Could anyone share the peer-reviewed journals articles or other medical evidence they have used to persuade insurance to approve Kalydeco off-label, for residual function or other mutations?
So far the best I have found is the Journal of Cystic Fibrosis - the slide from Van Goor, F et al. J. Cys. Fibrosis. 2012; 11 (Suppl. 1):S31. This slide shows the change in CFTR chloride transport caused by VX-770 in various mutations including R117C.
I also found an article that supports the idea that even a small improvement in CFTR function is clinically significant and thus of benefit to the patient:
Five Percent of Normal Cystic Fibrosis Transmembrane Conductance
Regulator mRNA Ameliorates the Severity of Pulmonary Disease
in Cystic Fibrosis by
Anabela S. Ramalho*, Sebastian Beck*, Michelle Meyer, Deborah Penque, Garry R. Cutting,
and Margarida D. Amaral
I also found the following from the European drug application for Kalydeco (Assessment report - Kalydeco - ivacaftor - Procedure No.: EMEA/H/C/002494//0000 ):
2.3.6. Discussion on non-clinical aspects
Ivacaftor increased in vitro the chloride transport of multiple mutant CFTR forms associated with a
variety of protein defects and disease severity.
The increase of chloride transport by ivacaftor was most pronounced in cells expressing CFTR gating
mutations when compared to other types of CFTR mutations. This group included, G551D, G178R,
S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D. The fold increase in chloride
transport for all 10 studied gating mutation proteins was greater than 10.
Ivacaftor also potentiated chloride transport, of cells carrying CFTR mutations that are associated with
residual CFTR function, although to a lesser extent than that observed for CFTR gating mutations,
including CFTR conductance mutations (R117H, D110H, R117C, R347H and R352Q), mild CFTR
processing mutations (E56K, P67L, L206W, A455E, D579G, S945L, R1070W and F1074L) and CFTR
mutations with uncharacterized defects in the CFTR protein (D110E, D1152H, S1235R and D1270N).
Finally, ivacaftor showed minimal effects in vitro on mutant CFTR forms that were associated with
minimal chloride transport, including severe CFTR conductance mutations (R334W, T338I, R347P and
L927P), severe CFTR processing mutations (F508del, A46D, G85E, E92K, S492F, I507del, V520F,
A559T, R560T, R560S, A561E, H1054D, G1061R, L1065P, L1065P, R1066C, R1066H, R1066M,
L1077P, H1085R, M1101K and N1303K) and CFTR synthesis mutations (G542X, W1282X, 2184InsA
and 2789+5G->A).
Studies that may be classified as secondary pharmacodynamics studies have been performed and
discussed under Safety Pharmacology. In view of ivacaftor CFTR target selectivity, the CFTR
dependence of the disease, lack of adequate animal disease model and low incidence of observed side
effects in animal and clinical studies, it is scientifically justified not to perform additional studies on
secondary pharmacodynamics. Similar reasons justify the absence of pharmacodynamic drug
interactions studies in the application (i.e. high CFTR selectivity, absence of other CF therapies
targeting the CFTR receptor).
In addition, the laws of many states including California require insurance coverage of off-label drugs if they have been recognized for treatment of that condition by either the American Hospital Formulary Service’s Drug Information or two articles from major peer reviewed medical journals present data supporting the proposed off-label use as generally safe and effective unless there is clear and convincing contradictory evidence presented in a major peer reviewed medical journal. See HSC 1367.21
My doctor needs help with this as it's a huge field with hundreds of articles. I don't want to miss out on the best ones.
Thanks!
So far the best I have found is the Journal of Cystic Fibrosis - the slide from Van Goor, F et al. J. Cys. Fibrosis. 2012; 11 (Suppl. 1):S31. This slide shows the change in CFTR chloride transport caused by VX-770 in various mutations including R117C.
I also found an article that supports the idea that even a small improvement in CFTR function is clinically significant and thus of benefit to the patient:
Five Percent of Normal Cystic Fibrosis Transmembrane Conductance
Regulator mRNA Ameliorates the Severity of Pulmonary Disease
in Cystic Fibrosis by
Anabela S. Ramalho*, Sebastian Beck*, Michelle Meyer, Deborah Penque, Garry R. Cutting,
and Margarida D. Amaral
I also found the following from the European drug application for Kalydeco (Assessment report - Kalydeco - ivacaftor - Procedure No.: EMEA/H/C/002494//0000 ):
2.3.6. Discussion on non-clinical aspects
Ivacaftor increased in vitro the chloride transport of multiple mutant CFTR forms associated with a
variety of protein defects and disease severity.
The increase of chloride transport by ivacaftor was most pronounced in cells expressing CFTR gating
mutations when compared to other types of CFTR mutations. This group included, G551D, G178R,
S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D. The fold increase in chloride
transport for all 10 studied gating mutation proteins was greater than 10.
Ivacaftor also potentiated chloride transport, of cells carrying CFTR mutations that are associated with
residual CFTR function, although to a lesser extent than that observed for CFTR gating mutations,
including CFTR conductance mutations (R117H, D110H, R117C, R347H and R352Q), mild CFTR
processing mutations (E56K, P67L, L206W, A455E, D579G, S945L, R1070W and F1074L) and CFTR
mutations with uncharacterized defects in the CFTR protein (D110E, D1152H, S1235R and D1270N).
Finally, ivacaftor showed minimal effects in vitro on mutant CFTR forms that were associated with
minimal chloride transport, including severe CFTR conductance mutations (R334W, T338I, R347P and
L927P), severe CFTR processing mutations (F508del, A46D, G85E, E92K, S492F, I507del, V520F,
A559T, R560T, R560S, A561E, H1054D, G1061R, L1065P, L1065P, R1066C, R1066H, R1066M,
L1077P, H1085R, M1101K and N1303K) and CFTR synthesis mutations (G542X, W1282X, 2184InsA
and 2789+5G->A).
Studies that may be classified as secondary pharmacodynamics studies have been performed and
discussed under Safety Pharmacology. In view of ivacaftor CFTR target selectivity, the CFTR
dependence of the disease, lack of adequate animal disease model and low incidence of observed side
effects in animal and clinical studies, it is scientifically justified not to perform additional studies on
secondary pharmacodynamics. Similar reasons justify the absence of pharmacodynamic drug
interactions studies in the application (i.e. high CFTR selectivity, absence of other CF therapies
targeting the CFTR receptor).
In addition, the laws of many states including California require insurance coverage of off-label drugs if they have been recognized for treatment of that condition by either the American Hospital Formulary Service’s Drug Information or two articles from major peer reviewed medical journals present data supporting the proposed off-label use as generally safe and effective unless there is clear and convincing contradictory evidence presented in a major peer reviewed medical journal. See HSC 1367.21
My doctor needs help with this as it's a huge field with hundreds of articles. I don't want to miss out on the best ones.
Thanks!
