Treating Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a condition that affects the pulmonary arteries (the arteries connecting blood flow from the heart to the lungs). The complex pathophysiology of the disease results in a narrowing of the pulmonary arteries and a subsequent increase in the pulmonary artery pressure. Blood flow to the lungs is restricted and the right side of the heart is placed under increasing strain, which over time develops into right heart failure.

For people with PAH, the disease manifests as breathlessness (dyspnea), fatigue, dizziness, fainting (syncope), peripheral edema and chest pain. According to European Heart Journal (2004) and in New England Journal of Medicine (2004), PAH clinical symptoms are generally not noticeable at the early stage but over time these develop on physical exertion, worsening with disease progression until they are present even when the person is at rest (see Table 1).

Just over a decade ago, the prognosis for untreated PAH was bleak, with a median survival of 2.8 years from diagnosis. For patients with severe disease median survival was six months – a prognosis worse than some cancers, according to Annals of Internal Medicine (1991) and Cancer (2001). There were limited treatment options: continuous intravenous infusion of epoprostenol (synthetic prostacyclin), a lung or heart-lung transplantation, or palliative care.

Endothelin Dysfunction

The endothelium is the single layer of cells separating every blood vessel from the blood stream. Endothelial cells produce endothelin, a protein-like substance essential for the maintenance of normal vascular tone and function. Journal of the American College of Cardiology 2004 said a characteristic of PAH is elevated levels of endothelin associated with detrimental effects on the pulmonary vasculature such as fibrosis, hypertrophy, inflammation and vasoconstriction, all of which contribute to disease development.

Actelion scientists were among the world’s first to work in the field of endothelin receptor antagonists (ERA) and Tracleer became the first commercially available oral dual ERA. Clinical trials demonstrated its significant benefit in the treatment of PAH and it was approved for this use in the US (2001), European Union (2002) and over 35 countries including Canada, Australia, Japan and within the Asia-Pacific region.

In addition to Tracleer, other agents were developed as more was learned of the disease pathogenesis. Prostacyclin analogues, phosphodiesterase inhibitors and other endothelin receptor antagonists have contributed to what is now a more hopeful outlook for people with PAH, stated New England Journal of Medicine (2004) and Chest (2007). Symptom relief offers improved quality of life and, in the case of Tracleer, delayed clinical worsening allows some optimism of improved survival when compared to historical data, reported Journal of the American College of Cardiology (2004) and European Respiratory Journal (2005).

Increased Awareness Reveals a Not-So-Rare Disease

With non-specific symptoms such as dyspnea and fatigue, PAH had historically been misdiagnosed or undetected until late-stage disease. According to Chest (1998), its diagnosis in clinical practice was sporadic and its estimated incidence was low: 1-2 per million for idiopathic PAH.

With the impetus of PAH-specific treatment, diagnosis has become more actively pursued in patients with a family history of the condition or in the presence of risk factors. European Heart Journal (2004) said there are a range of more common disease states where PAH is a known associated risk factor, such as connective tissue diseases (e.g. systemic sclerosis, systemic lupus erythematosus), congenital heart defects (CHD) and human immunodeficiency virus (HIV) infection (see Table 2). In the case of HIV and CHD, an increased incidence of PAH is emerging as improved treatment of the underlying condition prolongs survival in these patients.

There has also been a growing awareness of the need to intervene with targeted treatments as early as possible in the disease process, to delay and possibly limit damage to the pulmonary vasculature and prolong quality of life. Medical guidelines on PAH from the US and Europe now recommend periodic assessment of patients at risk of developing PAH due to underlying conditions e.g. CTDs, CHD. According to European Heart Journal (2004), for these patients, serial (annual) pulmonary function tests and/or echocardiogram assessment will allow for the detection of change which may indicate early stage disease prior to the appearance of clinical symptoms.

Changing Clinical Care

An interesting development stemming from the relatively recent clinical focus on PAH is the evolution of PAH specialist centers. Clinicians faced the dilemma of how to deliver best-practice medicine to these patients across the multidisciplinary scope of the disease and its associated conditions. Patients could potentially present to a cardiologist, respiratory physician, rheumatologist, immunologist, general physician or a primary care clinician. The severity of the disease and the diligent monitoring required on PAH medications highlighted the onerous expectation being placed on clinicians from varied medical disciplines to also be specialists of a disease state that no particular specialty seemed to “own” – a truly orphan disease.

These factors led to the creation of PAH specialist centers: hospitals with an established PAH clinic and a multidisciplinary team of specialist clinicians and healthcare professionals with expertise in various aspects of the relevant clinical care. These centers provide community physicians a referral point for diagnostic confirmation, initiation of treatment and ongoing monitoring and management of PAH. Of additional benefit is that these centers are proving to be pivotal in the collection of much needed data on PAH - a valuable contribution to the growing knowledge base in this disease area.

Actelion research interests: PAH and beyond

Actelion’s research interests extend to other forms of PAH and more. Clinical trials of Tracleer include other conditions such as pulmonary fibrosis and sickle cell disease related to PAH. Zavesca (miglustat) is Actelion’s second marketed product, approved as an oral treatment for the rare metabolic disorder of Gaucher disease. Two key late-stage product candidates in the Actelion pipeline are almorexant (an orexin receptor for sleep disorders) and clazosentan (an intravenous endothelin receptor antagonist for use in subarachnoid hemorrhage). Multiple other projects are in earlier-stage development.

Clinical research into less common diseases such as PAH present a challenge, given the need to provide sufficient patient numbers for robust studies to satisfy regulatory requirements, so drugs can evolve into commercially available treatments. In this context, Asia has always been a business target for Actelion, with the potential to significantly contribute to its drug development program and commercial goals.

Craig Weller, Actelion’s Asia-Pacific marketing director, has been working closely on the regional development. Partnerships have been formed with PharmaLink (marketing) and Zuellig (distribution) and Tracleer sales have been growing as more Asian markets become involved. “We currently have nine countries in the region contributing to Tracleer sales,” says Weller. “We anticipate that in the next five years, Asia-Pacific will significantly increase contributions to the company’s revenue.”

One decade on from its 1997 founding, Actelion now has approximately 1500 employees worldwide. In January 2008 it opened a regional management office in Singapore, to consolidate existing partnerships and extend into new ones within Asia-Pacific. While the new regional office will have an initial head count of 6-10 employees, it is clear that Actelion has plans for significant research and commercial expansion into the future.