Cystic fibrosis: What next for the “wonder drug” Kaftrio?

What is Kaftrio?

The management of patients with cystic fibrosis has been transformed over the past few years by the advent of treatments designed to correct the malfunctioning protein made by the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Kaftrio is the latest of these CFTR modulator treatments and consists of a triple treatment combination of ivacaftor, tezacaftor, and elexacaftor. It’s a long term treatment for patients with cystic fibrosis (CF) who have at least one F508del mutation in the CFTR gene—around 90% of people with CF.

In 2019, after a lengthy battle over cost, an agreement was reached between NHS England and the drug company Vertex to make two earlier CFTR modulator treatments—Orkambi (lumacaftor-ivacaftor) and Symkevi (ivacaftor-tezacaftor)—available on the NHS.12 As part of the interim access agreement NHS England, the National Institute for Health and Care Excellence (NICE), the UK Cystic Fibrosis Trust, and Vertex would collect and share real world data over four years to help resolve uncertainties in the evidence base. In 2020 this agreement was updated to include Kaftrio.3

The NHS described Kaftrio as a “miracle” treatment in January 2022, and Sajid Javid, then health secretary, described it as “life changing.”4 In the UK 10 600 people have CF, and data from 2021 showed that 72% were taking a CFTR modulator, almost three quarters of them taking Kaftrio. The proportion taking Kaftrio increased further in 2022, but the exact numbers are confidential.

Kaftrio was initially licensed for patients aged 12 and over, but the Medicines and Healthcare Products Regulatory Agency extended the licence to 6-11 year olds in 2022 and recently (15 November) to children aged 2-5.5

What has NICE said?

The NICE appraisal process started at the end of 2022 for Orkambi, Symkevi, and Kaftrio, and on 3 November 2023 it published its draft evaluation.6 The evaluation committee concluded that “there is a large and robust evidence base for the acute benefits of CFTR modulators.” Clinical trial evidence shows that Kaftrio improves lung function, growth, and weight gain and reduces the number of lung infections more than standard treatment. Clinical benefits are also seen with Orkambi and Symkevi, but the short and long term improvements are smaller than with Kaftrio.

The price the NHS pays for these drugs is confidential, but NICE said that the incremental cost effectiveness ratios “were all substantially above £30 000 per QALY [quality adjusted life year] gained.” It added, “Even when considering the condition’s severity and its effectiveness on quality and length of life the most likely cost effectiveness estimates are above the range that NICE considers an acceptable use of resources. So they are not recommended.”

However, the committee did say it was likely that there were benefits to the medicine that were not captured in the economic modelling, such as improved glycaemic control and reductions in CF related diabetes. It also noted the large emotional and financial impact of CF on caregivers. NICE has emphasised that the final decision on CFTR drugs is yet to be made and that patients taking any of the drugs when the final guidance is published would be able to keep taking them regardless of the outcome.

What effect has Kaftrio had?

Patient experts on the NICE committee told NICE about the drugs giving them more options, including in education and employment, and enabling parents and carers to return to work. They said that it was “difficult and distressing to think back to a world before CFTR modulators, having experienced their transformative effects.”

The Medicines and Healthcare Products Regulatory Agency’s decision to extend the licence for Kaftrio to 2-5 year olds was “very significant and hugely welcome,” said Jane Davies, professor of paediatric respirology and medicine at the National Heart and Lung Institute, Imperial College London.

A baby born with CF has healthy lungs at birth, but mucus accumulation, airway infections, and inflammation occur early and lead to lung damage, which can become irreversible. Bacterial infections are also common in people with CF and add to the burden of treatment.

Davies told The BMJ, “It seems logical that if we could restore the function of the defective CFTR protein before all of this has happened, we give that child a much greater chance of keeping the lungs healthy. Children taking these drugs will have fewer flare-ups—acute deteriorations requiring hospital admission and courses of intravenous antibiotics.”

CF also affects the pancreas, and a significant proportion of younger children starting CFTR modulator drugs can stop taking a replacement enzyme formulation needed to help digest food, said Davies. She added, “Studies in adolescents and adults suggest that we may also see long term benefits in the other function of the pancreas—insulin production—with a reduction in CF related diabetes. Intuitively, this seems more likely the earlier the drugs are started.”

What happens now?

The Cystic Fibrosis Trust is urging as many people as possible to submit evidence, as the opportunity to comment on the draft NICE guidance ends on 24 November.6 A second evaluation committee meeting is taking place on 14 December. In the meantime, NHS England has said that any 2-5 year olds can be started on Kaftrio while the NICE review is ongoing and can be given long term access to the drug. Most care centres have systems in place and are working to ensure access for 2-5 year olds over the next four months, which should be before the final NICE judgment.

However, for families with children aged under 2 the draft decision by NICE has been deeply upsetting.7 Davies said, “Imagine you are the parent of a child who is a few days or months too young for the deadline. How would you feel, knowing that the optimism you’ve been clinging onto since your baby’s diagnosis was going to be snatched away? CF is an awful diagnosis to receive, and for most families the hope of these drugs is what’s kept them going.”

NICE has confirmed that Kaftrio is of benefit to patients, but the problem is its high cost. The list price for a 56 tablet pack is £8346, which amounts to annual costs of £100 000 to around £160 000, depending on dosing. However, the actual price negotiated by NHS England remains confidential.

Kevin Southern, professor of child health at the University of Liverpool and chair of the UK Cystic Fibrosis Medical Association, told The BMJ, “Future iterations will probably improve the costing threshold, but it is unlikely that it will come down to a level that is ‘acceptable’ to NICE. Overall, the NICE methodology is robust, but it doesn’t reflect the clinical and real world evidence of long term benefit, especially for people with CF who are well.”

The current contract with Vertex expires next summer, and NHS England, on behalf of the UK, will start negotiating a new one shortly. However, the previous negotiations dragged on for years before an agreement was reached.

Davies said she hoped that NICE and Vertex would pursue a solution in a time frame that didn’t result in a delay, as “parents are really fearful for the health of their children—they feel like pawns in the negotiation process.” Southern added, “Hopefully they will find some middle ground: it’s unimaginable that a contract is not agreed.”