Why are Ataluren results considered disappointing?

Question

[In this Q/A two questions were summerized as the given answer was the same, both questions can be read here]

Hello,

I read about the phase-III study on Ataluren as well as the PTC press release on the website of the German CF patient association, and I do not really understand why the results are considered disappointing.

In the group of patients not inhaling antibiotics, the decline in lung function with administration of Ataluren over a one-year period was only at 0.2%, as compared to 7% with placebo. After all, this means that for these patients, their otherwise gradual decline in lung function has come to a standstill (at least for the time of the study). Provided that the patient is not dependent on permanent antibiotics inhalation, this can, after all, make the difference between normal and reduced life expectancy!

Could you tell me why the assessment in the report on the website is so decidedly negative nevertheless? Do you know what the next steps are in the development of Ataluren and in how far the developers are aiming at a quick approval?
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Another questioner asked the following question on the same topic:

Dear expert team,

I would be interested to know what the status quo is concerning the approval of Ataluren.

A report I read said it will not be approved now or ever!!, since the results of the phase-III study did not meet the expectations.

I cannot find anything on the web about this – neither that it will not be approved nor that the results were not sufficient – not even the PTC website provides any information – only concerning Duchenne muscular dystrophy, for which things do not look so bad I believe.

I would also be interested to know whether this drug will then not be approved at all – or whether it will be different in each country and how one can find out about this?

My daughter has the f508del and R1162X mutations.

Many thanks in advance and kind regards.

Answer

Dear questioner,

We received the following answer from Dr. Jutta Bend of the German CF patient organization (author of the report you mention), in which she explains in detail the basic issue of an assessment of the Ataluren study results:

“On the current results of the phase-III Ataluren study (see PTC press release dated June 8, 2012 and research news on www.muko.info [German site])

Many thanks for the thoughtful and good questions about the phase-III Ataluren (= PTC124) study. I will try to contextualize them, which requires going into some detail and highlighting the statistics behind the study.

Study planning: the results of the preceding phase-II study showed a “trend” of improvement in lung function (FEV1) through Ataluren. For this reason, the phase-III study was primarily targeted at showing a “significant difference” in lung function (FEV1).
Result: The results of the phase-III study that were presented did not primarily show a “significant difference” in lung function between the group that took Ataluren and the placebo group. At least, however, a positive “trend” was seen again for Ataluren.

What is the difference between “trend” and “significant difference”? With “significant difference,” the statistician assumes that it is highly unlikely that the result came about simply by chance. Therefore the significance of a study result is the basic prerequisite for the reliability of the data found. A “trend” is a non-significant basic tendency. A significant difference in favour of Ataluren would be the minimum requirement for its approval as a drug.

Next, the manufacturer, PTC Therapeutics, carried out “sub-group analysis” and found that there was a “significant difference” in the change of lung function of patients who chronically inhaled antibiotics (aminoglycosides) compared to those who did not – but it was a sub-group analysis and not the primary goal. In here, only the sub-group of patients not inhaling antibotics chronically showed a significantly lower delcline in lung function compared to placebo.

What is a sub-group analysis?
You have to keep in mind that studies can always only provide a small insight: A small number of patients are examined, and the duration of the study is limited. In order to derive general information from this situation, the number of cases required is calculated at the outset of each study, i.e. the number of patients necessary to show an anticipated effect (here: a difference in lung function). If only parts of the patient group are retroactively used as a reference for the evaluation (sub-group analysis), the case number is usually not sufficient to show a significant difference. There may be a significant result, but one which is “underpowered,” i.e. not meaningful due to the low case number. Therefore, such sub-group analyses can only provide hints as to how future studies can be planned in order to confirm the anticipated effect gathered in the sub-group analysis.

What does “clinical relevance” mean?
A significant difference also does not mean that the effect shown is actually clinically relevant to the patient; that would only be the next step. It is not clear whether the relative difference in lung function, i.e. the decline in lung function by 0.2% after Ataluren compared to a decline by 6.9% in the placebo group (each after 48 weeks), means a noticeable change in the long run. For comparison: For the recently approved Ivacaftor, which is used as a potentiator in patients with the rare G551D mutation, studies have shown an increase in lung function by ca. 10% (after 24 and 48 weeks, respectively).

Overall result: the phase-III study thus only showed a tendency for the effectiveness of Ataluren and, in a sub-group analysis, provided the hint that further studies would have to investigate whether Ataluren is more effective for certain patient groups. Furthermore, phase-III studies are approval studies, i.e. they are targeted at providing the basic data for approval and hence marketability. Overall, one has to say then that the study results do not meet the expectations, since they are not sufficient for the approval of the drug. At least there have to be further studies with Ataluren in order to show a significant therapy effect in a sufficient number of cases. Such studies are expensive and take a long time. In my opinion, it is therefore impossible to make reliable predictions about the approval given the current state of data. To my knowledge, the manufacturer has not provided any information on further steps to be taken, either.

Regardless of all hope we keep putting in new agents that are in clinical development, one also has to keep in mind that generally only a very small fraction of the substances found in the lab actually becomes ready for marketing at some point. The further developed a drug is, the more likely it is to get approval. A phase-III drug such as Ataluren is quite likely to be approved, but there are also examples of drugs that have proven to be ineffective even in such late stages of development.

As a patient organization, we follow the clinical development of drugs for patients with CF, such as Ataluren, very closely. It is important to us to objectively assess, pass on, and contextualize the data published by different sides and out of varying interests. We will certainly keep reporting, as we have in the past, about the progress of the clinical development of Ataluren (“research news”) and are happy to answer any further questions (e-mail welcome; jbend@muko.info).

Kind regards
Dr. Jutta Bend
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Links:
Research news:
muko.info/forschung/news-detail-und-archiv/detailansicht/article/ataluren-erste-ergebnisse-der-phase-3-studie/17.html (in German)

Manufacturer’s press release (PTC Therapeutics): ptct.client.shareholder.com/releasedetail.cfm?ReleaseID=681445
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11.09.2012