Ivacaftor / Tezacaftor / Elexacaftor (10) – Kaftrio®

• Clinical trials
  • For the assessment of the additional benefit of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor for the treatment of children aged 6 to 11 years with cystic fibrosis who are heterozygous for the F508delmutation in the CFTR gene and carry a mutation on the second allele that is neither a minimal function, a gating (including R117H) nor a residual function mutation, or in whom the mutation on the second allele is unknown (other mutations), no study data have been submitted by the pharmaceutical manufacturer.

Children aged 6 to 11 years with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and carry a mutation on the second allele that is neither a minimal function, nor a gating (including R117H)or residual function mutation, or in whom the mutation on the second allele is unknown (other mutations)

• An additional benefit is not proven.
• Additional benefit is not proven for ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor compared with the appropriate comparator therapy.
• For the assessment of the additional benefit of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor for the treatment of children aged 6 to 11 years with cystic fibrosis who are heterozygous for the F508delmutation in the CFTR gene and who carry a mutation on the second allele that is neither a minimal function, a gating (including R117H) nor a residual function mutation, or in whom the mutation on the second allele is unknown (other mutations), the pharmaceutical manufacturer has not submitted any study data.
• Even though the marketing authorisation for this therapeutic indication was granted by the EMA on the basis of data from children aged 6 to 11 years with a heterozygous F508del mutation and a minimal-function mutation or a homozygous F508del mutation (studies VX19-445-116 and VX18-445-106) on the assumption that the functionality of the chloride channels is primarily modulated via the major effect of the F508del mutation in the CFTR gene, no extrapolation of additional benefit from children aged 6 to 11 years with a heterozygous F508del mutation and a minimal-function mutation to children of the same age who are heterozygous for the F508delmutation and have a different/unknown mutation on the second allele, as not all the conditions required to justify the recognition of additional benefit are met.
• In its dossier for the present therapeutic indication under assessment, the pharmaceutical manufacturer does not provide any studies or other information on the course of the disease under best standard of care (BSC).
• Furthermore, the company does not adequately explain the extent to which children aged 6 to 11 years with a heterozygous F508del mutation, who carry different mutations on the second allele, are comparable to one another in terms of their clinical presentation.
• The additional benefit of ivacaftor/tezacaftor/Elexacaftor from the population of children aged 6 to 11 with a heterozygous F508del mutation and a minimal-function mutation to the population under consideration here—children aged 6 to 11 with a heterozygous F508del-mutation and another/unknown mutation, as considered here, is not justified due to the lack of sufficient certainty regarding the comparability of the pathophysiology and the absence of data for the patient population under assessment.
• In the present benefit assessment procedure, it is also not possible to extrapolate any additional benefit from individuals aged 12 years and over with a heterozygous F508del mutation and another/unknown mutation, as the benefit assessment procedure for this patient population (decision date: 19 November 2021) no additional benefit was identified because no data were available.
• Overall, the pharmaceutical manufacturer did not submit any study for the present therapeutic indication that would have been suitable for assessing the additional benefit of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor compared with the appropriate comparator therapy.
• Taking into account the available evidence on the medical benefit of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor, the progressive course of the disease and the statements from medical societies regarding the current reality of care, ivacaftor/Tezacaftor/Elexacaftor in combination with Ivacaftor may represent a relevant treatment option for children aged 6 to 11 years who are heterozygous for the F508del mutation in the CFTR gene and who have an unknown or different mutation on the second allele, may represent a relevant treatment option for individual patients.

Courtesy translation only, please refer to the German original.