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GenH
06-11-2012, 11:09 AM
<span class="commentBody" data-jsid="text"><span class="messageBody" data-ft="{"type":3}">Someone in the Kalydeco for Australians facebook group asked me to summarise the Ataluren press release and I thought I would paste it here as well: (sorry it is quite long, but it discusses a few things that have not been mentioned on the forums such as statistical significance and absolute v relative improvement): Treatment group went down 2.5% over the 48 weeks (relative change). Placebo group went down 5.5% (relative change), hence there is a 3% FEV1 difference (relative change) between the two groups from baseline to week 48. This was not statistically significant. Patients who were not on long term inhaled antibiotics went down 0.2% over the 48 weeks, compared to placebo who went down 6.9%, hence a 6.7% difference for those on Ataluren. This was statistically significant. All % change were relative. There was also a positive trend with those who were on Ataluren having less pulmonary exacerbations (23%), but this was not statistically significant. Those who were on Ataluren but did not have inhaled antibiotics were 43% less likely to have a pulmonary exacerbation (statistically significant). The study did not show a change in sweat chloride between Ataluren and placebo. Overall this means that Ataluren appears to have a greater effect when the patient is not on inhaled antibiotics. The effect also seems to be mainly slowing the decline/being more stable, rather than increasing the FEV1 and then being more stable (like the Kalydeco results). This is still positive, it means they may be more stable long term as their lung function hopefully will not decrease as quickly. Statistical Significance: If you are wondering about the statistical significance, normally the p value needs to be less than 0.05 (or 0.01, depends what the company decides), which means there is less than a 5% chance of the result being due to chance as opposed to the treatment. The lower the number the better, so the 3% lung function difference at p=0.124 means there is a 12.4% chance it was due to chance. I would imagine that when it comes to getting approval from the FDA it would be easier to get through if there is statistical significance, to prove it makes a difference. I think this is why they have looked at all patients over all post baseline visits, 2.5% relative difference p=0.0478, which is statistically significant if they set p=0.05 (not mentioned in the article). There is statistical significance with the people who were not on inhaled antibiotics, so it will be interesting to see what happens. The FDA and EMA have granted Ataluren orphan drug status. This does not mean that they have applied yet, it just means it is easier for PTC when they do apply (cost etc). It also does not specifically say that Ataluren for CF has been fast tracked, it says it was fast tracked for another condition. Ataluren Background: Ataluren helps CF patients who have a class 1 nonsense mutation (ends in X). The &lsquo;X&rsquo; just means a stop codon. Ataluren overcomes this stop codon by allowing the production of the full protein (allows the ribosome to continue translation instead of stopping). One more point: The study used relative % change instead of absolute %. This means the overall 3% improvement compared to placebo could actually be closer to 1.5-2% absolute improvement (it depends on the starting FEV1, if it was 50% then it would be 1.5%). Example: Absolute improvement- a 5% increase means I increase from 50 to 55%. Relative improvement means that my 5% increase from 50 to 55 is a 10% increase from my starting 50% (5/50 * 100), so they call that a 10% relative improvement. CF people generally refer to absolute improvement, so that number is more meaningful to us, if the starting FEV1% was 50-100 it means the overall improvement is 1.5-3% (and 3.4-6.7% in the group without the antibiotics). Finally, hopefully further studies may look at Ataluren and Kalydeco together (depending on safety) and also look at other class 1 mutations (splicing mutations that result in a stop codon, not sure if they have looked at this in the lab yet, or if they think it will work for these patients). Kalydeco could theoretically help the CFTR that does make it to the surface and if trafficking is not occuring well (ie if less than 100% of the full length protein makes it to the surface), could molecules like VX809/661 help it get to the surface? I have not heard if trafficking is an issue after Ataluren helps the protein to be produced, so it is just my speculation that a molecule may help if this is an issue! Hopefully these results mean that the CF community will get access to Ataluren in the near future, and then later on other medications may help Ataluren to work better (and we may see more of a difference with FEV1 and sweat chloride).

Mommafirst
06-11-2012, 09:07 PM
Thanks for the explanation. I'm pretty familiar with the stats part, but the relative vs. absolute change was new to me and I appreciate the clarification.

So this med may be able to slow progression, but doesn't seem to be reversing it. Not really a cure. . . but I wonder what the ataluren and kalydeco together might turn up. HOpefully there will be a synergistic effect that will help more people.

missT
06-12-2012, 03:02 PM
I heard that it worked better on some mutations then others. does anyone know which?

anien2
06-12-2012, 06:59 PM
How can ataluren work at all if there is no significant change in the sweat chloride levels?? I mean, if after taking ataluren there is the same amount of salt in the sweat that means that the body isnt taking any of it to be used, right? doesnt it mean that the CFTR function is not being accomplished?? in my opinion it looks quite disappointing.

missT
06-12-2012, 11:14 PM
yes, great question Anien. I have asked my Dr about sweat levels and they told me that "just because a level goes down it doesnt mean your body is working normal". what EXACTELY is the significance of the sweat test?

GenH
06-13-2012, 01:28 AM
During the May 29 Vertex press conference Vertex were saying that the CFTR protein may be different in the skin to the lung which could explain the lack of sweat chloride decrease during the VX809/Kalydeco trial. At this stage no one asked why a sweat chloride decrease was seen with G551D & Kalydeco then- thats what I would have asked if I could have!

A sweat chloride decrease shows the medication is working throughout your body, but there is no direct proof that this translates into a clinical benefit. This is all very new research so I think they are still trying to work out how important changing the sweat chloride is. Just because there is not a significant change in sweat chloride does not mean it isn't working in the lungs. The improvements in the lungs are shown through FEV1, and hopefully long term studies will show a slower rate of decline/best case scenario being stable.

During the conference in Europe last week PTC said there were no results about specific mutations doing well/not so well yet.

anien2
06-13-2012, 09:51 AM
<div class="FTQUOTE"><begin quote><i>Originally posted by: <b>missT</b></i> yes, great question Anien. I have asked my Dr about sweat levels and they told me that "just because a level goes down it doesnt mean your body is working normal". what EXACTELY is the significance of the sweat test?</end quote>

What your doctor said is exactly the opposite. Salt level can go down just because you are not taking it, but if you take a medication that is suposed to process "salt" (ok, its not salt, its only Cl, but anyways) and your salt levels anywhere in your body stay the same... It just looks like the body simply isnt processing it, right?? even if the medication only works in the lungs it should drop down salt levels all around the body, shouldnt it??? in the same way that if a diabetic takes insuline the sugar levels go down in blood, orine, and any other part of the body.

I dont want to look negative, I really wish ataluren worked, but it just doesnt seem to be working.

MargaritaChic
06-13-2012, 10:09 PM
I disagree. There are several CF drugs available that slow progression. I really doubt they all decrease sweat chloride. I don't think sweat chloride is the only predictor of whether the drug works or not.

ldy
06-13-2012, 11:06 PM
I think that none of us can determine whether it will slow progression based on the information they provided in their press release. It's some of what they did not mention that bothers me the most. There was no mention of kidney issues (while not hospitalized). There was no mention that not all participants were on the dose listed in the release. There were participants that were placed on half dose (5, 5, 10 mg per kg) due to kidney issues of high BUN and creatinine levels. If not all participants were on the same dose, how can you release information with the assumption that everyone was on the same dose (mg per kg)?

anien2
06-14-2012, 09:20 AM
<div class="FTQUOTE"><begin quote><i>Originally posted by: <b>MargaritaChic</b></i> I disagree. There are several CF drugs available that slow progression. I really doubt they all decrease sweat chloride. I don't think sweat chloride is the only predictor of whether the drug works or not.</end quote>

Of course there are many drugs that slow progression without any sweat chloride change, PT slows progression on lungs damage and dont change sweat chloride levels at all. But if a drug is supossed to activate CFTR function it does have to change chloride levels all over the body, simply because somewhere in the body (in this case the lungs) that chloride is being spent, so there is less chloride left for sweat.

What I say is that if sweat chloride levels stay the same there is no CFTR function going on.

Ataluren wasnt desingned to slow down the damage on lungs, but to activate CFTR function.

The good news is that if PTC has decided to keep on spending money on a phase III extension it means that they think they can fix whatever goes wrong.

ldy
06-14-2012, 05:14 PM
"Ataluren wasnt desingned to slow down the damage on lungs, but to activate CFTR function."
You are exactly on mark!It was thought that it would "correct the defect in X mutations"
Patients on the trial have made comments about recent changesto the trial with regards to what inhaled medications are being used.
Also, it is well documented that "it is <strong>not</strong> equally effective with every stop codon, working best on the sequence 'UGA'." I do not know which stop mutations fall into that group. There are two other classifications of stop codons.

CyrilCrodius
06-27-2012, 06:03 PM
<div class="FTQUOTE"><begin quote><i>Originally posted by: <b>ldy</b></i> "Ataluren wasnt desingned to slow down the damage on lungs, but to activate CFTR function." You are exactly on mark!It was thought that it would "correct the defect in X mutations" Patients on the trial have made comments about recent changesto the trial with regards to what inhaled medications are being used. Also, it is well documented that "it is <b>not</b> equally effective with every stop codon, working best on the sequence 'UGA'." I do not know which stop mutations fall into that group. There are two other classifications of stop codons.</end quote>
621+1G&gt;T falls into that category!I find it really interesting that it was less effective on people who also had Tobi. I wonder why it is so.

Johny81Johny
10-26-2012, 08:29 AM
<div class="FTQUOTE"><i>Originally posted by: <b>ldy</b></i> "Ataluren wasnt desingned to slow down the damage on lungs, but to activate CFTR function." You are exactly on mark!It was thought that it would "correct the defect in X mutations" Patients on the trial have made comments about recent changesto the trial with regards to what inhaled medications are being used. Also, it is well documented that "it is <b>not</b> equally effective with every stop codon, working best on the sequence 'UGA'." I do not know which stop mutations fall into that group. There are two other classifications of stop codons.
621+1G&gt;T falls into that category!I find it really interesting that it was less effective on people who also had Tobi. <begin quote>I wonder why it is so.</end quote>

Years ago, there were trials with Gentamicin and X mutations, Genta was somehow interacting with X mutations and stop codons...and TOBI and Genta are both in same class of antibiotics = aminoglycosides... so perhaps TOBI is interacting also - in disturbing way...

GenH
10-28-2012, 08:38 AM
Yes I believe it has been mentioned at the conferences that Ataluren and TOBI interact in the same way to allow read through past the stop codon. I've also heard they might bind at the same spot (therefore decreasing the effect of Ataluren if the TOBI is already doing the same thing).