May possibly be the longest post ever, but here are 6 published journal articles/abstracts that support use of Kalydeco in those with evidence of residual function. I wanted to thank ladybird, who is a member of this forum. She shared many of the articles with me and they were successfully used in her appeal.
Note: only pertinent sections of articles are included. I underlined most important parts of article. My comments are italicized. Happy reading : )
Breakthrough Therapies: Cystic Fibrosis (CF)
Potentiators and Correctors
George M. Solomon, MD,1 Susan G. Marshall, MD,2 Bonnie W. Ramsey, MD,2,3*and Steven M. Rowe, MD, MSPH 1,4
.
"Therapies That Potentiate the CFTR Channel
Potentiators are compounds developed in hopes of
restoring CFTR activity and function in patients with
cystic fibrosis. These agents increase the time that
activated CFTR channels at the epithelial cell surface
remain open and functional. Potentiators improve gating
and conductance defects by augmenting the open
configuration of the CFTR channel.
Class III and IV
mutations are the categories most likely to respond to
potentiator monotherapy, but any channel with some
residual expression (like mild Class II defects or noncanonical
Class V splicing mutations) have the potential
to benefit.31,32
Rather than a strict genotypic approach, a phenotypic approach may also be
implemented, such as identifying potential candidates for
therapy based on the presence of residual CFTR function,
which implies that there may be some CFTR present to
effectively potentiate.
Initial attempts at a phenotypic approach, involving patients
with at least one mutation that produces some functional
CFTR protein (termed residual activity), and case reports
suggest ivacaftor may be beneficial in this group.48"
Effect of ivacaftor on CFTR forms with missense mutations associated with
defects in protein processing or function☆,☆☆
Journal of Cystic Fibrosis 13 (2014) 29–36
Fredrick Van Goor a,b,⁎, Haihui Yu b, Bill Burton b, Beth J. Hoffman b
"These in vitro data examined the baseline levels of chloride
transport and the response to ivacaftor for single CFTR
mutations. Although not the scope of this study, variations in
the baseline level of CFTR chloride transport and the response to
ivacaftor among people carrying the same CFTR mutation may
occur due to a variety of factors, including differences in the
CFTR mutation on the second allele or the presence of a complex
CFTR allele that modulates CFTR protein levels.
Additional factors not associated with
the CFTR gene may also impact the clinical response to ivacaftor
and include modifier genes, environmental factors, disease
severity at the time of treatment, and pharmacokinetics
In people with CF, these mutant CFTR forms
are typically associated with common clinical measures of
residual CFTR function, such as lower incidence of pancreatic
insufficiency, sweat chloride levels typically below 90 mmol/L,
or a measurable increase in chloride transport in nasal potential
difference studies [8,23] .
It may be possible to use clinical
measures of residual CFTR function in addition to, or along with
genotype, to select people with CF for clinical studies evaluating
the benefit of ivacaftor mono therapy."
CLINICAL EFFECTIVENESS OF OFF-LABEL IVACAFTOR USE IN PATIENTS WITH CYSTIC FIBROSIS (2015), Poster Session Abstracts. Pediatr Pulmonol., 50: S193–S453. doi:10.1002/ppul.23297
Hoag, J.B.1; Stephen, M.J.1; Dorgan, D.2; Bonk, M.2; Alaag, P.2; Hadjiliadis, D.2
1. Pulmonary, Critical Care, and Sleep Medicine, Drexel University College of Medicine, Philadelphia, PA, USA; 2. University of Pennsylvania, Philadelphia, PA, USA
"Background: In 2012, ivacaftor (Kalydeco) was approved by the FDA for treatment of cystic fibrosis (CF) patients with one copy of G551D mutation in CFTR. Subsequently, an additional 9 mutations providing some CFTR activity have been approved for treatment with this medication. Although recent clinical trials seek to expand the approved mutations, access to this medication has been limited despite in vitro evidence for possible clinical benefit for some patients. We performed a two-center retrospective review of patients receiving off-label ivacaftor for treatment of CF.
Methods: A retrospective chart review was performed to identify patients receiving ivacaftor for treatment of CF without one of the 10 FDA-approved mutations. Baseline demographic information, lung function, and frequency of exacerbations was compared to post-treatment values. A qualitative evaluation of symptom changes was also extracted.
Results: Twelve patients were identified (age 30 ± 12.3 years, 7 female). Baseline values included FEV1 1.66 ±1.3 L, BMI 21.3 ±3.7, sweat chloride 98 ±20, and annual exacerbation frequency of 2.4 ±1.4 per year. Eight patients (66%) described improved symptoms (four with great and four with mild improvement) while three reported no change and one worse. Of the 4 that reported significant improvement in symptoms, there was an associated improvement in FEV1 (160 ±100 mL, 17%) and FVC (450 ±550 mL, 28%), increase in BMI (1.05 ±1.68 kg/m2, 5%), and 19% decrease in sweat chloride. Overall annual exacerbation frequency decreased from 2.42 ±1.42 to 0.6 ±1.2 for the entire cohort.
Conclusions: The majority of patients receiving off-label ivacaftor had improvement in symptoms with 33% enjoying marked objective improvement in lung function, BMI and exacerbation frequency. Further research is needed to find more patients who might benefit from ivacaftor."
****
There is a poster that goes along with this published abstract. It was presented at 2015 NACFC. I’m not sure if the poster is considered published. The poster gives genotypes tested. There were various responses from much improved (4), better(4), same(3), and worse(1). Of note is that of the 4 robust responders, 2 had residual function mutations that did not show favorable in-vitro response and will not be included on expanded label (R334W and M1101K). Another one of the robust responders may have also had a residual function mutation(s), but I couldn't find out any info. on either mutation (G463D var1 1556V var2 and I1023R) Neither of these mutations will be on proposed expanded label. Of the 4 people that were ”better”, 2 had residual function /splicing mutation that will not be included on label. (M1101RpolyT 7T and 9T and 621+1G>T) Specific in-vitro responses were not mentioned in poster or abstract. I’m making this conclusion based on article F. Van Goor et al. / Journal of Cystic Fibrosis 13 (2014) 32 Figure 2B. Baseline chloride transport (filled bars) and ivacaftor (10 μM) response (open bars) in FRT cells expressing the CFTR mutant forms indicated.
This is important for those appealing and trying to prove that in vitro results don’t necessarily correlate with clinical response.
“The use of ivacaftor in CF mutations with residual functioning protein” S. Guigui,
B. Condon,
R.I. Cohen
http://www.cysticfibrosisjournal.com...494-X/abstract
“We noted improvement in all patients and in all parameters at 6 months compared to baseline. One patient was retested at one month after stopping ivacaftor with worsening parameters.
These data support the beneficial effects of CFTR potentiators in CF mutations producing residual functioning protein.”
NOTE---Patient number 1 had 2 class IV residual function mutations (R347P & L1065P) . Neither showed significant in vitro response, but she had an excellent clinical response. Specific in vitro responses were not mentioned in abstract. I’m making this conclusion based on article F. Van Goor et al. / Journal of Cystic Fibrosis 13 (2014) 32 Figure 2B Baseline chloride transport (filled bars) and ivacaftor (T10 μM) response (open bars) in FRT cells expressing the CFTR mutant forms indicated.
Very little increase in CFTR is required for a clinical response/improvement in symptoms as evidenced by the following journal articles:
A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088564
Very scientific article that much of is beyond my understanding, however; the last sentence of the conclusion makes a very important, clear, and understandable broad conclusion statement that can be used in general terms, not mutation specific:
"
In sum, the corrected in vivo estimates of restored CFTR function overlap estimates based on patch clamp data, and suggest that excellent clinical responses can be expected by restoring less than 10% of CFTR function."
Along these same lines:
Five Percent of Normal Cystic Fibrosis Transmembrane Conductance Regulator mRNA Ameliorates the Severity of Pulmonary Disease in Cystic Fibrosis
Anabela S. Ramalho*,
Sebastian Beck*,
Michelle Meyer,
Deborah Penque,
Garry R. Cutting, and
Margarida D. Amaral
http://www.atsjournals.org/doi/full/10.1165/rcmb.2001-0004OC#.VlzvWEshUdt
