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.

Teriflunomide approved for paediatric use

24th June 2021

Oral teriflunomide has been granted a license extension for use in paediatric patients aged 10 years and over.

The European Medicines Agency, has extended the licensed indication for teriflunomide to include its use in children from 10 years of age. The drug is used for the treatment of relapsing-remitting multiple sclerosis, a chronic, inflammatory, autoimmune disease that affects an estimated 2.8 million people worldwide. However, MS is not purely an adult disease and it is estimated that over 30,000 cases occur in those 18 years or less. This paediatric MS is normally defined as an MS with an onset before the age of 16 years (sometimes before the age of 18 years). There are also noticeable differences between paediatric MS adult disease. For instance, more than 98% of those with paediatric MS experience a relapsing-remitting pattern (compared to 84% in adults) and children have a three-fold greater (than adults) rate of disease relapse. Moreover, paediatric MS has a negative impact on a child’s psychological wellbeing, affecting their self-image, role functioning, mood, cognition as well as an adverse effect on schooling.

The mode of action of teriflunomide in MS is thought to be related to its effects on the proliferation of stimulated lymphocytes. The drug selectively and competitively blocks the enzyme, dihydro-orotate dehydrogenase, which plays a key role in the de novo synthesis of pyrimidines and which are required in proliferating lymphocytes. An oral formulation of the drug was approved by the EU in 2013 for the use in adults based on the results of four studies involving over 2700 adults with relapsing-remitting MS.

The extension of the license for paediatric use was granted by the European Medicines Agency (EMA) based on the results of the TERIKIDS study, which is a 96-week, randomised, double-blind, placebo-controlled, parallel-group Phase III study of teriflunomide in paediatric RMS patients. Participants receive either placebo or teriflunomide (based on body weight equivalent to 14mg in adults) and the eligibility criterion is that patients had greater than one or two relapses within the last 12 or 24 months. The study enrolled patients, aged 10–17 years, with a mean age of 14.6 years (67% female) with 109 in the teriflunomide and 57 in the placebo arms. The primary endpoint was the time to first confirmed relapse and one of the secondary outcomes was MRI lesion number.

A summary of the results were presented at the 2020 EAN Virtual Congress which revealed how teriflunomide reduced the risk of clinical relapse by 34% relative to placebo (75.3 vs 39.1 weeks), however, this reduction was not statistically significant (hazard ratio, HR = 0.66, 95% CI 0.66–1.10, p =0.29). The MRI analysis revealed that teriflunomide significantly reduced the number of T1 gadolinium (Gd)-enhancing lesions per MRI scan (relative reduction 75%; p<0.0001) as well as the number of new and enlarging T2 lesions per MRI scan (relative reduction 55%, p=0.0006). Furthermore, overall incidences of adverse events and serious adverse events were similar in the teriflunomide and placebo groups (88.1% vs 82.5%, and 11.0% vs 10.5%) respectively and there were no deaths. Overall, teriflunomide appeared to be well tolerated.