How dornase alfa revolutionised treatment for cystic fibrosis patients
Thick sticky sputum is a major challenge for people with cystic fibrosis. Jenny Bryan takes a look at how dornase alfa has simplified airway clearance for patients
Before the introduction of the mucolytic agent DNase dornase alfa (Pulmozyme) in 1994, airway clearance was an arduous, time-consuming job for adults and children with cystic fibrosis (CF) and for their families, friends or carers.
Pummelling the chest, deep breathing and coughing were the only ways to get thick, sticky mucus out of the lungs and reduce the risk of infection, with its associated loss of lung function, and increased disability.
“DNase is now so much a part of the furniture of basic CF treatment that it’s easy to forget how hard people used to have to work to clear their pulmonary secretions. Initially DNase was only prescribed for patients who had already lost lung function, but then people realised there was no point in waiting until lung function deteriorated, it was important to use it to reduce the sputum early on and maintain function,” explains Diana Bilton, consultant chest physician at the Royal Brompton Hospital, London.
To this day, the UK has lagged behind Europe and the US in the prescribing of dornase alfa. It is still used by less than half of patients with CF, compared with an estimated nine out of 10 people with CF in the US.1,2
“Use of DNase has been increasing since 2007, but there have always been financial issues. In 2012, it became a national commissioning policy to include DNase in CF treatment, and this has, hopefully, put an end to the postcode lottery,” says Dr Bilton.
A long history
During the 1950s, researchers showed that large amounts of DNA were present in purulent, but not in uninfected, lung secretions in people with CF,3 and it was suggested that DNA, which is highly viscous, could contribute to the viscosity of lung secretions and to the reduced effectiveness of aminoglycoside antibiotics seen in CF patients.4
Subsequent experiments showed that incubating lung secretions with partially purified bovine pancreatic DNase I, an enzyme which breaks up extracellular DNA, reduced the viscosity of the secretions, and a bovine product was later marketed and used.4 However, severe adverse respiratory reactions sometimes occurred. Human DNase was investigated using the biochemical tools of the time, but it was not until the era of genetic engineering that researchers cloned, sequenced and expressed human recombinant DNase I, and showed that it could be used to reduce the viscosity of purulent CF sputum.4
Recombinant human DNase I (rhDNase) became one of the early products developed by Genentech, the founder of the biotechnology industry, and now part of Roche.
After phase I and II trials showed that aerosolised rhDNase for 10 days improved lung function, dyspnoea and well-being in CF patients, a large randomised placebo controlled trial was set up with nearly 1,000 adults and children with CF and reduced lung function who were treated once or twice daily for 24 weeks.5 This showed reductions in respiratory exacerbations of 28 per cent and 37 per cent, respectively (P=0.04 and P<0.01).5 There was a significant improvement in lung function and treatment was well tolerated, with none of the anaphylactic reactions seen with the earlier bovine preparation.
Patients in this first phase III trial had a mean forced expiratory volume in one second (FEV1) of 61 per cent,5 but the nearly 500 children aged six to 10 years who participated in a later study were younger and fitter, with a mean FEV1 of 95 per cent.6 Once again, beneficial effects were seen on lung function, together with a 34 per cent reduced risk of respiratory exacerbations (P=0.048) over the 96-week follow-up.6
Subsequent findings from a major CF clinic in Denmark showed that children started on dornase alfa at an early age had fewer positive microbial cultures from lung samples, suggesting that the reduced viscosity was stopping bacteria from taking hold.
“DNAse is now a fundamental part of aiding airway clearance and paediatricians are likely to think about it in children with CF as young as five or six years old who have nasty coughs and mucus plugging,” says Dr Bilton.
The outlook for children and young adults with CF has improved dramatically in recent decades, and the introduction of dornase alfa has undoubtedly played a part — alongside better nutrition, more effective use of antibiotics and, for those with the worst lung function, organ transplantation.
A study published in 2011 compared survival in 276 CF patients with low lung function (FEV1 <30 per cent) first observed between 1990 and 2003.7 It showed that median survival improved from 1.2 years in those found to have an FEV1 <30 per cent in 1990–91 to 5.3 years in the 2002–03 group.7 A marked improvement in survival occurred from 1994 — the start of dornase alfa era. Use of the agent was shown to be significantly associated with a reduced risk of death (hazard ratio 0.59, 95 per cent confidence interval 0.44–0.79).7
“In the past, when lung function was down to 30 per cent, we knew that patients would need a transplant within two to three years, but we now know that they can survive much longer without a transplant, and DNase has played a major part in that and in the improvement in overall survival,” says Dr Bilton.
Despite the positive statistics, about 30 per cent of patients appear not to respond to dornase alfa, and research suggests that, in some cases, this is due to low magnesium levels.8 Sputum from clinical responders to dornase alfa was shown to be extensively degraded when incubated with rhDNase I, while sputum from clinical non-responders was not degraded (median decrease in sputum elasticity was 32 per cent and 5 per cent, respectively).8
Magnesium concentrations were significantly higher in sputum from clinical responders (2.0mM versus 1.3mM; P=0.02), and sputum that could not be degraded by rhDNase I became degradable after preincubation with magnesium. RhDNase activity was only dependent on magnesium levels when the protein actin was present in sputum.
Because responders and non-responders have similar levels of actin, it was proposed that magnesium prevents inhibition of rhDNase I by the monomeric form of actin, G-actin, through mediating its conversion to the polymeric form, F-actin.8
Oral magnesium supplements were shown to boost magnesium levels in sputum, and the researchers suggested that magnesium supplementation could be the way forward for non-responders to dornase alfa.8
With its limited patient population and financial reward, dornase alfa has faced little competition over the past 20 years. Dr Bilton explains that, in Australia, where dornase alfa has never been licensed, CF patients use hypertonic saline as their mucolytic. In 2008, a study of twice-daily bronchodilator and hypertonic saline inhalation for 48 weeks showed a small, non-significant improvement in the primary endpoint (rate of change in lung function compared with placebo), a significant improvement in FEV1 and fewer exacerbations.9
“Hypertonic saline changes the osmotic gradient in the airways so that fluid moves into the airways. This results in more liquid on the inner surface so the tubes become less clogged. The lung function improvement was not as impressive as that seen with DNase, and hypertonic saline can be unpleasant for some patients. It makes patients cough immediately, which some like and others don’t,” says Dr Bilton.
Mannitol inhalation is another option for helping to reduce sticky mucus in the airways and it uses sugar instead of saline to alter the osmotic gradient, increase fluid and aid coughing.
“Hypertonic saline and mannitol are competing against each other but they are not competing with DNase because it works so differently,” Dr Bilton explains.
People with CF have higher expectations for leading near-normal lives than when dornase alfa was introduced and Dr Bilton points out that reformulation for administration from an inhaler instead of a nebuliser would be welcome, but no company seems willing to make the investment. She explains that there have been advances in nebuliser technology.
For example, instead of blowing air through the product, as in traditional nebulisers, electric pulses can be used to make a mesh vibrate and release DNase particles as a fine mist. A variation on this co-ordinates administration so that DNase is only released when patients breathe in. “These nebulisers are quieter and enable treatment time to be cut from 15 to 20 minutes to two to five minutes, which is a big advantage in the morning for people wanting to get to school or work, so most patients should now be offered one of the newer devices,” she says.
Dornase alfa has not removed the need for physiotherapy, and patients are still advised to use breathing exercises to help keep their airways clear — usually an hour after taking the mucolytic.
“It’s advisable to clear the lungs before going to bed, otherwise the DNase liquefies the mucus and then it lies in the lungs overnight with the potential to increase the risk of infection. A lot of people have their DNase at tea time, and then do their airway clearance during the evening,” says Dr Bilton.
Despite the recent introduction of ivacaftor, the first CF treatment targeting a mutation in the CF transmembrane conductance regulator (CFTR) gene which causes the mucus and other abnormalities seen in the disease, Dr Bilton predicts that there are still a lot of years ahead for dornase alfa in CF management.
“Ivacaftor targets a rare CFTR mutation which affects less than 5 per cent of people with the disease. But, even when a similar agent is developed for the more common mutation, a child will need to start taking it at about five years old to avoid the need for DNase later on. That still leaves a lot of teenagers and adults who will continue to need DNAse, so it isn’t time to put it back on the shelf just yet.”
Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11125779
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