Question about F1052V and Drugs on the Pipeline

[Justinsmama]

Hi,

My son has F1052V and (the doctors agree) a duplication/deleation mutation that he has not been tested for yet (they did not test for these in his sequencing). My question is, does anyone know which group of mutations (F1052V) would fall under for the new drugs coming on the pipeline? I was under the impression that we would have to wait until they target F1052V (because the deleation/duplication will be even more rare) but was told by a wondeful retired CF doctor that he might fall into one of the groups that will have treatments? Does anyone have any idea?

Thank you!!

PS: I posted this question under another area, was not sure where it should go.

 

[SoyaSauce]

I haven't really heard much about drugs for the really very rare mutation like your son's, but drugs for class 3-4, and nonsense sets of mutations like my weird one "17-17->1A-G " which makes NOTHING/ not even a protein. There is one drug called 'ATALAUREN' that seems very promising on these mutations. It acts on the code protein to tell the code to finish the protein making process instead of stopping halfway, but that's for a Splice/Nonsense mutation only they think.

LUMACRAFTER is going to be for F508del and double F508, which both proteins are trashed in the cell process, but LUMACRAFTOR helps make the protein and IVACRAFTER get the protein up to the surface. I am not %100 sure on all that and what I said, but something like that.....Also, with some good luck, since those are rarer /exotic mutation, his symptoms of CF may not be as 'bad' . But again, everyone is different.

 

[kyeev]

View attachment 287
F1052V is on the far right of the graph.
As you can see, kalydeco (ivacaftor) has a large effect.
With the mutation being so mild, it already generates near normal chloride secretion.
(these results were generated in vitro, so not patient data - therefore might not work as well in patient etc.)

 

[Justinsmama]

Kyeev,

Thank you so much!! If his mutation is so mild, why is he completely pancreatic insufficient and showing small airway issues at 8 years old? Does this mean that the second mutation may be more severe or that together they are more strong? If so, would fixing the F1052V with Kalydeco negate the problems? Thanks for any thoughts.

 

[amykay1965]

So I have never seen this chart. Very interesting. My daughter has Delta F508 & v520F. From looking at the chart, it doesn't look like Kalydeco will help her. Is that correct?

 

[kyeev]

@Justinsmama: You could expect Kalydeco to certainly help your sons symptoms looking at that increase in chloride secretion. The only way to know for sure, is start taking kalydeco I guess.

@amykay1965: These in vitro results only reflect kalydeco monotherapy. And we know from the phase II patient trials of VX661+kalydeco and VX809+kalydeco, that you only get good effects for df508 if you use both drugs i.e. kalydeco on its own is no good for DF508 (very little of DF508 makes it to the cell membrane surface without VX661 or VX809)
Have a look at genH's post on the VX661 results which showed DF508 homozygotes got a nice 9% FEV1 boost with dual therapy. You would have to hope DF508 heterozygotes are going to get some FEV1 boost.

There's hardly any data on V520F. Believe me, I've looked cos I'm DF508/V520F too. Its class III, but I can't tell you a) if it makes it to the cell membrane surface with VX661/VX809 or b) if it did make it to the cell membrane surface, whether kalydeco would have any effect.

 

[GenH]

Kyeev,

Thank you so much!! If his mutation is so mild, why is he completely pancreatic insufficient and showing small airway issues at 8 years old? Does this mean that the second mutation may be more severe or that together they are more strong? If so, would fixing the F1052V with Kalydeco negate the problems? Thanks for any thoughts.

Some people can have 'mild' genes but still have severe symptoms due to other factors. Yes the other gene could be more severe, the F1052V could be with 5T (means less protein is made) or other genes/other factors could be involved. Based on the in vitro Kalydeco data, F1052V changes from about 70% of normal CFTR function to about 170% (carrier is about 90% and normal is 100%). Kyeev is right that it is likely that Kalydeco would help his symptoms, but its hard to say what type of difference without trying Kalydeco. What was his sweat test at diagnosis?

 

[GenH]

Have a look at genH's post on the VX661 results which showed DF508 homozygotes got a nice 9% FEV1 boost with dual therapy. You would have to hope DF508 heterozygotes are going to get some FEV1 boost.

There's hardly any data on V520F. Believe me, I've looked cos I'm DF508/V520F too. Its class III, but I can't tell you a) if it makes it to the cell membrane surface with VX661/VX809 or b) if it did make it to the cell membrane surface, whether kalydeco would have any effect.

Just wanted to add that yes its a 9% relative change, but most CFs think about absolute improvement and both VX809 and VX661 so far have had 4-5% absolute improvements. This hopefully will become larger with better combinations of meds & the second generation correctors.

In terms of V520F- last time I researched this I could not conclusively find anything that said what class it is? Given the in vitro Kalydeco data, it is unlikely to be at the cell surface (unless its at the surface and kalydeco cannot help it), which would make class 3 unlikely. CFTR2 suggests it does not mature normally, which would be class 2, along with a conductance defect.

Have you seen the study that looked at whether VX809 could help other class 2 processing mutations? Your mutation was not tested but its possible that if there is a processing defect, that one of the correctors may help (along with a potentiator to help with any conductance issues): http://sixtyfiverosesblog.wordpress...p-other-processing-mutations-besides-f508del/

 

[Justinsmama]

Hi,

Justin passed the sweat test with flying colors. His numbers I think were around 19. I was told that this mutation gives a false negative. We were told that we could do nasal testing at Hopkins (where he is a patient) but that they were convinced that he has CF so it would only be to assure us. We didn't want to put him through any more. His fecal elastase was 25 when last tested (stopped because they can not detect anything lower) and his BMI was below 3% when he went on enzymes and gained 10 pounds or so in less than a year (7 to 8 years old). He had 4 pneumonias in a few months last year and mucus plugs. He has culted staph, h. influ, strep. His 25/75 runs around 60 - 80%, with the 75 running down to the 50's. He has been on oral steroids twice in a little more than a year and is now on Symbicort along with xopenex, saline, vest and others. I am sure he is not severe for an 8 year old, but we do not want him to suffer at all. He is such a trooper that it hurts to see him have to stop running to catch his breath. He also gets some broncho spasms with exercise.

Thank you for your thoughts.

 

[kyeev]

Just wanted to add that yes its a 9% relative change, but most CFs think about absolute improvement and both VX809 and VX661 so far have had 4-5% absolute improvements. This hopefully will become larger with better combinations of meds & the second generation correctors.

In terms of V520F- last time I researched this I could not conclusively find anything that said what class it is? Given the in vitro Kalydeco data, it is unlikely to be at the cell surface (unless its at the surface and kalydeco cannot help it), which would make class 3 unlikely. CFTR2 suggests it does not mature normally, which would be class 2, along with a conductance defect.

Have you seen the study that looked at whether VX809 could help other class 2 processing mutations? Your mutation was not tested but its possible that if there is a processing defect, that one of the correctors may help (along with a potentiator to help with any conductance issues): http://sixtyfiverosesblog.wordpress...p-other-processing-mutations-besides-f508del/

V520F is consistently listed as class III in reviews.
However, there is no published protein work so nobody can say for sure.

I'm hoping it doesn't make it to the surface by itself, cos that V520F chloride conductance was pathetic...