Ivacaftor use in cystic fibrosis ‘safe and effective’ from one month old, study finds

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.

MHRA extends license of two cystic fibrosis drugs for children aged two to five

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.

Cystic fibrosis treatment under NICE review

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.

Kaftrio approval for cystic fibrosis extended by EMA from 6 years of age

17th January 2022

Kaftrio, which represents a triple therapy for patients with cystic fibrosis, can now be used in children from 6 years of age

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.