National Horizon Scanning Centre. Oral and inhaled treprostinil for pulmonary arterial hypertension: NYHA class III. April 2008

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1 Oral and inhaled treprostinil for pulmonary arterial hypertension: NYHA class April 2008 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The Research Programme is part of the National Institute for Health Research

2 Oral and inhaled treprostinil for pulmonary arterial hypertension: NYHA class Target group Pulmonary arterial hypertension (PAH) - NYHA Class : 2 nd line after failure of current 1 st line oral therapy (oral and inhaled treprostinil) 1 st line therapy (oral treprostinil). Technology description Treprostinil is a long acting, stable analogue of prostacyclin with potent vasodilator and antiplatelet effects 1. Oral treprostinil diethanolamine (UT-15SR) is a slow release tablet that sustains blood concentrations of treprostinil for 8-10 hours following a single dose. The maintenance dosing schedule is anticipated to be between 2.5 and 10mg administered twice daily. Inhaled treprostinil sodium is delivered via a hand-held ultrasonic nebulizer (e.g. Optineb manufactured by NEBU-TEC) in 4 inhalation periods per day, each consisting of up to 9 breaths. The anticipated dose delivered at each inhalation period is between 18mcg and 54mcg. Innovation and/or advantages Both the oral and inhaled formulations are less invasive than the current intravenous prostanoid, and the inhaled version is administered less frequently than the current inhaled prostanoid option. Inhaled treprostinil may reduce systemic side effects and have an increased duration of action. Developer United Therapeutics. Availability, launch or marketing dates, and licensing plans: In phase clinical trials. NHS or Government priority area: This topic is relevant to: Specialised Services National Definition no. 13. Although pulmonary hypertension is not specifically mentioned, it is stated that services covered by this definition should be seen within the context of the National Service Framework for Coronary Heart Disease 2. Relevant guidance NICE multiple technology appraisal in development. Pulmonary arterial hypertension (adults) - drugs (iloprost (inhaled), bosentan, sitaxsentan and sildenafil). Expected April European Society of Cardiology. Guidelines on diagnosis and treatment of pulmonary arterial hypertension British Cardiac Society guidelines: recommendations on the management of pulmonary hypertension in clinical practice

3 Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. National Pulmonary Hypertension Services Clinical need and burden of disease The prevalence of PAH is estimated to be between 15 and 26 per million based on numbers recorded by the French and Scottish registries 7,8. This approximates to between 825 and 1,430 people in the UK. In England, in , IPAH was responsible for 3,889 hospital admissions and 4,386 finished consultant episodes, accounting for 17,096 bed days 9. In England and Wales, in 2005, there were 197 deaths registered due to IPAH 10. Existing comparators and treatments Drugs that target different potential mechanisms underlying the development of PAH are listed below: Drug Trade name Company Mechanism of Action Route of administration Epoprostenol Flolan GlaxoSmithKline Prostanoid Continuous intravenous infusion Iloprost Ventavis Schering Health Prostanoid Inhalation via Care nebuliser Bosentan Tracleer Actelion Endothelin Oral, twice per Pharmaceuticals receptor antagonist day Sitaxsentan Thelin Encysive Endothelin Oral, once per receptor antagonist day Sildenafil Revatio Pfizer Phosphodiesterase- Oral, three times 5 PDE-V inhibitor per day Functional class: & IV Drugs in late clinical development or licensing include: tadalafil (PDE-V inhibitor oral) and ambrisentan (endothelin receptor antagonist oral). Other prostanoids used off-licence: iloprost (intravenous); treprostinil sodium (SC/IV). Calcium channel blockers - work in a minority of patients with PAH. Management of symptoms: diuretics for oedema anticoagulants for preventing clots in the blood vessels inhaled oxygen digoxin Efficacy and safety Trial name or code TRIUMPH 11 : Class or IV PAH; inhaled treprostinil with bosentan or sildenafil; phase FREEDOM C 12 : PAH; oral treprostinil with endothelin receptor antagonist and/or (PDE5) inhibitor with extension trial; phase. FREEDOM M 13 : PAH; oral treprostinil with extension trial; phase. Sponsor United Therapeutics. United Therapeutics. United Therapeutics. Status Ongoing Ongoing Ongoing Location USA; Europe; Israel Europe (inc. UK), USA, Canada, Israel, Australia. Europe, USA, Canada, Israel, Mexico. Design Randomised, doubleblind, placebo control. Randomised, doubleblind, placebo control. Randomised, doubleblind, placebo control. 3

4 Participants in trial n=235; adults; class or IV PAH; 125mg twice daily of bosentan or any dose sildenafil for 3 months prior to start of study. Randomised to inhaled treprostinil or placebo 4 times daily (maximum 54mcg per dose). n=354; years; on PDE5 inhibitor and/or endothelin antagonist; idiopathic/familial PAH, associated with repaired congenital systemic-topulmonary shunts, collagen vascular disease, or HIV. Randomised to oral treprostinil or placebo twice daily (dose range 0.5mg to 16mg daily). 16 weeks; 36 month openlabel extension. n=150; years; idiopathic/familial PAH associated with repaired congenital systemic-topulmonary shunts, collagen vascular disease, or HIV. No background or additional therapy. Randomised to oral treprostinil or placebo twice daily (dose range 0.5mg to 12mg daily). Follow-up 12 weeks with open label extension study. 12 weeks; 36 month openlabel extension. Primary outcome 6-minute walk distance. 6-minute walk distance. 6-minute walk distance. Secondary outcomes Key results NYHA functional classification; Borg dyspnea scoring; signs and symptoms of PAH; QOL; time to clinical worsening. Preliminary analysis: improvement in median 6-minute walk distance of approximately 20 metres (p<0.0006), with inhaled treprostinil compared to placebo 14. Borg dyspnea score; clinical worsening assessment; dyspneafatigue index; WHO PAH classification; symptoms. - - Estimated cost and cost impact The cost of oral and inhaled treprostinil have yet to be determined. The cost of other drugs licensed for PAH are: Borg dyspnea score; clinical worsening assessment; dyspneafatigue index; WHO PAH classification; symptoms. Drug Dose Cost a Approx. cost per annum Epoprostenol (IV) 9.2 ng/kg/min per 500 µg vial 25,158 94,951 ng/kg/min Iloprost (inhaled) µg, 6-9 times daily per 1ml (10 µg) 31,000-46,500 vial Bosentan (oral) mg twice daily, per 62.5 mg or 20,075 max 250 mg twice daily b 125 mg tablet Sitaxsentan (oral) 100 mg once daily per 100 mg 20,075 tablet Sildenafil (oral) 20 mg three times daily 4.15 per 20 mg tablet 4,545 a Based on British National Formulary 55, March 2008 b Expert comment suggests that bosentan is rarely used at 250mg twice daily the cost calculations are therefore based on mg twice daily 4

5 Potential or intended impact speculative Patients Reduced morbidity Reduced mortality or increased survival Quicker, earlier or more accurate Other: diagnosis or identification of disease Improved quality of life for patients and/or carers None identified Services Increased use Service reorganisation required Staff or training required Decreased use Other: None identified Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment New costs: Savings: Other: Increased costs: capital investment needed References 1 Benedict N, Seybert A, Mathier MA. Evidence-based pharmacologic management of pulmonary arterial hypertension. Clin Ther 2007; 29 (10): Specialised Services National Definition Set: 13 Specialised cardiology and cardiac surgery (adult) including cardiothoracic transplantation (all ages) (Accessed 17/01/2008). 3 National Institute for Health and Clinical Excellence. Drugs for the treatment of pulmonary arterial hypertension. Technology appraisal in development. Expected April The task force on diagnosis and treatment of pulmonary arterial hypertension of the European Society of Cardiology. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. European Heart Journal 2004; 25(24): British Cardiac Society Guidelines and Medical Practice Committee. Recommendations on the management of pulmonary hypertension in clinical practice. Heart 2001; 86 (suppl I):i1-i13. 6 National Pulmonary Hypertension Centres of the UK and Ireland. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Heart 2008; 94: Humbert M, Sitbon O, Chaouat A. Pulmonary arterial hypertension in France. Results from a national registry AJRCCM 2006;173: Peacock AJ, Murphy NF McMurray JJV et al. An epidemiological study of pulmonary arterial hypertension in Scotland. Eur. Respir. J., published online before print 14/3/07 as doi:doi: / The Information Centre for health and social care, Primary Diagnosis HES , HES Online, (Accessed 17/01/2008). 10 Office for National Statistics. Mortality statistics: Disease of the nervous system: underlying cause, series DH2, no. 32, ClinicalTrials. Clinical investigation into inhaled treprostinil sodium in patients with severe pulmonary arterial hypertension (PAH) (TRIUMPH). Available at: (Accessed 13/3/2008). 12 ClinicalTrials. Freedom C: Oral treprostinil in combination with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase-5 (PDE-5) inhibitor for the treatment of pulmonary arterial hypertension (PAH). Available at: (Accessed 17/03/2008). 13 ClinicalTrials. Freedom M: Oral treprostinil as monotherapy for the treatment of pulmonary arterial hypertension (PAH). Available at: +m&rank=1n (Accessed 17/03/2008). 14 United Therapeutics. Triumph-1 trial of viveta in pulmonary arterial hypertension meets primary endpoint. Available at: (Accessed 13/03/2008). 5

6 The National Institute for Health Research Research Programme is funded by the Department of Health. The views expressed in this publication are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health The, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0)