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Denufosol for Cystic Fibrosis with Mild Lung Disease December 2009

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Denufosol for Cystic Fibrosis with Mild Lung Disease December 2009 Denufosol for cystic fibrosis with mild lung disease December 2009 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 National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research December 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Denufosol for cystic fibrosis with mild lung disease Target group a • Cystic fibrosis with mild lung disease (FEV1 ≥75% of predicted normal). Technology description Denufosol (Denufosol tetrasodium, INS37217) is a second generation pyrimidine that has agonistic activity on the purinocepter Y2 (P2Y2) receptor. Stimulation of the P2Y2 receptors on the apical surface of the respiratory epithelium activates alternative chloride channels and enhances mucosal hydration and mucociliary clearance through increased chloride secretion, reduced sodium absorption and increased cilia beat frequency. Denufosol is administered at 60mg three times daily by inhalation via a nebuliser and is intended to be used as a primary or adjunctive therapy in patients with cystic fibrosis (CF) lung disease. Innovation and/or advantages Denufosol is a new class of drug with a novel mechanism of action, which may help slow the deterioration in pulmonary function associated with CF. Developer Inspire Pharmaceuticals (originator). EU licensee to be determined. Availability, launch or marketing dates, and licensing plans Denufosol is a designated orphan drug in the EU and USA. NHS or Government priority area This topic is relevant to The National Service Framework for Long-Term Conditions (2005) and The National Service Framework for Children, Young People and Maternity Services (2004). Relevant guidance • NICE technology appraisal in development. Cystic fibrosis – mannitol dry powder (inhalation). Expected date of issue to be confirmed1. • Cystic Fibrosis Trust. Antibiotic treatment for cystic fibrosis. 20092. • Association of Chartered Physiotherapists in Cystic Fibrosis. Clinical guidelines for the physiotherapy management of cystic fibrosis. 20023. • The Cystic Fibrosis Trust’s Clinical Standards and Accreditation Group. Standards for the clinical care of children and adults with cystic fibrosis in the UK. 20014. Clinical need and burden of disease CF is the most common life-limiting, autosomal recessively inherited disease in Caucasian populations, with a carrier frequency of 1 in 25 and incidence of 1 in 2,500 live births5. In 2006, approximately 270 babies were born with CF in England and Wales and it is estimated that over 8,000 people in the UK have the condition6 with just over half being older than 16 years of age7. In 2007/08, there were 6,760 in-patient finished consultant episodes of CF with pulmonary manifestations (ICD10 E840) accounting for 42,572 bed days8. a Forced expiratory volume in 1 second. 2 December 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Overall, survival for people with CF has improved and approximately half of the population can expect to live over 35 years6. Most of the morbidity and more than 90% of the mortality of CF is related to chronic pulmonary sepsis and its complications4. In 2007, 115 deaths from CF were recorded in England and Wales, 70 of which had pulmonary manifestations9. Existing comparators and treatments • Airways clearance therapy. • Inhaled pulmonary therapy: o Bronchodilators: short-acting and long-acting inhaled beta-2 agonist. o Inhaled corticosteroids. o Inhaled mucolytics and recombinant human deoxyribonuclease. o Nebulised hypertonic saline. • Antibiotics. As CF is a multi-organ disease other therapies are used such as; pancreatic enzyme supplements, dietary advice, vitamin supplements and treatment for CF related diabetes. Efficacy and safety Trial TIGER-1; NCT00357279; 08-108; NCT00056147; 08-103; denufosol vs denufosol vs placebo; phase III. placebo; phase II. Sponsor Inspire Pharmaceuticals. Inspire Pharmaceuticals; Cystic Fibrosis Foundation. Status Trial complete and published in abstract. Trial complete and published. Source of Abstract10,11,12; trials registry13. Publication14; trials registry15. information Location USA and Canada. USA. Design Randomised, placebo controlled. Randomised, placebo controlled. Participants n=352; ≥5 years old; CF; FEV1≥75% n=89; 8-50 years old; CF; FEV1 ≥75% and schedule predicted; stable with no acute pulmonary predicted; oxyhaemoglobin saturation exacerbations for at least 4 weeks. ≥90%; clinically stable. Randomised to nebulised denufosol 60mg Randomised to nebulised denufosol 20, 40 or placebo three times daily for 24 weeks. or 60mg or placebo three times daily for All enter 24 week open-label denufosol 28 days. extension. Follow-up 24 week placebo controlled treatment 28 day placebo controlled treatment period. period. b Primary Lung function. Lung function (FEV1, FVC , FEV1/FVC outcome and FEF25%-75%)). Secondary Pulmonary exacerbation requirement for Respiratory symptoms, sputum weight, outcomes concomitant CF medications, quality of pulmonary exacerbations, high-resolution life (QoL). computed tomography (hyperinflation, mucus plugging, peribronchial thickening, bronchiectasis, ground glass, opacity and cysts/bullae. Key results At week 24: adjusted mean change in At day 28 adjusted mean difference vs FEV1 of 48ml vs 3ml (p=0.047) for placebo for denufosol 20, 40 and 60mg denufosol and placebo respectively. respectively: Difference compared to placebo in mean FEV1 (L): 0.18 (p=0.004), 0.09 (p=0.135) change in FEV1 of 41ml (p=0.101) in and 0.15 (p=0.021). patients with no exacerbation vs 101ml Change in FEV1 of predicted value: 5.9% b Forced Vital Capacity. 3 December 2009 National Horizon Scanning Centre News on emerging technologies in healthcare with exacerbation (p=0.062). (p=0.010), 2.5% (p=0.281), and 4.2% (p=0.066). FEF25%-75% (L/s): 0.40 (p=0.004), 0.19 (p=0.178) and 0.30 (p=0.031). FVC (L): 0.12 (p=0.047), 0.10 (p=0.115) and 0.13 (p=0.041). FEV1/FVC: 0.03 (p=0.005), 0.01 (p=0.646) and 0.02 (p=0.139). Statistically significant increase in waking at night due to cough: 29% for denufosol vs 0% for placebo. Pulmonary exacerbation in 4%, 9%, 0% and 10% (placebo). Adverse Most common AEs for denufosol and For denufosol 20, 40, 60mg and placebo effects (AEs) placebo respectively: respectively; Cough: 55% vs 59%, nasal congestion Any AE: 78%, 91%, 91% and 95%. 15% vs 19%, pharyngolaryngeal pain 19% Most common AE was cough in 35%, vs 18%, rhinorrhea 10% (p<0.05 vs 59%, 48% and 52%. Other AEs included placebo) vs 18%, productive cough 17% vs headache, pharyngitis, nasal congestion, 17%, sinusitis 10% (p<0.05) vs 18%, and chest tightness. Five patients (2 on pseudomonas infection 8% vs 13%, placebo, 3 on denufosol) discontinued due pulmonary exacerbation 34% vs 29%, to hemoptysis, pulmonary function test pyrexia 20% vs 15% and headache 11% decrease, lung infiltration and cough. (p<0.05) vs 25%. Trial TIGER-2; NCT00625612; 08-110; CF; Extension of TIGER-2; NCT00846781; denufosol vs placebo; phase III. 08-114; denufosol; phase III. Sponsor Inspire Pharmaceuticals. Inspire Pharmaceuticals. Status Ongoing. Ongoing. Source of Trials registry16. Trials registry17. information Location USA, Canada, Australia and New Zealand. USA, Canada, Australia and New Zealand. Design Randomised, placebo-controlled. Open-label. Participants n=450; ≥5 years old; CF; FEV1 ≥75% n=380; completed TIGER-2 study. All and schedule ≤110% predicted; reproducible spirometry; participants given nebulised denufosol stable with no acute pulmonary 60mg three times daily. exacerbations for at least 4 weeks. Randomised to nebulised denufosol 60mg or placebo three times daily for 12 months. Follow-up 12 mth placebo controlled treatment 12 mth extension period. period. Primary Lung function. Lung function. outcome Secondary Pulmonary exacerbation, antibiotic use, Pulmonary exacerbation, antibiotic use, outcomes incidence of hospitalisation or emergency incidence of hospitalisation or emergency room visits, health resource utilisation, room visits. QoL. Expected Study started Feb 2008 with estimated Study started Feb 2009 with estimated reporting completion Dec 2010. completion Dec 2011. date Estimated cost and cost impact The cost of denufosol is not yet known. 4 December 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Potential or intended impact – speculative Patients Reduced mortality or increased ; Reduction in associated Quicker, earlier or more accurate length of survival morbidity or improved quality of diagnosis or identification of life for patients and/or carers disease Other: None identified Services Increased use Service organisation Staff requirements Decreased use Other: ; None identified Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed ; New costs: Additional treatment Savings: Other: option. References 1 National Institute for Health and Clinical Excellence. Cystic fibrosis – mannitol dry powder (inhalation). Technology appraisal in development. Expected date of issue to be confirmed. 2 Cystic Fibrosis Trust. Antibiotic treatment for cystic fibrosis. London: Report of the UK Cystic Fibrosis Trust Antibiotic Working Group; May 2009. 3 Association of Chartered
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