Residual Functions Mutations going to be on label for Kalydeco


New member
Yes, I know that 661-108 trial doesn’t include the other ½ of residual mutations. I guess I was being overly optimistic in estimating 18 months since there isn’t even a study in place to address the other ½ of residual function mutations. It’s just inconceivable to me that there is so much evidence supporting use of Kalydeco for those with evidence of residual function, yet it isn’t even presently being tested in ½ of those with residual function. I'm not sure where to start in trying to convince Vertex or CFF of adding arm. Any ideas?

I think the phase 3 also requires that the other mutation be f508del, which, unfortunately, is not the other mutation for my daughter (it is w1282x).

Also, anyone who has one of the mutations that is on the list for sure should be jumping up and down and I am definitely happy for all of them. It is not their fault that the list is limited or that Kalydeco is ridiculously expensive.

I guess we can try off label (probably will wait until the residual function label expansion is actually approved). However, I am currently fighting united healthcare trying to get a pancreatic enzyme for my son (he has the same two mutations, but no lung issues, is pancreatic sufficient, but has recurrent attacks of pancreatitis). He's been on zenpep and his Mayo doctor has prescribed Viokase. UHC is insisting that he try Creon first and only after failure, will they approve the viokase. Failure means more trips to the hospital because of pancreatitis (which is incredibly painful). Economically, it makes far more sense for UHC to approve the Viokase, but they haven't yet. Note that my son's doctor has told everyone involved that based on his years of experience, creon will not function any differntly than Zenpep (they're both coated as compared to Viokase). Still, nothing from UHC. Note also that the cost of Viokase pales in comparison to Kalydeco.

We'll keep forging ahead though....


Super Moderator
I apologize to anyone who has been trying unsuccessfully to access residual function articles from the CFF’s patient resource center that I said would be available to them. Unfortunately my contact at CFF resource center is now denying that he ever told me that articles would be available for public use. I am 100% positive that he agreed to pass on articles to people who specifically called in asking for them. The only thing he said that he would not be able to do was post articles to be viewed on their online database.
I am beyond frustrated and angry right now. I was lied to by a representative of a foundation that I have supported for the past 20+ years and have raised over $100,000 for.
I have asked multiple people from CFF to try to explain to me why the foundation is so resistant to off-label use. No one has given me an answer. I’m a reasonable person. I can try my best to understand another’s point of view; but there has to be validity and justification to back up their answer. I basically have been told “because that’s the way it is. We have to be careful...” Be careful of what??? Saving and improving lives???
As far as I can tell, there is no legal reason that is preventing them from giving information to patients. I have researched other reputable nonprofit organizations and there are many that advocate for off-label use for their patients, some even going so far as to provide sample letters of appeal for off-label use.
The CFF mission is “ to cure cystic fibrosis and to provide all people with the disease the opportunity to lead full, productive lives by funding research and drug development, promoting individualized treatment, and ensuring access to high-quality, specialized care. “ The foundation should be doing everything in its power to provide patients access to a potentially life-saving drug if there is reason to believe that it may be effective for them. If a patient has evidence of residual function, such as pancreatic sufficiency, there is justification for a trial of the drug. Will it work for everyone with residual function? No. I think it’s becoming obvious that there is going to be very individualized responses to these medicines. But that shouldn’t mean that people shouldn’t be given the opportunity to at least try.
For the moderators of this site- please let me know if this site is capable of housing all of these articles somewhere. Maybe there could be a separate tab for journal articles for off-label use? If this is not possible, please let me know if anyone has any ideas on where we can have these localized in a central place.


Super Moderator
I am so very sorry. Given how the benefit you have experienced first hand it must be especially painful! I'm not sure of the capabilities but let me chat with others. I think that would be wonderful!!


Super Moderator

So sorry. That must be beyond frustrating and maddening. I agree with Love and think it would be great if we could post that info somewhere. We'll put our heads together! :)



Super Moderator
I’m feeling MUCH better about things. I just spoke to the director of clinical communications for the CFF who just happened to be one of the nurses that I’ve had in the past. Talk about a stroke of serendipity : ) We had a long conversation about off-label use, collecting data for off-label use, and many other ideas/concerns that have been rolling around my head for the past year. I FINALLY feel like my words were not falling on deaf ears and that she understood what I was talking about. And it seems like she knows who to direct questions to and how to at least get a dialog going about some of my ideas.
She said that the CFF can provide patients with articles when they call in and ask. She is going to talk with people at PARC and when someone calls in, they will direct them to her.
Just thought I’d give an update. Persistence pays off but I almost lost my mind in the process. My patience was wearing thin. I'm so glad I finally connected with the right person.


Super Moderator
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

“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
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


Super Moderator
Oops- I almost forgot one of the most important ones. This is from the 2014 NACFC.


Jerry A. Nick, M.D.1, David Rodman2, Connie St Clair1, Marion C. Jones1, Haihong Li2, Mark Higgins3 and on
behalf of the VX12-770-113 Study team2
1. National Jewish Medical & Research Ctr., Denver, CO, USA; 2. Vertex Pharmaceuticals Incorporated, Boston,
MA, USA; 3. Vertex Pharmaceuticals (Europe) Limited, Milton Park, United Kingdom

" Background: Although more than 1900 CFTR mutations
have been identified, the resulting protein defect
is unknown for the majority of mutations (1). Furthermore,
even among patients with the same genotype, significant
variability in the presentation of clinical symptoms
is observed. As such, the “personalized medicine”
approach to treating CF must consider broadening selection
criteria beyond genotype to also include phenotypic
characteristics in order to identify patients who may
derive benefit from a particular therapy.
CFTR modulators
are a class of therapeutic agents designed to treat the
underlying cause of CF by addressing the CFTR protein
defect. Ivacaftor, a CFTR potentiator, provided significant
improvements in FEV1 in patients with CF who
have one of 9 gating mutations (2-4). In vitro, ivacaftor
increased the channel open probability of cell surface-localized
CFTR, increasing total chloride transport (5).
This suggests that ivacaftor may have the ability to facilitate
chloride transport and provide benefit for patients
who demonstrate residual CFTR protein activity. Broadly
speaking, these patients often are pancreatic sufficient
with delayed presentation of pulmonary symptoms. Frequently
these patients are diagnosed in adulthood, with
lower sweat chloride values compared to patients diagnosed
at infancy with classic features of the disease (6)
While CF patients with residual CFTR may be expected
to achieve a significantly greater lifespan compared to
those with a more classical CF disease course, respiratory
disease ultimately becomes the primary cause of
premature morbidity and mortality (7). Clearly, randomized,
double-blinded placebo-controlled studies for all
known mutations will not be possible to guide the use of
ivacaftor in every patient with CF.
In some cases, such as
R117H-CFTR, the patient population is large enough to
define a study group based on genotype and phenotype
and perform a standard randomized, placebo-controlled
clinical study. However, the low prevalence and frequent
uncertainty as to the functional significance of the vast
majority of CFTR mutations will make it impossible to
assemble study cohorts of the same mutation or mutational
class to evaluate the clinical response for each
according to traditional study designs. Moreover, the
ultimate goal for any therapy is to objectively determine
if the agent is of benefit in an individual patient, independent
of specific genetic abnormalities or other predetermined
disease characteristics such as age or severity of
This pilot study (VX12-770-113) was designed
to examine the utility of novel trial methods to identify
patients with CF who may benefit from treatment with
ivacaftor monotherapy based on a clinical phenotype
consistent with residual CFTR protein activity."


Super Moderator
So strategerizing here and thinking fda is going to ok kalydeco for residual functions and maybe before feb date. Here's my thinking...this link shows tentative meetings and pulmo had dec 9-10 but only had something on dec 9...and nothing listed for 2016 whereas other committees show dates for 2016... So I'm thinking fda doesn't think it need a committee recommendation or it would have scheduled it by now to get few target and if it doesn't think it needs committee review likely has already decided that approval is appropriate, or at least tentatively. All pure speculation but seems logical...


Super Moderator
So strategerizing here and thinking fda is going to ok kalydeco for residual functions and maybe before feb date. Here's my thinking...this link shows tentative meetings and pulmo had dec 9-10 but only had something on dec 9...and nothing listed for 2016 whereas other committees show dates for 2016... So I'm thinking fda doesn't think it need a committee recommendation or it would have scheduled it by now to get few target and if it doesn't think it needs committee review likely has already decided that approval is appropriate, or at least tentatively. All pure speculation but seems logical...

That would be wonderful. Fingers crossed. (great detective work!)