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Ataluren Update with

PTC Therapeutics

Compiled by PPMD Senior Director of Research and Advocacy,
Sharon Hesterlee, Ph.D.
March 5, 2010

In response to the press release that went out on March 3, 2010 from PTC Therapeutics regarding the results of the ataluren trials in Duchenne, PPMD thought it essential to put together, immediately, an open conference call for parents and families to have their questions answered by PTC’s senior staff members. On Friday, March 5, 150 people joined this call. PPMD President Pat Furlong and Senior Director of Research and Advocacy Sharon Hesterlee moderated the call.

President and CEO of PTC Therapeutics, Dr. Stuart Peltz, opened the conference call by stating how much he appreciated the opportunity to address everyone on the call.  He explained that he understood the manner by which the results of the phase 2b trial were announced came across as abrupt, but that PTC was required by the Securities and Exchange Commission to release the information within 48 hours of getting the results back itself because their co-development partner Genzyme is a public company.  He explained that they were disappointed about the results, but are not giving up—the company is still combing through huge amounts of data to complete a full analysis and really understand what is going on, with many staff working from 7am to midnight every night. 

In the next part of the call specific questions, representative of those most commonly received in advance of the call, were put to Dr. Peltz by Dr. Sharon Hesterlee, PPMD’s Senior Director of Research and Advocacy.

Question: Why was the trial stopped?  What contributed to that decision? 

Dr. Langdon Miller, Chief Medical Officer for PTC Therapeutics, explained that the unblinded study results did not show any statistical difference between the distance walked in six minutes by the boys on high dose or low dose compared to the boys on placebo.  

[Note added by Sharon:  a trial result that is “statistically significant” typically means that the “p value” is less than or equal to 0.05—this means that there would only be a five percent chance that you could explain the results by sheer chance and a 95 percent chance that the results showed a real effect of the drug.  There are standard mathematical equations to calculate the significance of the data based on the variability of the data and the number of boys who participated in the study]

The data from the higher dose, in particular, was difficult to distinguish from placebo.  Although the company is still examining the results from the boys on the lower dose, at this point they can’t say that there was any benefit from the drug at either dose. 

The decision to stop the trial was made in consultation with an independent group of regulatory consultants.  Dr. Miller did say that the boys were all able to complete the requirements for the six minute walk test (6MWT) very well and there was almost no unusable or missing data from any individual test.  This is important because it helps establish the 6MWT as a useful endpoint in this disease and provides a track record of positive experience with this endpoint at the FDA.  Until recently there was no standardized way for measuring the impact of a drug in DMD that was clinically meaningful by the FDA so PTC had to pioneer the adaptation of the 6MWT for DMD.

[Note added by Sharon: The 6MWT was developed in response to the FDA requirement that the primary outcome of the trial should be “clinically meaningful” to the participant, in other words directly impacting some aspect of daily life.  This means that other types of measurements like the amount of dystrophin produced or a score in a muscle strength test could not be used as the primary outcome because it’s hard to tell how these things directly impact daily life.  Now, if you could correlate the amount of dystrophin produced with a predictable increase in the ability to walk or some other daily function, then it might be possible to use dystrophin production as “surrogate marker” for that clinically meaningful endpoint at least at earlier phases of a drug study.  Even so, for a phase 3 study or any study whose data will be used to try to get final approval to market the drug the FDA still requires a clinically meaningful endpoint]

Dr. Peltz added that this points out to the challenges of drug development in DMD.  There was no history of regulatory directed trials, no endpoints validated, and no long term current natural history, so it was difficult to choose outcomes that would be accepted by the regulatory agencies.   This issue of endpoints is important for Ataluren and for all other drugs that come through the pipeline.  Everyone will have to address the question of how to understand and evaluate endpoints.    As disappointed as the community may be, we are analyzing the data to understand if there is a more sensitive measure.

Question: Is 6MWT a reliable measure?  How do you know?  Can you use it to measure slower progression or a plateau in function? 

Dr. Miller responded that obviously they’d like to see an improvement but would also look for a decline in progression.  Dr. Peltz pointed out that they were comparing the results of each boy compared to the placebo group; not looking for an absolute improvement over a boy’s beginning score.  So a boy who declined more slowly than the placebo group would be considered to have “improved.”

[Note added by Sharon:  The 6MWT was tested in a small separate study before the trial started to see if it could reliably detect the decline in function you would expect to see in most boys over the trial period.  The company looked at the variability of the data and determined that it was low enough for the test to be useful, although the youngest children did tend to improve somewhat on the test before showing a decline.  The company will analyze the data sorted by different age groups to see if removing the youngest children’s data makes a difference.]

Question: What were secondary endpoints and were any positive?

[Note added by Sharon:  “Secondary endpoints” are things that are measured as part of a clinical study because they are of interest, but the success or failure of the study does not typically hinge upon the outcome of these secondary measurements.]

Dr. Miller responded that there were over 30 different other endpoints with many variables in the study [a “variable” is a source of difference such as whether or not a boy is on steroids or how old he is or how well he could walk when he started the study)  in the study and the statistical analysis was very complicated.  He also indicated that this analysis is still ongoing.

Question: Has the level of dystrophin been analyzed?  How much dystrophin do you need to make to see a response?

Dr. Miller explained that it’s not known how much dystrophin will be required to show benefit.  The biopsies are still being quantified and the amount of dystrophin produced has not been analyzed yet.  They are working with their academic partners to do this analysis, which is very complex and time-consuming and likely to take weeks. 

Question: Will people ever get to see their sons’ biopsy results?

Dr. Miller said they haven’t gotten that far yet.  The treatment assignment is available from the site investigator. When technical issues have been worked out, the company should be able determine if and how the information will be provided.

Question:  If the amount of dystrophin produced has not yet been determined, why stop the trial?

Dr. Miller responded that the primary outcome, the 6MWT did not show that there was any benefit.

[Noted added by Sharon:  So, it will be very interesting to learn how much, if any dystrophin was produced by boys in different arms of the trial, but keep in mind that even if significant amounts of dystrophin were produced the fact that the drug didn’t provide a clinical benefit is still the main issue.  There are rare boys out there who make near normal levels of dystrophin but still have Duchenne—typically because their particular mutations render the protein that is produced nonfunctional.  So you can’t just go by the amount of dystrophin made—you really have to link that with a specific clinical benefit even though the amount of dystrophin made usually does correlate to some extent with the severity of the disease]

Question: Future plans---why are studies stopped instead of being modified?  Will there be more studies in the future?  Is the program for Ataluren in DMD completely finished?  Any second generation compounds planned?

Dr. Miller responded that the evidence in hand suggested the dose might make a difference in the response to the drug and that they were still trying to regroup and figure out what to do next, something that would be done in consultation with regulatory authorities. 

[Note added by Sharon:  The phase 2a and 2b extension studies and the nonambulatory study were all designed to use the higher dose, the one that definitely showed no benefit compared to placebo in the phase 2b study]

Dr. Peltz pointed out that, although they were hugely disappointed in this result, the company is committed to combing through all of the data to see if there is a path forward.  This will take time, he said, but the commitment is unwavering.  It’s not as if they got these results back and are done with it, he said.  He also stated that PTC has back-up molecules for Ataluren and the work to test Ataluren in other disease areas continues.

Question:  If an individual participant who was on drug seems to have responded, is there any way to get compassionate access?

Dr. Miller responded that the company had provided the unblinded treatment assignments to all the study site doctors [in other words, the information about whether each child was on low dose, high dose or placebo] and suggested that families consult with their study site doctor about these results in the context of how the child performed on the 6MWT.  As for compassionate use, he stated that it’s imperative that the company establish a regulatory path forward based on the implications of the data.  The company will focus on whether or not there is a way to determine if the drug is beneficial in the context of a clinical trial.

Question:  If there was a suggestion that the low dose might work better, why not just lower the dose and allow everyone currently participating in the study to continue on medication?

Dr. Leone Atkinson,  MD, Ph.D., PTC’s Senior Medical Director , responded saying  they would have to formally change the clinical protocol, reconsent everyone in the trial and get each study site’s Institutional Review Board to approve the protocol changes, which would likely take months.  In addition to these hurdles, the data you would obtain would be so confounded it would not be useable.

[Note added by Sharon:  Confounding data: In this scenario the boys would be off drug for several months while the protocol changes and IRB approvals were being engineered and then would all go back on the lower dose so that some boys would have experienced low dose, high dose and then low dose again and others high dose and then low dose and still others placebo, high dose, and low dose all with a gap of several months between the final two doses. There would be other issues as well concerning how many doses of the high dose each individual boy received before he was moved to the low dose since the boys enroll at different times.]

Question: Is it ok to stop taking the drug abruptly? Should people wean their sons off the drug? 

Dr. Miller responded that there does not seem to be any inherent harm in stopping the use of the drug. But people should consult with their physicians if they have concerns.

Question: What is the status of the Ataluren studies in CF and hemophilia?  Are they affected by this outcome in Duchenne?

Dr. Peltz responded that these programs are ongoing.  Ataluren is a mechanism-based drug that allows read through of premature stop codons.  The CF trial is ongoing and hemophilia is moving forward. It’s the job of the drug developer to find out where drug works best and in what indications.  He further elaborated that all of these diseases are very different and deserve to be studied in their own right.

Question: Is there any post-trial follow up for participants?

Dr. Miller said that the company encourages patients and families to seek advice from the study site investigators and from physicians about whether to continue to monitor their son’s progress from a medical standpoint.   At this time a follow up is not planned.  Dr. Peltz added that they would have a constant dialogue with people.   Dr. Miller said that he would not discourage site investigators from continuing to follow the boys with the 6MWT now that they are off drug.

Question:  Did any of the boys show a plateau or a slowing of progression?

Dr. Miller responded that factors like age, steroid use, and how well a boy was walking when he started the trial, and even  a boy’s height and weight make up a complex interplay that makes it difficult to define exactly whether an individual boy was benefiting or not from Ataluren.  This means that PTC has to look at the boys as groups, not as individuals, because the statistics won’t support drawing any conclusions from the results of a single boy.

Question: When can the community expect an update?

Dr.  Peltz explained that the analysis will be ongoing for some time and that the company will bring investigators and experts to help them map out a plan to take to the regulatory authorities.   This will be a multi-month process, but that the best thing they can do is to keep the community informed as to where they are in that the process.  PPMD will be able to provide these updates. At appropriate time, the company will get back on the phone to have another conversation.

Question:  Have you analyzed the responses for different type of premature stops?

Dr. Peltz answered that the planned sub analyses will allow them to determine if there were responders and non responders in these groups.   The company will analyze not just the different types of stops but many other variables such as age, baseline walking ability and steroids.


While we were not able to have all of your questions addressed on the call, we were assured by PTC that they would respond to any questions that were sent to them, in a timely manner. We have forwarded and will continue to forward your questions to PTC as they come in and we will share the answers PTC provides if they are beneficial to the community. Your questions can be submitted to

We appreciate PTC’s participation on last Friday’s call. It is extremely rare for a pharmaceutical company to make itself accessible to the community it is working with, and we thank PTC for answering the questions that they could.  As you read above and as you will continue to hear, the data from these trials is substantial and it will take time to properly analyze the results before making decisions about next steps. However, PPMD will continue to advocate for you, pushing PTC and any other companies working in the Duchenne field to find us all answers quickly, efficiently, safely. We are here for you and your families and we are as confident as ever that as a community – a community made up of parents, grandparents, children, researchers, physicians, care givers, dedicated organizations, and Industry – we will end Duchenne.



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