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.

RCT finds dupilumab effective for children under six with atopic eczema

26th September 2022

An RCT has found that dupilumab improves the signs and symptoms of atopic eczema in children aged 6 years and under

Although dupilumab is licensed for moderate to severe atopic eczema from 6 years of age, the drug also appears to be effective in children under 6 years of age according to the findings of a randomised, double-blind, placebo-controlled trial by US researchers.

Atopic eczema is a common childhood condition with a global real-world prevalence study in the paediatric population finding that the 12-month prevalence ranged from 2.7% to 20.1% across countries but that severe disease was generally less than 15%. Dupilumab is a human monoclonal antibody against the interleukin-4 receptor alpha, inhibiting the signalling of interleukin-4 and interleukin-13. The drug has been shown to be effective for adults with moderate to severe disease.

For example, in two identical randomised, placebo-controlled trials, where the primary outcome was the proportion of achieving a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in their score from baseline at week 16, this occurred in 36% of those who received dupilumab every other week and in 36% who received dupilumab weekly.

As mentioned earlier, whilst licensed from age 6, to date, there is limited data on the effectiveness in children under 6 years of age apart from one phase 2, open-label study, which found that a single-dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of eczema.

The present study was the first, large scale, randomised, placebo-controlled trial of dupilumab in children as young as 6 months old. The US team recruited children aged 6 months to under 6 years with moderate to severe atopic eczema (investigator’s Global assessment, IGA score of 3 – 4) with an inadequate response to topical corticosteroids. These children were then randomised 1:1 to either subcutaneous placebo or dupilumab 200 mg (body weight > 5 kg to < 15 kg) or 300 mg (> 15 kg but less than 30 kg) every 4 weeks in addition to a low-potency topical corticosteroid (hydrocortisone acetate 1%) for a total of 16 weeks.

The primary endpoint at week 16 was the proportion of patients who achieved an IGA score of 0 or 1 (indicating that their skin was either clear or almost clear). For the secondary endpoint, the team assessed the proportion achieving an EASI75, i.e., a 75% improvement in their eczema area and severity index also at week 16.

Dupilumab and improvement in disease severity

A total of 162 children with a mean age of 4 years (61% male) were randomised to dupilumab (83) or placebo. Among those assigned to dupilumab, 76% had an IGA score of 4 and both groups received hydrocortisone.

At week 16, a significantly higher proportion of patients taking dupilumab achieved the primary outcome (28% vs 4%, p < 0.0001) and this also occurred for the secondary endpoint of an EASI75 (53% vs 11%, p < 0.0001).

A similar proportion of patients had at > 1 treatment-emergent adverse event (64% vs 74%, dupilumab vs placebo).

The authors concluded that dupilumab with concomitant low potency topical steroids significantly improved disease severity compared to placebo in children under 6 years of age and that the drug was well tolerated.

Citation
Paller AS et al. Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial Lancet 2022