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Denufosol (denufosol tetrasodium) for cystic fibrosis with mild lung disease

Source agency:

NHSC

Date of Submission:

15/12/2009

Date of Printing:

05/02/2012

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Denufosol (Denufosol tetrasodium, INS37217)

Technology - description:

Denufosol (Denufosol tetrasodium, INS37217) is a second generation pyramidine 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.

Company or developer:

Inspire Pharmaceuticals (originator). EU licensee to be determined.

Reason for database entry:

New potential technology for cystic fibrosis.

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Investigational - phase III

Licensing, reimbursement and other approval:

Denufosol is a designated orphan drug in the EU and USA

Technology - type(s):

Drug

Technology - use(s):

Therapeutic

Patient Indication & Setting

Patient indications:

Cystic fibrosis with mild lung disease (FEV1 ≥75% of predicted normal).

Disease description and associated mortality and morbidity:

In 2007/08, there were 6,760 in-patient finished consultant episodes of CF with pulmonary manifestations (ICD10 E840) accounting for 42,572 bed days (8).

Overall, survival for people with CF has improved and approximately half of the population can expect to live over 35 years (6). Most of the morbidity and more than 90% of the mortality of CF is related to chronic pulmonary sepsis and its complications (4). In 2007, 115 deaths from CF were recorded in England and Wales, 70 of which had pulmonary manifestations (9).

Number of Patients:

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 births (5). 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 (6)have the condition with just over half being older than 16 years of age (7).

Technology - specialities(s):

Respiratory disease & thoracic surgery

Technology - setting(s):

Community and primary care

Setting - further information:

 

Impact

Alternative and/or complementary technology:

Additive or complementary technology

Current Technology:

• Airways clearance therapy.
• Inhaled pulmonary therapy:
-Bronchodilators: short-acting and long- acting inhaled beta-2 agonist.
-Inhaled corticosteroids.
-Inhaled mucolytics and recombinant human deoxyribonuclease.
-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.

Health Impact:

Reduction in associated morbidity or improved quality of life for patients and/or carers.

Diffusion:

-

Cost, infrastructure and economic consequences:

The cost of denufosol is not yet known.

Ethical, social, legal, political and cultural impact:

-

Evidence & Policy

Clinical evidence and safety:

Trial: TIGER-1; NCT00357279; 08-108; denufosol vs placebo; phase III.
Sponsor: Inspire Pharmaceuticals.
Status: Trial complete and published in abstract.
Source of information: Abstract (10,11,12); trials registry (13).
Location: USA and Canada.
Design: Randomised, placebo controlled.
Participants and schedule: n=352; ≥5 years old; CF; FEV1≥75% predicted; stable with no acute pulmonary exacerbations for at least 4 weeks. Randomised to nebulised denufosol 60mg or placebo three times daily for 24 weeks. All enter 24 week open-label denufosol extension.
Follow-up: 24 week placebo controlled treatment period.
Primary outcome: Lung function.
Secondary outcomes: Pulmonary exacerbation requirement for concomitant CF medications, quality of life (QoL).
Key results: At week 24: adjusted mean change in FEV1 of 48ml vs 3ml (p=0.047) for denufosol and placebo respectively. Difference compared to placebo in mean change in FEV1 of 41ml (p=0.101) in patients with no exacerbation vs 101ml with exacerbation (p=0.062).
Adverse effects (AEs): Most common AEs for denufosol and placebo respectively:
Cough: 55% vs 59%, nasal congestion 15% vs 19%, pharyngolaryngeal pain 19% vs 18%, rhinorrhea 10% (p<0.05 vs placebo) vs 18%, productive cough 17% vs 17%, sinusitis 10% (p<0.05) vs 18%, pseudomonas infection 8% vs 13%, pulmonary exacerbation 34% vs 29%, pyrexia 20% vs 15% and headache 11% (p<0.01) vs 25%.

Trial: NCT00056147; 08-103; denufosol vs placebo; phase II.
Sponsor: Inspire Pharmaceuticals; Cystic Fibrosis Foundation.
Status: Trial complete and published.
Source of information: Publication (14); trials registry (15).
Location: USA.
Design: Randomised, placebo controlled.
Participants and schedule: n=89; 8-50 years old; CF; FEV1 ≥75% predicted; oxyhaemoglobin saturation ≥90%; clinically stable. Randomised to nebulised denufosol 20, 40 or 60mg or placebo three times daily for 28 days.
Follow-up: 28 day placebo controlled treatment period.
Primary outcome: Lung function (FEV1, FVC , FEV1/FVC and FEF25%-75%)).
Secondary outcomes: Respiratory symptoms, sputum weight, pulmonary exacerbations, high-resolution computed tomography (hyperinflation, mucus plugging, peribronchial thickening, bronchiectasis, ground glass, opacity and cysts/bullae.
Key results: At day 28 adjusted mean difference vs placebo for denufosol 20, 40 and 60mg respectively:
FEV1 (L): 0.18 (p=0.004), 0.09 (p=0.135) and 0.15 (p=0.021).
Change in FEV1 of predicted value: 5.9% (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 effects (AEs): For denufosol 20, 40, 60mg and placebo respectively;
Any AE: 78%, 91%, 91% and 95%.
Most common AE was cough in 35%, 59%, 48% and 52%. Other AEs included headache, pharyngitis, nasal congestion, and chest tightness. Five patients (2 on placebo, 2 on denufosol) discontinued due to hemoptysis, pulmonary function test decrease, lung infiltration and cough.

Trial: TIGER-2; NCT00625612; 08-110; CF; denufosol vs placebo; phase III.
Sponsor: Inspire Pharmaceuticals.
Status: Ongoing.
Source of information: Trials registry (16).
Location: USA and Canada.
Design: Randomised, placebo-controlled.
Participants and schedule
:n=450; ≥5 years old; CF; FEV1 ≥75%
≤110% predicted; reproducible spirometry; stable with no acute pulmonary 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 period.
Primary outcome: Lung function.
Secondary outcomes: Pulmonary exacerbation, antibiotic use, incidence of hospitalisation or emergency room visits, health resource utilisation, QoL.
Expected reporting date: Study started Feb 2008 with estimated completion Dec 2010.

Trial: Extension of TIGER-2; NCT00846781; 08-114; denufosol; phase III.
Sponsor: Inspire Pharmaceuticals.
Status: Ongoing.
Source of information: Trials registry (17).
Location: USA and Canada.
Design: Open-label.
Participants and schedule: n=380; completed TIGER-2 study. All participants given nebulised denufosol 60mg three times daily.
Follow-up:12 mth extension period.
Primary outcome: Lung function.
Secondary outcomes: Pulmonary exacerbation, antibiotic use, incidence of hospitalisation or emergency room visits.
Expected reporting date: Study started Feb 2009 with estimated completion Dec 2011.

Economic evaluation:

-

Ongoing research:

-

Ongoing or planned HTA:

-

Web link:

http://www.nhsc-healthhorizons.org.uk/outputs/specialties/

References and sources:

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 Physiotherapist in Cystic Fibrosis. Clinical guidelines for the physiotherapy management of cystic fibrosis. London: Cystic Fibrosis Trust; January 2002.
4) 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. Cystic Fibrosis Trust. London: May 2001.
5) Radhakrishnan M, Van Gool K, Hall J et al. Economic evaluation of cystic fibrosis screening: a review of the literature. Health Policy 2008;85:133-147.
6) Cystic Fibrosis Trust. What is cystic fibrosis. http://www.cftrust.org.uk/aboutcf/whatiscf/. Accessed 10 October 2009.
7) Cystic Fibrosis Trust Registry. UK CF registry annual data report 2007. London: Cystic Fibrosis Trust; 2009.
8) NHS. Hospital episode statistics. NHS England 2007-08. HES data 2009. www.hesonline.nhs.uk.
9) Office for National Statistics. Mortality statistics. Deaths registered in 2007. http://www.statistics.gov.uk/downloads/theme_health/DR2007/DR_07_2007.pdf
10) Moss RB, Anbar RD, Wilmot RW et al. Phase 3 study of denufosol tetrasodium for the treatment of cystic fibrosis. American Thoracic Society. 2009. Poster.
11) Accurso FJ, Durham TA, Schaberg AE. Relationship between pulmonary exacerbations and lung function decline in a six month placebo-controlled trial of denufosol. European Cystic Fibrosis Society Annual Conference. 2009. 101. Poster.
12) Moss RB, Anbar RD, Willmott RW et al. Phase 3 study of denufosol tetrasodium for the treatment of cystic fibrosis. American Journal of Respiratory Critical Care Medicine 2009;179: A1189.
13) Clinicaltrials.gov. Study of denufosol inhalation solution in patients with mild cystic fibrosis lung disease. http://www.clinicaltrials.gov/ct2/show/NCT00357279?term=08-108&rank=1 Accessed 12 October 2009.
14) Deterding RR, Lavange LM, Engels JM et al; for the Cystic Fibrosis Therapeutics Development Network and the inspire 08-103 working group. Phase 2 randomized safety and efficacy trial of nebulized denufosol tetrasodium in cystic fibrosis. American Journal of Respiratory Critical Care Medicine 2007; 176:362-364.
15) ClinicalTrials.gov. Study of INS37217 inhalation solution in mild to moderate cystic fibrosis lung disease http://www.clinicaltrials.gov/ct2/show/NCT00056147?term=NCT00056147&rank=1 Accessed 12th October 2009.
16) ClinicalTrials.gov. Study of denufosol tetrasodium inhalation solution in patients with cystic fibrosis (CF) lung disease. http://www.clinicaltrials.gov/ct2/show/NCT00625612?term=NCT00625612%3B&rank=1 Accessed 12th October 2009.
17) ClinicalTrials.gov. Study 08-114 Open-label extension of study 08-110 - a multi-center study of denufosol tetrasodium inhalation solution in patients with cystic fibrosis lung disease. http://www.clinicaltrials.gov/ct2/show/NCT00846781?term=NCT00846781&rank=1 Accessed 12th October 2009.

Notes: