Effect of Trikafta

Question

Dear experts,
our son is 1 year old and has the mutations del508 and W1218X. We have a question on the effect of modulator therapy. He will get Kaftrio (Trikafta) due to his one del508 mutation. Is there any knowledge about the effect of Kaftrio (Trikafta) in case of this mutation combination? We have read, that modulators are not effective in nonsense (stop-) mutations, but they are effective in del508. Is the del508 mutation, that is corrected by modulators overtaking the whole functioning? Or how could one imagine it works? Many thanks for your answer!

Answer

Dear questioner,
this question is interesting but however not so easy to answer. In general we know, that carriers of one del508 mutations are "healthy carriers" and therefore the functioning of the second gene location, which is not carrying a mutation, is sufficient for sustaining a normal function of the CFTR channel (sometimes however, indeed slightly increased sweat test values are found in carriers). Therefore one could speculate, that if I have a nonsense (stop-) mutation and one delta508 mutation, and Kaftrio (Trikafta) corrects the delta508 mutation, it should be sufficient.
Now it is getting more complicated. The mentioned nonsense-mutation belongs to the group of so-called minimal-function mutations, shortly MF-mutations, which have only a very small residual function of the CFTR-channel. To this group however, do not only belong nonsense-mutations, in which Kaftrio is for sure not effective, but also mutations, for which Kaftrio has been shown in the laboratory to be effective, and therefore, such mutations are already licensed in the USA for Kaftrio. The problem is, however, that in studies, only homozygous people with delta508/delta508 and those with delta508/MF have been investigated. In order to prove the theory, it would be necessary to compare all delta508/delta508 together with delta508/MF with a proven effect of Kaftrio against a group that carries delta508/MF without effectiveness of Kaftrio (e.g. stop-mutations). Therefore one has to devide the group with MF mutations further into those with MF with and without effectiveness of Kaftrio. In one study, they did it indeed, however then only very small patient numbers remain, e.g. 14 patients, so a statistical relevant result is not possible. There is seen a slight difference in the chloid concentrations in the sweat with the tendency, that they are lower if Kaftrio can be effective on 2 mutations compared to 1 mutation, however this is far away from being statistically relevant.
In children aged 6-11 years delta508/delta508 were compared to delta508/MF. If we assume, that in the group of delta508/MF are mainly those mutations, on which Kaftrio is not effective, it would probably be possible to see a trend, that Kaftrio would be more effecitve if it can address 2 mutations instead of one.
Quality of life, FEV1, sweat chlorid absolute values did not differ significantly in both groups, however if the percentage of patients was addressed, that achieved sweat chloride levels below 30 mmol/l, 43% of patients from the group deltaF/deltaF achieves such low levels under therapy compared to only 3% of patients from the deltaF/MF group. This supports the assumption, that Kaftrio has a stronger effect, if it can address 2 instead of 1 muation, even if the rest of the data could not show a significant difference between groups.
However it can be also said, that this drug is for sure effective in the combination of delF508 and W1282X according to the study data, even if the effect is possibly stronger in case of two sensitive mutations for Kaftrio. The clinical data can not prove this, however, but a lot of research is done and it will remain exciting which further results on this topic we will get.
Best regards,
Daniela d'Alquen

07.11.2023