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2nd September 2024
Professor Andy Bush has been at the forefront of paediatric respiratory medicine and research for over three decades. Most recently, he was awarded the Royal College of Paediatrics and Child Health’s highest honour – the James Spence medal – for his outstanding contribution to the field. He spoke to Julie Penfold about his career highlights, his passion for improving children’s respiratory health and campaigning to ban the promotion of e-cigarettes to young people, and his research into the early origins of asthma.
At the outset of his career in respiratory medicine, Professor Andy Bush initially worked in adult medicine as a trainee chest physician. At the time, he didn’t have any intention of going into paediatrics.
What changed the course of his career was working in a research role in the physiology laboratory led by the late Professor David Denison in the field of pulmonary circulatory physiology. He credits the nearly five years he worked with Professor Denison as being one of his standout career highlights.
‘David Denison was undoubtedly one of the main influences on my career. He was a brilliant respiratory physiologist. At the time, he was collaborating with Dr Elliot Shinebourne who was a great paediatric cardiologist, and I got involved with their research,’ explains Professor Bush.
‘As the research became more and more paediatric, I decided to dip my toe in the water and take on a paediatric job. I went to University College Hospital in London, UK, where I worked as a very junior trainee in the neonatal intensive care unity headed by the legendary Professor Os Reynolds. The job nearly killed me, but it was terrific, and I’ve been in paediatrics ever since.’
Indeed, Professor Bush has been a consultant paediatric chest physician at the Royal Brompton Hospital in London for more than 30 years. He is also professor of paediatrics and paediatric respirology at Imperial College London.
Recently, he was ‘immensely surprised and thrilled’ to learn he had been awarded the Royal College of Paediatrics and Child Health’s (RCPCH) highest honour, the James Spence Medal, for 2024, alongside an honorary fellowship. This highly prestigious medal is awarded by the RCPCH for outstanding contributions to the advancement of knowledge and understanding in paediatrics and child health. But he says it’s an award for his whole team.
‘I had no idea anyone had nominated me for it,’ he says. ‘I’m part of an incredibly brilliant team that also includes nurses, physiotherapists, pharmacists, psychologists and dietitians. If you’re going to look after a child who has a complex condition properly, no one person can do it flying solo.’
Campaigning on public health issues is something that’s very important to Professor Bush. ‘As clinicians, we see the consequences, we read the scientific literature, we see the studies and we can actually produce the evidence,’ he explains. ‘We can and should use this to convince the policy makers that, actually, something needs to be done.’
Professor Bush has had longstanding involvement in a campaign to introduce legislation to stop the advertising and promotion of e-cigarettes to young children, based on a concern that ‘nobody actually knows what they contain’.
He says: ‘There’s a statement that they are 95% safer than cigarettes and it’s based on no evidence whatsoever. What we do know is if you inhale e-cigarettes, you can get an acute lung injury and end up in intensive care.
‘For young people to be inhaling these toxic chemicals into their lungs is really frightening, particularly since there’s evidence of vulnerability. There’s enough animal data to make me really worried about the safety of e-cigarettes. It’s a subject I feel very strongly about.’
In 2024, the UK Government confirmed the marketing, sale and supply of disposable vapes will be banned in the UK from 1 April 2025.
While this is welcome news, Professor Bush feels enforcement is needed to really make the ban work, which is also something a British Medical Association report recently championed.
There are plenty of opportunities to make a difference to children and young people’s health in terms of the range of treatments clinicians in the UK can now offer. However, prohibitive costs for some of these is creating barriers to treatment.
‘Basic science is delivering us the most fantastic new treatments such as the new medications for cystic fibrosis such as Kaftrio, Symkevi and Orkambi. These are absolute game changers as these modulator drugs work by correcting basic defects and making the abnormal proteins work. It’s really fantastic science. But one of the challenges of offering these treatments is the cost as the NHS spends around £1bn annually on them,’ Professor Bush explains.
‘Another example is a promising treatment for the rare condition spinal muscular atrophy. In its most severe form, a baby will never sit up or walk independently, but this now seems to be curable with gene therapy,’ he continues. ‘But a single injection of gene therapy costs the NHS £1.7m. In this country, we are getting a lot of these expensive medications, but across the world, there are places that just simply can’t afford them, so cost is a big challenge.’
Professor Bush’s research interests include the invasive and non-invasive assessment and measurement of airway inflammation in asthma and cystic fibrosis. This includes the use of endobronchial biopsy in the management of severe asthma, and also respiratory mass spectrometry.
He and his team are currently focused on researching the early origins of asthma. ‘There is a lot of evidence that if as a baby you are in an environment of high bacterial diversity, such as on a farm, you are less likely to develop asthma,’ Professor Bush explains.
‘Collaboration with a team led by Professors Saglani and Lloyd at Imperial College has led to beginning to unpick how specific environmental bacteria suppress the development of allergic disease in babies, and the next step after understanding the pathways to allergy and asthma is to design treatments to prevent it – not all babies are going to be brought up on a farm!’
As such, with support from the Wellcome Foundation, his team has recruited a birth cohort of over a thousand mothers and their babies. Samples, such as brushings from the inside of the lung and nose, are taken in the first two weeks of life, analysed for infection and then followed up as they get older.
‘What we’re learning is when you look at a child when they’re first born, those who are going to go on to have asthma will have reduced lung function compared to normal,’ Professor Bush explains. ‘Over the first five or six years of their life, they lose more lung function. They go through a phase of routine viral colds with wheezing and not much in the way of allergy to then developing allergic asthma. But what drives that? If we could find a pathway to stop a child going down the route to develop asthma, it would be such a major thing to do.’
Similar research was undertaken by the Tucson research group in which they followed up 849 of the 1,246 newborn babies who were enrolled in their original children’s respiratory study. They found for some participants the onset of asthma started from their mid-teens to early 20s. Yet this wasn’t a new onset as these individuals had previously experienced asthma symptoms such as wheezing and airway obstruction when they were aged four to six years.
‘What drives those who go into remission and stay in remission is fascinating. If we could switch someone to go into remission who would otherwise go on to have asthma, it would be really exciting,’ Professor Bush adds.
On the horizon, Professor Bush sees more care and monitoring taking place in a patient’s home so regular trips to hospital can be phased out. For conditions such as bronchiolitis, his team is currently looking to find subgroups with particular problems so they can devise a targeted therapy. ‘I also think, increasingly, we will see a move to personalising medicine rather than having a one-size-fits-all approach,’ he says.
Training the next generation of paediatricians is also important to Professor Bush. He has co-supervised more than 50 doctoral students, and more than 100 of his trainees now occupy senior clinical and academic positions.
‘What you really want to do is train people up to be much brighter than you and that, I think I can say without fear of contradiction, I’ve managed to do,’ he says. ‘I’ve been lucky in my career to work some very bright young people who are absolutely soaring ahead in their careers now which is brilliant.’
25th April 2024
The cystic fibrosis (CF) medication ivacaftor (brand name Kalydeco) is safe and effective in infants aged four weeks and over, paving the way for earlier initiation of therapy for newborns diagnosed with the condition, a phase 3 open-label study has found.
Ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, was originally approved for use in adults but has since been shown to be safe and efficacious in children as young as four months.
The therapy increases channel gating activity at the cell surface in patients with CTFR gating mutations. These mutations, which prevent chloride from moving in and out of cells, are thought to cause approximately 4% of CF cases worldwide.
The latest study involved the youngest cohort treated with any CTFR modulator to date, researchers reported in the Journal of Cystic Fibrosis, with infants aged from one month to less than four months old.
Seven infants with mean age at baseline of 1.9 months with CF and an ivacaftor-responsive CTFR variant were enrolled in the phase 3 open-label trial, receiving an initial low dose of ivacaftor based on age and weight.
‘Because ivacaftor is a sensitive CYP3A substrate and CYP3A maturation is uncertain in this age group, an innovative study design was developed wherein each infant initially received a low dose of ivacaftor that was subsequently adjusted based on individual pharmacokinetic results to ensure safe dosing,’ researchers wrote.
They observed a mean decrease in sweat chloride concentration of -40.3 mmol/L from baseline through Week 24, which was generally comparable to the decreases previously reported in children aged four months to less than six months (-50 mmol/L) and in children aged six months to less than 12 months (-58.6 mmol/L).
Infants also had improvements in pancreatic function, intestinal inflammation and growth parameters, according to the study, which was sponsored by the ivacaftor manufacturer Vertex Pharmaceuticals and conducted at four medical centres in the US and Ireland.
The researchers reported ivacaftor was generally safe and well tolerated, with all adverse events being mild in severity and non-serious and generally consistent with common manifestations of CF.
‘One infant discontinued ivacaftor due to an adverse event of elevated alanine aminotransferase/aspartate aminotransferase concentration more than eight times the upper limit of normal that was not considered by the site investigator to be related to be related to ivacaftor and occurred in the context of recurrent viral illnesses in the infant,’ they added.
‘Since pharmacokinetics were predictable, an ivacaftor dosing regimen in infants one to under four months of age based on weight and age is proposed.’
Lead author Professor Paul McNally, associate professor at the Royal College of Surgeons in Ireland and consultant in respiratory medicine at Children’s Health Ireland, said the study findings were a ‘huge moment’ in CF.
‘Over the years ivacaftor… has been put through clinical trials in younger and younger children. Now, through this study, it has been shown to be safe and effective all the way down to four weeks of age,’ Professor McNally said.
Almost all children were diagnosed through newborn screening at around this time, he noted.
‘The availability of a treatment that targets the underlying cause of the disease in newborns and can be started immediately at diagnosis will provide a huge sense of reassurance and hope for families,’ Professor McNally added.
Vertex Pharmaceuticals is applying to the European Medicines Agency for an extension to the marketing authorisation for ivacaftor to infants aged one month.
Last year the UK’s Medicines and Healthcare Products Regulatory Agency extended the licence of another CF medication ivacaftor-tezacaftor-elexacaftor (brand name Kaftrio) in combination with ivacaftor to include children aged two to five years old.
17th November 2023
The licence of the cystic fibrosis (CF) medicines ivacaftor-tezacaftor-elexacaftor (Kaftrio) and ivacaftor (Kalydeco) have been extended by the Medicines and Healthcare products Regulatory Agency (MHRA) to include children aged two to five years old.
These medicines, which are manufactured by Vertex Pharmaceuticals, are already authorised for use in the long-term treatment of CF with at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in adults and children aged six years and older.
F508del is the most common CF causing mutation.
Taken together, the CFTR modulator therapies work by interacting with certain abnormal CFTR proteins so they open more often to improve chloride movement in and out of cells.
They are available as sachets of granules to be mixed with 5ml of soft food and consumed immediately, just before or after a fat-containing meal or snack.
The license extension was based on the results of a study looking at this combination of drugs in patients aged 12 years and older in addition to data from a 24-week, phase 3 clinical study involving 75 patients aged 2-5 years old with a confirmed diagnosis of CF and at least one F508del mutation.
Participants continued their CF therapies, such as bronchodilators or inhaled antibiotics, but came off any CFTR modulator therapies other than the study drugs.
Safety was assessed by observing side effects to the medication and the effect of the treatment was assessed using the change in chloride concentrations in sweat.
Chloride concentrations in sweat reduced by 57.9 mmol/L over the course of the study in those aged two to five. This effect was comparable to the effect on sweat chloride in older children and adults where clinical efficacy and a comparable safety profile was demonstrated.
The most common side effects are a common cold, including sore throat and nasal congestion; headache, dizziness; diarrhoea; stomach pain; changes in the types of bacteria in the mucus; increased liver enzymes; and a rash.
Commenting on the license extension, John Stewart, national director for specialised commissioning at NHS England, said: ’Children as young as two years old with CF will now be eligible to receive the triple therapy if determined to be suitable by their treating clinician.
’We anticipate that as many as 600 children could benefit from this approval under the terms of the existing commercial agreement, and NHS England will publish an updated policy confirming this expansion in access and funding to coincide with stock arriving in England, which is anticipated in a few weeks.
’Patients, families and carers should be assured that NHS CF centres across the country have plans in place to ensure that all eligible children can be initiated on treatment while the NICE review of the CFTR modulators remains ongoing – meaning that all children eligible today can be confident about their long term access to these life-changing treatments.’
Earlier this month, the National Institute for Health and Care Excellence (NICE) published a first-stage draft recommendation for Kaftrio and two further CF treatments, which highlighted their clinical effectiveness.
However, it also stated that the ’most likely cost-effectiveness estimates’ were ’above the range that NICE considers an acceptable use of NHS resources. So they are not recommended’.
Commenting on the ’disappointing’ news, David Ramsden, CEO of Cystic Fibrosis Trust, said: ’It is important to emphasise that those already taking any of the modulator drugs are not affected by the NICE process because of the agreements already in place but this update creates uncertainty for those not yet on treatment.
’Vertex, NICE and the NHS must now urgently work together to find a solution to make these treatments available for all those who could potentially benefit. We must never return to a situation where people with CF die far too young, knowing there’s a treatment that could change that.’
The draft guidance is out for consultation until 24 November and a second evaluation meeting will be held on 14 December. Final publication is expected in March 2024.
17th January 2022
Kaftrio has been granted an extension to its marketing authorisation by the European Medicines Agency (EMA) for children as young as age 6 who have cystic fibrosis (CF) and at least one F508del mutation in combination with ivacaftor.
Kaftrio is a combination treatment containing 75mg ivacaftor, 50mg tezacaftor and 100mg elexacaftor and is already indicated in a combination regimen with ivacaftor 150mg tablets for the treatment of CF in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
CF is a rare, monogenic disease (i.e., caused by variation in a single gene) which is thought to affect at least 100 000 people worldwide. The condition is best described as a progressive, multi-organ disease that affects the lungs, liver, pancreas, GI tract, sinuses, sweat glands, reproductive tract and a reduced life expectancy. However, according to Cystic Fibrosis, the life expectancy of children born today is likely to surpass 50 years for the first time.
CF is caused by mutations in the genes responsible for encoding of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This defect results in a reduced chloride secretion and increased sodium absorption through epithelial sodium channels and removal of water from secretions, which therefore become abnormally viscous. Although more than 2000 gene variants of the disease have been discovered, the most predominant is the F508del mutation.
The three drugs present in Kaftrio work in combination. For example, ivacaftor functions as a potentiator of the CFTR protein for common gating mutations, allowing for an increase in chloride ion flow. Tezacaftor ensures correct folding and presentation of the mature CFTR protein to the cell surface, improving CFTR function for the F508del mutation.
Finally, elexacaftor is also helps to ensure correct folding of the CFTR protein but acts at an alternate binding site to tezacaftor on the CFTR protein. Overall, this triple combination increases the function of the F508del mutated CFTR protein at the cell surface resulting in increased chloride ion transport and ultimately help hydrate and clear mucus from the airways.
Clinical data already support the use of Kaftrio in children aged 12 years and over though a more recent study demonstrated the combination therapy was also effective in children from 6 years of age and enabled the EMA to extend its licensed usage.
In addition to approval from the EMA, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has also confirmed the same license extension for Kaftrio.
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