Warning to those with the A455E mutation

[knobby]

Hi, I have been waiting 8 years for Ivacaftor to be approved for residual function CFTR mutations. The day finally came on May 17th and soon after, we had my son signed up and taking his first dose. We did this with a little trepidation based on the results of a small N-of-1 study (https://www.ncbi.nlm.nih.gov/pubmed/28068001) where Ivacaftor had the opposite effect for 2 of the people in the study; both with the A455E defect. I thought how can that be possible with all the preclinical work that has been done? I wanted to believe it was a mistake.
However, I did not want to keep my son on the drug if it really did have the same negative effect on him so we scheduled a sweat test for 2 weeks after he started. We got the results yesterday and it was shocking. His original test was 75 mmol/L in one arm and 85 mmol/L in the other (this was done with the old testing methodology 8 years ago). The test yesterday after being on Ivacaftor went all the way up to 97 mmol/L in both arms. Very similar to the N-of-1 study.
We immediately stopped the medication.
There has not been any long term studies of what happens when you increase someone's sweat chloride but common sense (for what that's worth) would indicate more severe symptoms and potentially permanently clogging the pancreas for those that are pancreatic sufficient (like many with A455E are).
I wanted to pass this along for those with this defect to be very aware of the results from at least 3 patients.

 

[RWCO]

check with a CF specialist before stopping ivacaftor

Hi, I have been waiting 8 years for Ivacaftor to be approved for residual function CFTR mutations. The day finally came on May 17th and soon after, we had my son signed up and taking his first dose. We did this with a little trepidation based on the results of a small N-of-1 study (https://www.ncbi.nlm.nih.gov/pubmed/28068001) where Ivacaftor had the opposite effect for 2 of the people in the study; both with the A455E defect. I thought how can that be possible with all the preclinical work that has been done? I wanted to believe it was a mistake.
However, I did not want to keep my son on the drug if it really did have the same negative effect on him so we scheduled a sweat test for 2 weeks after he started. We got the results yesterday and it was shocking. His original test was 75 mmol/L in one arm and 85 mmol/L in the other (this was done with the old testing methodology 8 years ago). The test yesterday after being on Ivacaftor went all the way up to 97 mmol/L in both arms. Very similar to the N-of-1 study.
We immediately stopped the medication.
There has not been any long term studies of what happens when you increase someone's sweat chloride but common sense (for what that's worth) would indicate more severe symptoms and potentially permanently clogging the pancreas for those that are pancreatic sufficient (like many with A455E are).
I wanted to pass this along for those with this defect to be very aware of the results from at least 3 patients.

I am not a medical doctor but I have a daughter with a residual function mutation and have read EVERYTHING for the past 11 years about ivacaftor. I would caution you not to stop ivacaftor without getting an opinion from an informed CF doctor in a larger clinic with experience with patients with residual function on ivacaftor. The effects of ivacaftor cannot be assessed after only 2 weeks with only one sweat test. It is also highly possible, indeed probable, that your son's sweat chloride level went up naturally from his original test 8 years ago. Sweat chloride can increase with age, especially with residual function mutations, CFTR function is highly variable. I would want a sweat test immediately prior to starting ivacaftor and another one a couple of months later to assess the influence of ivacaftor.

 

[jricci]

Hi, I have been waiting 8 years for Ivacaftor to be approved for residual function CFTR mutations. The day finally came on May 17th and soon after, we had my son signed up and taking his first dose. We did this with a little trepidation based on the results of a small N-of-1 study (https://www.ncbi.nlm.nih.gov/pubmed/28068001) where Ivacaftor had the opposite effect for 2 of the people in the study; both with the A455E defect. I thought how can that be possible with all the preclinical work that has been done? I wanted to believe it was a mistake.
However, I did not want to keep my son on the drug if it really did have the same negative effect on him so we scheduled a sweat test for 2 weeks after he started. We got the results yesterday and it was shocking. His original test was 75 mmol/L in one arm and 85 mmol/L in the other (this was done with the old testing methodology 8 years ago). The test yesterday after being on Ivacaftor went all the way up to 97 mmol/L in both arms. Very similar to the N-of-1 study.
We immediately stopped the medication.
There has not been any long term studies of what happens when you increase someone's sweat chloride but common sense (for what that's worth) would indicate more severe symptoms and potentially permanently clogging the pancreas for those that are pancreatic sufficient (like many with A455E are).
I wanted to pass this along for those with this defect to be very aware of the results from at least 3 patients.

I read this article when it was released and was upset when I saw the results for this mutation. So sorry to hear that your son’s increased sweat test correlated with the other 2 patients in the study with A445E who started Kalydeco. I can only imagine how devastating this was for you to find out when you’ve had such high hopes all of these years. I passed on your son’s response to someone involved with clinical trials at the CFF. Hopefully Vertex or CFF will start tracking real world results with these drugs.

I have the full article if you want me to share it with you. The authors give a possible explanation for the unexpected results. I can’t say I completely understand the explanation. But what is clear is just how complex this disease is on the molecular level.

Try not to lose hope. I think N-of-1 trials are coming soon and that way they will be able to test these new drugs directly on a patient’s cells to see if there’s a response. Is your son’s second mutation df508? If so, do you think you will try VX-661 when it’s hopefully approved?

 

[knobby]

I read this article when it was released and was upset when I saw the results for this mutation. So sorry to hear that your son’s increased sweat test correlated with the other 2 patients in the study with A445E who started Kalydeco. I can only imagine how devastating this was for you to find out when you’ve had such high hopes all of these years. I passed on your son’s response to someone involved with clinical trials at the CFF. Hopefully Vertex or CFF will start tracking real world results with these drugs.

I have the full article if you want me to share it with you. The authors give a possible explanation for the unexpected results. I can’t say I completely understand the explanation. But what is clear is just how complex this disease is on the molecular level.

Try not to lose hope. I think N-of-1 trials are coming soon and that way they will be able to test these new drugs directly on a patient’s cells to see if there’s a response. Is your son’s second mutation df508? If so, do you think you will try VX-661 when it’s hopefully approved?

Hi Jricci,
Thanks so much for the comments and for the reply! Yes, I would love to see the full article. I had tried to get my son in that original quoted study but we are on opposite coasts so it didn't work out. I did send a note to Dr Nielson, study lead already as well.
As for his other mutation, unfortunately, it's a frameshift and not DF508. It would be interesting to see if the combo of VX-661 with Ivacaftor can offset what's happening with Ivacaftor alone.

 

[knobby]

I am not a medical doctor but I have a daughter with a residual function mutation and have read EVERYTHING for the past 11 years about ivacaftor. I would caution you not to stop ivacaftor without getting an opinion from an informed CF doctor in a larger clinic with experience with patients with residual function on ivacaftor. The effects of ivacaftor cannot be assessed after only 2 weeks with only one sweat test. It is also highly possible, indeed probable, that your son's sweat chloride level went up naturally from his original test 8 years ago. Sweat chloride can increase with age, especially with residual function mutations, CFTR function is highly variable. I would want a sweat test immediately prior to starting ivacaftor and another one a couple of months later to assess the influence of ivacaftor.

Hi RWCO,
We work with one of the best CF centers in the country - Boston Children's Hospital. Can you please share a reference that details how chloride levels rise over time? From every study I have seen with this defect, the average chloride level is exactly what my son's was when he had it originally done. Additionally, every Ivacaftor study I have seen shows chloride levels hitting near peak effectiveness at the first test, 2 weeks in. Here's an example:

https://www.biologycorner.com/worksheets/case_study_cystic_fibrosis.html

Based on the small clinical study and our own results, I think it would be unconscionable to further risk my son's health with what is currently known without further study and understanding of what's going on.

 

[jricci]

Hi Jricci,
Thanks so much for the comments and for the reply! Yes, I would love to see the full article. I had tried to get my son in that original quoted study but we are on opposite coasts so it didn't work out. I did send a note to Dr Nielson, study lead already as well.
As for his other mutation, unfortunately, it's a frameshift and not DF508. It would be interesting to see if the combo of VX-661 with Ivacaftor can offset what's happening with Ivacaftor alone.

Sure, send me a personal message with your e-mail address and I'll send you the article. It's in pdf format so it has to be e-mailed as an attachment.

 

[jricci]

Encouraging story for those with A445E

Hi, I have been waiting 8 years for Ivacaftor to be approved for residual function CFTR mutations. The day finally came on May 17th and soon after, we had my son signed up and taking his first dose. We did this with a little trepidation based on the results of a small N-of-1 study (https://www.ncbi.nlm.nih.gov/pubmed/28068001) where Ivacaftor had the opposite effect for 2 of the people in the study; both with the A455E defect. I thought how can that be possible with all the preclinical work that has been done? I wanted to believe it was a mistake.
However, I did not want to keep my son on the drug if it really did have the same negative effect on him so we scheduled a sweat test for 2 weeks after he started. We got the results yesterday and it was shocking. His original test was 75 mmol/L in one arm and 85 mmol/L in the other (this was done with the old testing methodology 8 years ago). The test yesterday after being on Ivacaftor went all the way up to 97 mmol/L in both arms. Very similar to the N-of-1 study.
We immediately stopped the medication.
There has not been any long term studies of what happens when you increase someone's sweat chloride but common sense (for what that's worth) would indicate more severe symptoms and potentially permanently clogging the pancreas for those that are pancreatic sufficient (like many with A455E are).
I wanted to pass this along for those with this defect to be very aware of the results from at least 3 patients.

Knobby-
I read the CFF blog post today, which gave a summary of the first plenary at the NACFC:
https://www.cff.org/CF-Community-Bl...Will-Bring-Modulators-to-More-People-With-CF/

In this video, which is included in the blog,
https://www.youtube.com/watch?v=q_yBKyvSqE4
one of the patients has DF508 and A445E, and has had a very positive response to Kalydeco!
I realize not everyone with the same mutation will respond similarly, and there are still unknowns, but having an account of someone's personal experience that has this mutation and has responded to Kalydeco is very encouraging.
I know how upset you were when you found out about increased sweat chloride in your son and a few others with this mutation when Kalydeco was started despite its positive in-vitro response. So, I thought of you right away and wanted to share this news.

The CFF blog post is also very encouraging for anyone with a rare mutation that has felt left out of these clinical trials. It's such a promising time in CF research. Hopefully, everyone with CF, no matter how rare your mutations, will soon benefit from these modulators.