of the delivery of nitric oxide, is inhaled diazeniumdiolates (NONOates), but further basic research is needed.

TABLE . Emerging Therapies in Development for Pulmonary Arterial Hypertension lists agents in commercial development for pulmonary arterial hypertension.

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