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The specialty pharmacy market developed treatments that have significantly improved outcomes for patients with pulmunary artierual hypertension, progressive, incurable disease.

Disease Overview^1-4

Pulmonary Arterial Hypertension (PAH) is increased pressure in the blood vessels that carry blood from the heart to the lungs to be oxygenated before being pumped out to the rest of the body. PAH is a progressive disease characterized by abnormal cell proliferation, remodeling, vasoconstriction, and thrombosis of the pulmonary vasculature. The fibrosis causes the walls of the arteries leading from the heart to the lungs to tighten and become stiff. These changes make it harder for the heart to push blood through the arteries, causing the arterial pressure to rise. As the heart works harder, the extra pressure can lead to hypertrophy of the right ventricle as it enlarges and becomes less flexible. Eventually, less blood flows out of the heart and into the lungs, leading to decreased oxygenation throughout the body. At this stage, the patient is considered to be in heart failure. Heart failure is the most common cause of death for PAH patients.

Although it is not known exactly what causes PAH, there are several general classifications of its etiology. Idiopathic PAH has no known cause and accounts for approximately 40% of cases. Familial (congenital) PAH has a genetic component that is passed from generation to generation within a family. Certain diseases have also been shown to cause PAH. These include HIV, thyroid disease, connective tissue diseases, scleroderma, and sickle cell anemia. In addition, ingestion of certain drugs can cause PAH. These can include prescription weight management medications such as Phen-Fen as well as street drugs such as cocaine or methamphetamine.

Symptoms of PAH develop gradually over time, which may be one of the reasons that many patients do not seek medical attention until the disease has reached a severe state. Common symptoms seen in early disease include shortness of breath, fatigue, and nonproductive cough. As the disease progresses, more severe symptoms may develop, including angina or racing heart, fainting, syncope, or peripheral edema in the legs or ankles. Hemoptysis (coughing up blood) is seen in rare cases.

In 1998, the World Health Organization (WHO) published a functional classification system for PAH based on the New York Heart Association (NYHA) PAH classifications. These classifications are used by the FDA in labeling pharmaceutical agents for PAH treatment. The classifications are:

Class I – No limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.
Class II – Slight limitation of physical activity. Patients are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class III – Marked limitation of physical activity. Patients are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class IV – Inability to carry out any physical activity without symptoms. These patterns manifest signs of rightheart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

Pharmacologic agents used in PAH treatment include calcium channel blockers, endothelin receptor antagonists, phosphodiesterase-5 (PDE5 ) inhibitors, and prostacyclins. Anticoagulants are also prescribed due to the increased risk of clot formation as blood flow through the heart slows. Other treatments include oxygen, lifestyle modifications, and physical activity.

Economics ^5-7

Treatment options for PAH have expanded significantly since 1995, when epoprostenol was introduced as the first diseasespecific medical therapy targeting PAH. While this has given physicians a larger arsenal of weapons to control PAH symptoms, it has also made treatment decisions more complex. The associated treatment costs have also risen, with current annual costs ranging from $18,000 to $244,000 per patient. Early diagnosis and accurate classification of PAH patients are key to managing associated costs. Incorrect classification can lead to inappropriate treatment, increased risk to patients, and unnecessary utilization of health care resources. Furthermore, efficacy and financial considerations of treatment must be balanced against quality of life. The high burden of illness suggests opportunity for savings from improved management.

Demographic/ Prevalence Data ^8-12

PAH is considered a rare disease, with literature estimating a prevalence of 30 to 50 cases per million (0.0003% to 0.0005%). However, because most patients are not diagnosed until reaching later stages of disease, the true prevalence may be much higher.

PAH can be diagnosed at any age, but is usually diagnosed between the ages of 20 and 60 years, with a mean diagnosis age of 36 years. The average age of a PAH patient is 52.2 years.

Adult women are almost 3 times more likely to develop idiopathic PAH than adult men. Idiopathic PAH in children is more evenly distributed across genders.

PAH secondary to certain disease states shows much higher than average prevalence. Up to 60% of scleroderma patients may suffer from PAH, as do 20% to 40% of sickle cell patients. Approximately 0.5% of HIV patients have PAH.

From 1995 to 2002, 1.9 million patients were hospitalized in the United States due to PAH and 117,000 deaths were attributed to PAH. Mr. Allinson is chief executive officer and chief clinical officer of Therigy, LLC.

Current Market Observations ^13-15

The significant cost of PAH care, along with the potential for serious complications and adverse events, has made it difficult for managed care organizations to determine the most appropriate yet cost-effective PAH management strategy. Most of the pharmaceutical therapies approved to treat PAH over the last 10 to 15 years received orphan drug status in addition to patent protection. This granted them market exclusivity for 7 years. As those patents and exclusivity protections expire over the next 6 years, generics should hit the market and reduce the overall cost of treating PAH.

The medical community continues to learn more about the pathophysiology of PAH. Research into novel PAH therapies continues, bringing new PAH therapies to market. The 4th World Symposium on Pulmonary Hypertension, held in 2008, included a Future Perspectives working group that reviewed new PAH research in many exciting areas, including potential pharmacogenetic applications in PAH therapy. Also discussed were antiangiogenesis strategies, growth factor inhibitors, endothelial stem/progenitor cells, and right-ventricle remodeling therapies. These all represent potential new PAH therapies. As these therapies are developed, they should further improve outcomes, but may keep PAH treatment costs high.

Summary Points ^16-19

PAH is progressive and there is no cure. Treatment focuses on decreasing symptoms and improving quality of life for patients. With advances in therapy over the last 2 decades, pharmacologic treatment uses 4 drug classes: calcium channel blockers, PDE5 inhibitors, endothelin receptor antagonists, and prostacyclins. A treatment algorithm was recently proposed that bases therapy on symptom severity and response to acute vasoreactivity testing. That algorithm suggests that high-dose oral calcium channel blockers be prescribed to patients who positively react to the testing. Patients who have little to no reactivity, and who are considered lower risk (Class II or III), should be started on PDE5 inhibitor monotherapy first line, while non-reactive high risk (Class IV) patients should be prescribed prostacyclins.

Additions to the therapeutic options of PAH treatment over the last 2 decades have improved outcomes. Through the mid- 1980s, the average survival rate post-diagnosis was approximately 2.8 years, with 1-, 3-, and 5-year survival rates of 68%, 48%, and 34%, respectively. A recent study of patients taking an endothelin receptor antagonist showed a 2-year survival rate of 89%. However, more than 50% of patients continue to experience significant limitations in exercise capacity (WHO Class III or IV).

With improvements in therapy, earlier diagnosis, and increases in survival rates, more patients will be dealing with PAH at any given time. As patents and market exclusivity for current therapies expire, generic medications will enter the market and help to lower the overall health care expenditures needed to treat PAH. PT

Table 1. Current Therapies for PAH

Brand (Manufacturer)	Generic	Class of Drug	Current Indication	Dosing Frequency*	Route of Administration	Limited Distribution?	Approval Date	Patent Expiration
Procardia XL (Pfizer)	Nifedipine	Calcium channel blocker	Vasospastic angina Chronic stable angina Hypertension	Initial: 30 or 60 mg once daily Max: 120 mg once daily	Oral	N	1989	Expired
Cardizem CD Cardizem LA (Biovail)	Diltiazem	Calcium channel blocker	Hypertension Chronic stable angina Vasospastic Angina	Initial: 180 mg once daily Max: 480 mg once daily	Oral	N	1989	Expired
Norvasc (Pfizer)	Amlodipine	Calcium channel blocker	Hypertension Chronic stable angina Vasospastic angina CAD in patients without heart failure or EF <40%	Initial: 5 mg once daily Max: 10 mg once daily	Oral	N	1992	Expired
Letairis (Gilead)	Ambrisenten	Endothelin receptor antagonist	PAH	Initial: 5 mg once daily Max: 10 mg once daily	Oral	Y	2007	2015
Tracleer (Actelion)	Bosenten	Endothelin receptor antagonist	PAH	Initial: 62.5 mg twice daily Max: 125 mg twice daily	Oral	N	2001	2015
Flolan (GSK)	Epoprostenol	Prostacyclin vasodilator	Pulmonary hypertension	Initiate at 2 ng/kg/min Increase dose by 1 to 2 ng/kg/min every 15 minutes until dose limited side effects or tolerance is seen	Continuous infusion	N	1995	Expired
Revatio (Pfizer)	Sildenafil	Phospho diesterase-5 (PDE₅) inhibitor	PAH	Oral: 20 mg 3 times per day with doses 4-6 hours apart IV: 10 mg 3 times per day via bolus injection	Oral or IV	N	2009	2012
Adcirca (Lilly)	Tadalafil	Phospho diesterase-5 (PDE₅) inhibitor	PAH	40 mg once daily	Oral	N	2009	2017
Ventavis (Actelion)	Iloprost	Synthetic prostacyclin	PAH	Initial: 2.5 mcg per inhalation, 6 to 9 inhalations per day during waking hours with at least 2 hours between doses Max: 5 mcg per inhalation	Inhalation via nebulizer	N	2004	2011
Remodulin (United Therapeutics)	Treprostinil	Prostacyclin vasodilator	PAH transition from Flolan (epoprostenol)	Initial: 1.25 ng/kg/min Max: 40 ng/kg/min	Continuous SQ or IV infusion	N	2002	2014
Tyvaso (United Therapeutics)	Treprostinil	Prostacyclin vasodilator	PAH	Initial: 3 breaths (6 mcg per breath) 4 times daily during waking hours, approximately 4 hours apart Max: 9 breaths (54 mcg) per treatment	Tyvaso inhalation system	N	2009	2017

*Dosing frequency reflects the standard adult dose only. Pediatric and dose reduction/adjustment frequencies have been omitted. See package insert for complete dosage guidelines.

CAD = coronary artery diease; EF = ejection fraction; IV = intravenous; PAH = pulmonary arterial hypertension; SQ = subcutaneous.

Adapted from references 16 and 17.

Table 2. Currently Approved Drugs with Pending New Indications

Brand (Manufacturer)	Generic	Class of Drug	Phase (Fast-track, III, NDA/BLA)	Current Indication	Pending Indication	Frequency of Dosing	Route of Administration	Est. Approval	Comments
Tracleer (Actelion)	Bosentan	Endothelin Receptor Antagonist	Phase IV	PAH	PAH in combo with sildenafil	125 mg twice daily with 20 mg sildenafil 3 times per day	Oral	2012	COMPASS trial is assessing improvements in morbidity/ mortality in symptomatic PAH patients currently being treated with sildenafil
Revatio (Pfizer)	Sildenafil	Phospho Diesterase-5 (PDE₅) Inhibitor	Phase II	PAH	Cardiac surgery	Single 12.5-mg dose post-surgery with optional second dose	Oral	Not Available	Sildenafil is being evaluated as a therapy to decrease mean PAH after cardiac surgery.
Tyvaso (United Therapeutics)	Treprostinil	Prostacyclin Vasodilator	Phase III Phase II Phase II	PAH	Novel oral prostacyclin vasodilator for PAH Peripheral Vascular Disease Scleroderma related digital ulcers	Twice daily Dosing varies	Oral	2012	The FREEDOM trial is assessing a novel oral prostacyclin vasodilator to treat PAH. Oral delivery would allow the use of prostacyclin therapy earlier in PAH progression.

PAH = pulmonary arterial hypertension.

Adapted from references 18 and 19.

Table 3. Investigational Products

Brand (Manufacturer)	Generic	Current Approvals	Class of Drug	Phase (Fast-track, III, NDA/BLA)	Pending Indication	Frequency of Dosing	Route of Administration	Est. Approval	Comments
Tenstaten (Gilead)	Cicletanine	None	Furopyridine antihypertensive	Phase II	PAH	2 mg twice daily	Oral	Not Available	Cicletanine exhibits diuretic effects and also thought to enhance coupling of endothelial nitric oxide synthase (eNOS), and may directly stimulate vascular nitric oxide production.
Not available (Actelion)	Macitentan	None	Not available	Phase III	PAH	3 and 10 mg once daily	Oral	2012	The SERAPHIN trial is assessing the effects of macitentan on the morbidity/mortality of PAH patients.
Not available (Actelion)	Selexipag	None	Not available	Phase III	PAH	Twice daily	Oral	2013	The GRIPHON trial is currently enrolling patients.
Not available (United Therapeutics)	Beraprost-MR	None	Prostacyclin vasodilator	Phase II	PAH	60 mcg twice daily titrated up to max of 600 mcg twice daily	Oral	Not Available	There are several ongoing Phase II trials to assess the safety and efficacy of beraprost in PAH.

PAH = pulmonary arterial hypertension

Adapted from references 20 and 21.

Mr. Allison is chief executive officer and chief clinical offier of Therigy, LLC.

References

1. What is pulmonary hypertension? National Heart Lung and Blood Institute. Diseases and Conditions Index. www.nhlbi.nih.gov/health/dci/Diseases/pah/pah_what.html. Accessed March 22, 2011.

2. Farber H, et al. Mechanisms of disease: pulmonary arterial hypertension. New EnglandJournal of Medicine. 2004;351:1655-1665.

3. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. American Journal of Respiratory and Critical Care Medicine. 2006;173(9):1023-1030.

4. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. Journal of the American College of Cardiology. 2004;43:40S-47S.

5. Gandhi R, Baker N, et al. Pulmonary arterial hypertension: bridging the gap between efficacy, quality of life, and cost-effectiveness. Formulary. 2010;45:190-199.

6. Kirson N, Birnbaum H, et al. Pulmonary arterial hypertension (PAH): direct cost of illness in the US privately insured population. Chest Pulmonary Hypertension Posters. 2010:138:376A.

7. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. Journal of the American College of Cardiology. 2004;43:40S-47S.

8. Gandhi R, Baker N, et al. Pulmonary arterial hypertension: bridging the gap between efficacy, quality of life, and cost-effectiveness. Formulary. 2010;45:190–199.

9. Peacock A. Treatment of pulmonary hypertension. BMJ. 2003;326:835-836.

10. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. American Journal of Respiratory and Critical Care Medicine. 2006;173(9):1023-1030.

11. Gaine S, Rubin L. Primary pulmonary hypertension. Lancet. 1998:352:719-725.

12. Kirson N, Birnbaum H, et al. Pulmonary arterial hypertension (PAH): direct cost of illness in the US privately insured population. Chest Pulmonary Hypertension Posters. 2010:138:376A.

13. Gandhi R, Baker N, et al. Pulmonary arterial hypertension: bridging the gap between efficacy, quality of life, and cost-effectiveness. Formulary. 2010;45:190-199.

14. Barst R. Pulmonary hypertension: past, present and future. Annals of Thoracic Medicine. 2008:3(1):1-4.

15. Fagan K. Future perspectives for the treatment of pulmonary arterial hypertension. Adv in Pulmonary Hypertens. 2009;8(2):85.

16. Gandhi R, Baker N, et al. Pulmonary arterial hypertension: bridging the gap between efficacy, quality of life, and cost-effectiveness. Formulary. 2010;45:190-199.

17. Badesch D, Abman S, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. American College of Chest Physicians. Available online at chestjournal.chestpubs.org. Published 2004. Accessed March 21, 2011.

18. McLaughin V, Sitbon O, Badesch D, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25(2):244-249.

19. Barst R. Pulmonary hypertension: past, present and future. Annals of Thoracic Medicine. 2008:3(1):1-4.

20. Drugs@FDA.gov. Online database. www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed March 22, 2011.

21. Clinical Pharmacology online database. Accessed March 22, 2011.

22. Manufacturer Web sites. Drug pipeline reports. Accessed March 23, 2011.

23. Clinicaltrials.gov Web site. www.clinicaltrials.gov/ct2/search. Accessed March 23, 2011.