Kalydeco® off-label

Question

Dear expert team,
my son has the following CFTR mutations:
1717-1G>A (class 1) und die mutation S549R (gating/connection, class 2 oder 3)
Kaleydeco ® has indeed at the moment only market authorization for the class 3 mutation G551D. However, tests with other mutations have been done. There it could be shown, that Kalydeco® is supposed to have a similar effect on all other gating mutations as it has on the mutation G551D. An application for all other non-G551D gating mutations has been subscribed to the FDA [American Food and Drug Administration].
Furthermore, other tests are underway, e.g. residual function.
The other mutation of my son belongs to this group. Whereby it has to be remarked that besides the mutation still a little function of the CFTR has to be present. I cannot make a judgement about this. It is simply like this, that my son is doing well. The weight is all right, i.v. therapy only about one to two times a year, frequently Staphylococci, no Pseudomonas, or other bacteria.
Whereby this is however true only for the moment. In order to avoid a worsening of the health situation of my son or to delay it, we would like to implement Kalydeco®.
Now to my question: What do you think, is Kalydeco® medically indicated for my son?
Many thanks for your answer

Answer

Dear parent,
in the last years we have learned, that one mutation can belong to several classes. Now it becomes clear, that the usage of potentiators, like e.g. Ivacaftor (Kalydeco®) and their clinical effect is not class specific but rather mutation specific.
Therefore, I will concretely and without any furhter accomplishment answer your question if the usage of Ivacaftor in case of S549R is promising.
On this, there are very good in-vitro data from Fredrick van Goor published in the Journal of Cystic Fibrosis (2012 May;11(3):237-45). In comparison to the other investigated mutations with "residual function" in this study, the effect of Ivacaftor in case of S549R was in my opinion not so clearly appraisable. This could be explained by the fact, that furhter in-vitro studies could show for this mutation, that besides the very low probability of an opening of the channel of less than 1%, there is additionally a mild maturation defect with this mutation. These studies, however, have been in-vitro experiments and not clinical studies. At least the data has been judged that way, that it was decided to perform clinical studies also on this mutation.
The mutation S549R has/is investigated in 2 studies: A Konnection: other Gating Mutations and B KIWI: children of 2-5 years of age. The results of KIWI are expected for the 2nd quartile 2014. Konnection is analysed and the results seem to be comparable concerning the increase in lung function to patients with G551D. This is really good news. A single analysis concerning S549R is at the moment not available for me, however this would not last very long anymore.
Best regards,
Olaf Eickmeier

12.02.2014