Currently approved with Kalydeco:
G551D (7.4% of CFs in Australia)
Currently involved with Kalydeco trials:
Gating: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D (1% Aus)
Conductance: R117H (3.4% Aus)
Residual function: 10-15% Aus. The inclusion criteria for the Denver trial is based on clinical characteristics and mutations. This is the criteria for the Denver study: 1) pancreatic sufficiency or 2) sweat chloride below 80, or 3) age of diagnosis above 12 years and at least 1 copy of a CFTR mutation associated with residual CFTR function or defective mRNA splicing. These are the mutations: R117H, E56K, P67L, D110E, D110H, R117C, R347H, R352Q, A455E, D579G, S945L, L206W, R1070W, F1074L, D1152H, S1235R, D1270N, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1898+1G->A, 1717-1G->A, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, 621+3A->G and 621+1G->T.
The second trial has similar criteria: normal digestion or sweat chloride 55-85 or milder than expected CF disease in a CF patient with severe gene mutations.
Currently involved in Kalydeco/VX809, Kalydeco/VX661 and N6022 trials:
F508del- homozygotes (2 copies F508del) & heterozygotes (1 copy F508del).
In Aus 85% have F508del and 50% are homozygotes.
Laboratory evidence supports that these mutations may be helped by VX809/Kalydeco:
Class 2: H1054D, G1061R, L1065P, Q1071P, L1077P, H139R, R258G, S945L
Previously involved with Ataluren trials:
Class 1 nonsense mutations that end in X such as: G542X, W1282X, Q493X, R553X, E1104X, R1162X, W846X, W882X, Q1313X (about 5% Aus)
Other rare mutations that are not listed above may be helped by these medications. These mutations are not listed in the Kalydeco trials but are listed in the Kalydeco Patent: E193K, F1052V, G1069R, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A. Hopefully we will find out the results from the residual function trial soon, so we can see if the splicing mutations improved (traditionally many of the splicing mutations listed above have been classified as class 1 splicing, and it was believed that little cftr is produced, which would make it hard for Kalydeco to help).
Residual Function: http://www.clinicaltrials.gov/ct2/show/NCT01685801?term=ivacaftor&rank=16
Kalydeco Patent: http://www.faqs.org/patents/app/20110288122