Ivacaftor Trial 102 and 103 Data Analysis

This is a speculative analysis of the data presented at the FDA by Vertex pharmaceuticals ® and reported in 203188Orig1s000ClinPharmR.pdf in fda.gov site. These data were the results of the Ivacaftor trials n° 102 and 103 on patients with at least one G551D mutation allele.

First of all, data were collected and analyzed to mathematically estimate baseline values of both Fev1 and SC.
Values on this graph represent a single patient’s data. Multiple patient data often resulted in incorrect values (using both positive and negative integers resulted in unbalanced mean result).





The next step consisted of grouping all data results into the common 5 cftr mutation classes plus 1 unknown. .

As we can see there are peaks in the FEV1 changes at 24weeks. As for R560T in the placebo group and negative peaks (even if lower) in Ivacaftor group as for R347H and G551D mutations (this last is weird, unexplained but right even according to the graph in the same document about Chloride transport measurements reported below; maybe dosages had to be increased for such patients with 2 gating mutation alleles or, given the variability of FEV1, it was just a temporary cold).



Sweat Chloride data is more homogenous. One peak for the mutation 2183AA (that could be explained with a salty diet prior to the 24weeks testing) and one negative peak for the EX14_15 mutation, this difference can be explained for the lack of information on this kind of mutation, for which such mechanism of action has not yet been fully understood.
For the Ivacaftor Sweat Chloride group we find a lack of information for class IV mutation.
R347H is the only within this class and resulted in a little improvement.
(Further in vitro testing on conductance mutations has been performed and is shown below).





Class V mutations too are not represented in this scheme but in the synthesis group we find a splicing mutation considered to be a Class I. That specific form scored an awesome -84 mmoles.


To underscore the influence of splicing mutations on Ivacaftor response for people who had at least a G551D mutation, we assumed a -33 mmoles due to G551D mutation alone and a buffer of another 15mmoles for temporary fluctuation (as seen in the placebo group). Results are summarized below:


1717 G>A mutation is the only mutation in the Ivacaftor group that, starting from a baseline of >100 value, scored such a significant important improvement. Note that the effect of Ivacaftor on this mutation scored an almost 80% SC relative improvement. In few words, splicing mutations producing a small fraction of wild type (together with an aberrant isoform) cftr, could be potentiated equally well or more than other non-gating mutations.


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