Commissioning position

NHS England has confirmed that ivacaftor will be made available as a treatment option in line with its licensed indications. NHS England has confirmed that tezacaftor/ivacaftor and lexacaftor/tezacaftor/ivacaftor will be made available as treatment options for people with cystic fibrosis who have one of an expanded range of cystic fibrosis transmembrane conductance regulator (CFTR) mutations within the criteria set out in this commissioning statement.

Tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor will be available to patients with named mutations approved by the US Food and Drug Administration (FDA) for which the use of the medications would be off-label in England.

The treatments in this policy will be available through the access agreement in place between NHS England and Vertex pharmaceuticals.

Licensed indications for ivacaftor-tezacaftor-elexacaftor plus ivacaftor, tezacaftor-ivacaftor plus ivacaftor alone, and lumacaftor-ivacaftor respectively, are covered by NICE TA988 and are outside the scope of this commissioning statement.

The condition

Cystic fibrosis (CF) is the most common, life-limiting, recessively inherited disease in the UK, affecting approximately 10,500 people (8,700 in England). A defect in the CFTR protein results in a reduction in quantity of the CFTR channels and/or a reduction in function of the CFTR channels resulting in a reduction in the passage of chloride ions through the open channel pore. This affects the balance of salt ions and fluids inside and outside of the cell (1). This imbalance leads to thick, sticky mucus in the lungs, pancreas, and other organs.

Complications of CF include increased susceptibility to serious infections, reduced lung function, pancreatic insufficiency and CF related diabetes, liver cirrhosis, osteoporosis and osteopenia.
There is no cure for CF. In severe cases of CF, when the lungs stop working properly and all medical treatments have failed to help, a lung transplant may be recommended. Therapeutic treatments for CF include antibiotics to prevent and treat chest infection and medicines to reduce the levels of mucous in the body. The latter includes the CFTR modulator therapies ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor.

*From 1st January 2021 the Medicines and Healthcare Products Agency (MHRA) is the standalone medicine’s regulator for the UK.

Ivacaftor (Monotherapy) licensed use

This commissioning statement updates the licensed indications and supersedes the previous relevant clinical commissioning policy: ‘Cystic Fibrosis Modulator Therapies Access Agreement for licensed mutations: [200810P]’. Under this updated commissioning statement NHS England commissions ivacaftor (monotherapy) within its licensed indications:

• as monotherapy for the treatment of infants aged at least 1 month, toddlers and children weighing 3 kg to less than 25 kg with CF who have an R117H CFTR mutation or one of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R

• as monotherapy for the treatment of adults, adolescents, and children aged 6 years and older and weighing 25 kg or more with CF who have an R117H CFTR mutation or one of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R – as licensed as monotherapy

The look-up table of licensed mutations from the manufacturer can be found here.

For all these CFTR products where the UK licence is amended in the future, eligible patients will automatically have access under those terms. The manufacturer will be responsible for supplying an age-appropriate product within the UK.

Ivacaftor off-label use

Where the UK medicines regulator may not consider the evidence for some named CFTR mutations, NHS England will reimburse the off-label use of ivacaftor in line with the approach to in vitro data taken by the US FDA, and the approved list of named mutations as outlined in the NHS England commissioning statement.

A clinician considering prescribing a medication outside the terms of the licence (‘off-label’) should do so in accordance with MHRA and General Medical Council (GMC) guidance which apply throughout England and the UK. The GMC guidance states prescribing unlicensed medicines may be necessary where ‘there is no suitably licensed medicine that will meet the patient’s need’. Should clinicians consider this appropriate for their patients and they have followed local medicines governance arrangements for off-label use, then NHS England will meet these costs as follows:

Ivacaftor: People with CF aged 1 month and older who are heterozygous in the CFTR gene for any one of the r FDA-approved mutations outside the UK licence.

Eleven mutations* are marked as being of ‘varying clinical consequence’* (VCC) (5). It is therefore important that supportive diagnostic criteria are used in addition to the presence of the mutation. In these cases, a definitive CF diagnosis requires sweat chloride >60mmol abnormal nasal potential difference or abnormal intestinal current measurement on rectal biopsy (6).

*D74W, S977F, R1070Q, D1152H, D110E, F1052V, R1070W, D1270N, D579G, G1069R, F1074L

*This means that some patients with this gene change, combined with another CF causing mutation, have CF.

Combination therapy off-label use

Where the UK medicines regulator may not consider the evidence for some named CFTR mutations, NHS England will reimburse the off-label use of tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor in line with the approach to in vitro data taken by the US FDA, and the approved list of named mutations as outlined in the NHS England commissioning statement.

A clinician considering prescribing a medication outside the terms of the licence (‘off-label’) should do so in accordance with MHRA and GMC guidance which apply throughout England and the UK. The GMC guidance states prescribing unlicensed medicines may be necessary where ‘there is no suitably licensed medicine that will meet the patient’s need’. Should clinicians consider this appropriate for their patients and they have followed local medicines governance arrangements for off-label use, then NHS England will reimburse the off-label use of tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor as outlined below:

Named CFTR mutations that have not been considered by the UK regulator

Where the UK medicines regulator has not considered the evidence for some named CFTR mutations, NHS England will reimburse the off-label use of tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor in line with the approach to in vitro data taken by the US FDA and the approved list of named mutations as follows:

• Tezacaftor/ivacaftor: People with CF aged 6 years and older who have any one of the FDA-approved named mutations outside the UK licence. In addition, 14 mutations licensed by the UK regulator for people with CF who have the F508del mutation are included for off -label prescribing when combined with any mutation other than F508del.
• Elexacaftor/tezacaftor/ivacaftor: For people with CF aged 2 years and older who are heterozygous for any one of the FDA-approved mutations outside the UK licence which can be combined with any other mutation.

In reaching this decision, NHS England has considered the FDA approach using a cell-based in vitro system/study* to validate the efficacy of all three drugs for an expanded range of mutations (clinical data were not available or readily feasible due to the rarity of the mutations under consideration).

*The in vitro system allowed for the assessment of changes in CFTR mediated chloride transport in response to ivacaftor and tezacaftor/ivacaftor in Fischer rat thyroid (FRT) cells expressing mutant CFTR channels. A shift in “percentage normal” CFTR chloride transport of at least 10% above baseline was the designated threshold for determining mutant CFTR channel response to the medications.

For further details on prescribing, dosage, monitoring and stopping criteria, please see Appendix
1.

Mechanism for funding

NHS England will fund these treatments through specialised commissioning teams.

Commissioning Statement review date

This is an urgent commissioning statement, which means that a full independent evidence review has not been conducted and public consultation has not been undertaken. If a review is needed due to a new evidence base, then NHS England should be contacted at this email address:
england.CET@nhs.net

Links to other policies

NICE:
TA988: Ivacaftor–tezacaftor–elexacaftor, tezacaftor–ivacaftor and lumacaftor–ivacaftor for treating cystic fibrosis: https://www.nice.org.uk/guidance/ta988 Supersedes:

• Clinical Commissioning Urgent Policy Statement ‘Cystic Fibrosis Modulator Therapies Access Agreement for licensed mutations: [200810P] published November 2023.
• Clinical Commissioning Urgent Policy Statement ‘Cystic Fibrosis Modulator Therapies Access Agreement for licensed mutations: [200810P] published May 2023.
• Clinical Commissioning Urgent Policy Statement ‘Cystic Fibrosis Modulator Therapies Access Agreement for licensed mutations: [200810P] published January 2022.
• Clinical Commissioning Urgent Policy Statement ‘Cystic Fibrosis Modulator Therapies Access Agreement for licensed mutations: [200810P] published on 21 January 2021.
• Clinical Commissioning Urgent Policy statement ‘Ivacaftor and tezacaftor/ivacaftor for cystic fibrosis: “off-label” use in patients with named rarer mutations: [200809P]’ published on 21 January 2021.
• Commissioning Statement ‘Ivacaftor, tezacaftor/ivacaftor, lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor for licensed and off-label use in patients with cystic fibrosis who have named mutations [210508P) published on 10 May 2021.

Equality statement

Promoting equality and addressing health inequalities are at the heart of NHS England’s values. Throughout the development of the policies and processes cited in this document, we have:

• given due regard to the need to eliminate discrimination, harassment and victimisation, to advance equality of opportunity, and to foster good relations between people who
  share a relevant protected characteristic (as cited under the Equality Act 2010) and those who do not share it
• given regard to the need to reduce inequalities between patients in access to and outcomes from healthcare services and to ensure services are provided in an integrated way where this might reduce health inequalities

Definitions

• CFTR gene: refers to the cystic fibrosis transmembrane conductance regulator (CFTR) gene which contains the instructions for making the CFTR protein
• COVID-19: refers to the disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus
• In-vitro system/study: this refers to a study performed or taking place in a test tube, culture dish, or elsewhere outside a living organism
• Mutation: in this context ‘mutation’ refers to the changing of the structure of a gene, resulting in a variant form that may be transmitted to subsequent generations
• Osteoporosis: a medical condition in which the bones become brittle and fragile, typically as a result of hormonal changes, or deficiency of calcium or vitamin D
• Osteopenia: a medical condition in which the protein and mineral content of bone tissue is reduced, but less severely than in osteoporosis

References

Cystic Fibrosis Trust. How does CF affect the body, Available from: https://www.cysticfibrosis.org.uk/.

2. COVID-19 rapid guideline: cystic fibrosis. NICE 2020
   Accessed 13/08/2020.
3. Advice for clinicians on Cataract Related to CFTER Modifying Drug of Cystic Fibrosis. The Royal College of Opthalmologists 2019
4. U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs.
5. Clinical and Functional Translation of CFTR
6. Farrell, P., White, T., Clement L., Hempstead, S., Accurso, F.Derichs, N. Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. The Journal of Paediatrics (2017). 181S: S4-S15.e1.
7. Costa, E. et al. (2022) ‘The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis’, Orphanet Journal of Rare Diseases, 17(1). doi:10.1186/s13023-022-02350-5.

Appendix 1: prescribing guidance and monitoring

The CFTR therapies must only be prescribed by physicians with experience in the treatment of CF working within NHS England commissioned CF services in line with this commissioning statement. For patients whose genotype is unknown, an accurate and validated genotyping method will be performed before starting treatment to confirm the presence of an indicated mutation in the CFTR gene (see below under ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor).

Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are common in subjects with CF. Liver function tests will be done for all patients prior to initiating ivacaftor either in monotherapy or in a combination regimen as tezacaftor/ivacaftor or as the triple therapy elexacaftor/tezacaftor/ivacaftor.

As ivacaftor contains lactose, ivacaftor either in monotherapy or in a combination regimen as tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor will not be prescribed to patients with rare hereditary problems of galactose intolerance, total lactase deficiency or congenital glucose- galactose malabsorption.

Dosing

Ivacaftor dosage: all information regarding dosage can be found in the respective SmPCs for ivacaftor, linked here:

• Kalydeco (ivacaftor) 13.4mg granules in sachet
• Kalydeco (ivacaftor) 25mg granules in sachet
• Kalydeco (ivacaftor) 50mg granules in sachet
• Kalydeco (ivacaftor) 59.5mg granules in sachet
• Kalydeco (ivacaftor) 75mg granules in sachet
• Kalydeco (ivacaftor) 75mg Film-coated tablets
• Kalydeco (ivacaftor) 150mg Film-coated tablets
  Tezacaftor/ivacaftor dosage: all information regarding dosage can be found in the respective SmPCs for tezacaftor/ivacaftor, linked here:
• Symkevi (ivacaftor, tezacaftor) 50mg/75mg film-coated tablets
• Symkevi (ivacaftor, tezacaftor) 100mg/150mg film-coated tablets
  Elexacaftor/tezacaftor/ivacaftor dosage: all information regarding dosage can be found in the respective SmPCs for elexacaftor/tezacaftor/ivacaftor, linked here:
• Kaftrio (Elexacaftor, ivacaftor, tezacaftor) 60mg/40mg/80mg granules in sachet
• Kaftrio (Elexacaftor, ivacaftor, tezacaftor) 75mg/50mg/100mg granules in sachet
• Kaftrio (Elexacaftor, ivacaftor, tezacaftor) 37.5mg/25mg/50mg film-coated tablets
• Kaftrio (Elexacaftor, ivacaftor, tezacaftor) 75mg/50mg/100mg film-coated tablets

Monitoring criteria

Liver function tests and blood pressure monitoring will be done at least every 3 months during the first year of treatment and annually thereafter for all patients taking ivacaftor treatment, either in monotherapy, in a combination regimen with lumacaftor, tezacaftor/ivacaftor or as the triple therapy elexacaftor/tezacaftor/ivacaftor (2).

In line with guidance from the Royal College of Ophthalmologists (3) it is recommended that paediatric patients when starting ivacaftor treatment, either in monotherapy, in a combination regimen with lumacaftor, tezacaftor/ivacaftor or as the triple therapy ivacaftor/tezacaftor/elexacaftor, should be seen on a regular basis by their local optometrist to detect any significant visual difficulties which may prompt referral to hospital eye services for further assessment.

Stopping criteria

In the event of significant elevations of transaminases (e.g. patients with ALT or AST > 5 x the upper limit of normal (ULN), or ALT or AST > 3 x ULN with bilirubin > 2 x ULN), dosing with ivacaftor, tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor will be interrupted and laboratory tests closely followed until the abnormalities resolve.

Consideration will be given to delaying or discontinuing therapy if hepatotoxicity or renal toxicity occurs.
During pregnancy it is preferable to avoid the use of ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor. For women who are breast-feeding and taking ivacaftor, tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ivacaftor, tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor taking into account the benefit of breast-feeding for the child and the benefit of therapy for the women.

Effective from

The commissioning statement is effective from the date of publication.

Recommendations for data collection

Hospital trusts should submit data on the numbers of patients treated with CFTR modulators to the national Cystic Fibrosis Registry which is hosted by the Cystic Fibrosis Trust.

Publication ref: 210508P