The Story of Ataluren, or in simple terms:   Looking beyond the p-value

I recently participated in a “DAY OF DIALOGUE, ” in an effort to explore the development of ataluren, the story of the science of post transcription , or the possibility and probability of interfering with mRNA in order to affect the course of a disease.   Thankfully, they started with Duchenne.


Founded in 1998, PTC  has focused on developing  ataluren as well as other molecules for Duchenne (Project Catalyst), SMA, and other neuromuscular disorders. PTC is a pioneer, developing the path forward for DMD.   PTC will soon file the NDA on ataluren.  There has never been any such filing in DMD.   It is a new day.


Dr. Richard Klausner was part of venture group that invested in PTC Therapeutics.  Dr. Klausner invested in PTC because he thought PTC’s technology would be transformative for health.  He struggles with the term “personalized medicine” because he believes the concept is bigger than a bumper sticker; it is a way of describing the fundamental driver of science-based medicine; a manifestation of the process by which we rethink the definition of what is a disease or illness and design interventions directed toward that cause.  It’s really the end goal of doing science well.  The name we give things shapes the way we think about things.  But, he cautioned, “It is easier to imagine the future than to get there—it’s really, really hard.”


Dr. Klausner talked about the statistics of clinical trials and the impossible task of hanging success or failure on a single (primary) outcome measure, especially in progressive, debilitating conditions such as Duchenne.  He suggested the issue of how we think about whether something works needs to move to the science of overall evidence and not the ‘religion’ of p-values.


In the development of clinical trials, a hypothesis is made on the outset, the protocol developed, and the statistical methodology for analysis of the data determined.  It took ten years for ataluren to reach the pivotal study.  As ataluren moved into the pivotal trial, it was breaking new ground in Duchenne.  PTC focused on Duchenne, recognizing the journey would be difficult.  At that time there was no natural history data, no standardized care, no consistent steroid dose, no validated outcome measures, no standardized procedures for quantifying dystrophin and none sensitive enough to measure exact concentrations below 15% in the context of multicenter trial.  And thankfully, they stayed the course.


If the Duchenne community was ever to have treatments, someone had to lead – and PTC did just that.  Their hypothesis was that the mean change would be 30 meters longer in at least one of the treatment arms for ataluren.  The trial was stratified for age, steroid use, and current walking ability.  There was a very high completion rate with only one boy discontinuing the study.  The compliance was 97%, reflecting dedicated participants and study staff.  The safety profile was similar to placebo, with no discontinuations due to adverse events (AEs) and so serious adverse events (SAEs) considered related to the treatment.


Today, PTC has opened an access program in the United States.  This access program is open to all boys/young men who participated in an ataluren study in the US.  Currently, ten sites are activated and more than 50 patients enrolled right now.  PTC expects the number should double as last sites come online.


But what makes the story real is the families.  What was their experience, what did they see, what did they learn.  In their view – Did ataluren have an effect on their son?


Two of the moms whose sons participated in the original Phase 2a trial and, later, its extension, discussed their experiences.   Both described how Duchenne affects every part of life and everyone around you.  They talked about lost jobs, refocused careers.  One mom referred to Duchenne as “similar to throwing Miracle-Gro on all of your character defects.”  Both talked about the ripple effect throughout the family, the extended family, the essential requirement to educate people around you all day long, and the stresses of marriage (many ending in divorce).  They talked about the financial implications, changing jobs or leaving jobs in order to provide care, pay for necessities.  Both talked about planning, planning for everything, making sure things were accessible, making sure of necessary accommodation, a 24/7 job that has to be done.  The Duchenne version of a normal life.


The moms were asked to talk about the trial.  Both commented on gait, one mom suggesting that her son’s posture was entirely different, that he started alternating feet on stairs for the first time and became more verbal, more energetic.  She noticed that when the 2a trial ended, there was a dramatic increase in her son’s emotional difficulties.  The second time on ataluren (in the 2a extension), she again saw dramatic changes, again noticed posture changes within three weeks and commented that he looked taller and was less tired, more talkative, and had an improved attention span.  She relayed a funny story about ‘losing’ him one day while playing with friends.  Typically he is a cautious child, unlikely to follow others, but she found him standing on top of a small hill surrounded by other kids.  Who would ever think, losing your son might make you smile?  The trial was then suspended and he went from a 6-second Gower to not being able to get off the floor by himself.  Now in the access program, he has regained the ability to get up by himself with an 8-second Gower about 75% of the time.  Family, friends, and teachers comment on the changes and the behavior differences at home are obvious.


The other mom talked about the process of getting into the car, how one day her son was able to open the car door and then climb in himself for the very first time.   It was such a surprise when she found him in the car that she made him repeat opening the car door, getting in, and closing the door, just to prove that he was able to do it on his own.  With tears in her eyes, she talked about the suspension, the loss of ataluren.  She described simple things in human terms, but big things in Duchenne terms: the loss of balance and not trying stairs; being emotional and paranoid; and the fact that now he can no longer hold his arm up for pledge of allegiance and couldn’t reach for snacks.  Three months after, he fell and fractured his hip.  He was no longer able to hold his pencil the whole day.  She is anxious for her son to participate in the access program. 


It’s the stories, not the p-value.


Here’s the thing.  In the discovery phase, it can take 2-10 years to identify a druggable target.  The whole discovery/development process timeline averages about 16 years from the beginning to end.  The problems in rare conditions are significant –no natural history, few validated endpoints, lack of standards of care, and small numbers.  Even without these risk factors, drug development is risky.   There are 7,000 rare diseases that collectively affect 30 million Americans.  There are special challenges for reviewers and academic challengers.  They include:


1.  Heterogeneity of disease onset and progression (genotype and phenotype not well-correlated)

2.  Limited data on outcome measures over time with applying six-minute walk test (6MWT) in Duchenne and Becker.

3.  Extremely small subset of disease that is already rare

This is really tough stuff. PTC tried to balance groups to address variability.  They had to show that results are able to be generalized across multiple sites in multiple countries.  The trends in the aggregate data are extremely consistent.  The preclinical data supports the low dose rather than the high dose.  The trends are consistent in every subgroup with and without steroids. Some of the secondary endpoints were shown to be inconclusive and/or unfeasible while others, such as timed function tests and the rate of accidental falling are supportive of the results in the 6MWT.  The trends in the aggregate data are extremely consistent.


The FDA regulates $.25 of every consumer dollar spent.  And soon reviewers will be considering the “story of ataluren.”   They want to get it right and we want them to get this right.  We are all hopeful ataluren will become the poster child – the Duchenne community’s first born – and the FDA will have to decide whether all of the evidence adds up to a benefit/risk profile that makes sense.  And (cross fingers and pray) when ataluren is approved, it will be the first for Duchenne, a sign of change, and a path to a future for all of our sons.

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Comment by Ofelia Marin on April 6, 2011 at 3:40pm
One question, very curious about this. If preclinical data supported the LOW dose rather than the high dose, why have they designed the trial such as all the boys were given the high dose after the trial ended?
Comment by Sharon Hesterlee on April 6, 2011 at 2:21pm
(Pat is in China)
Comment by Sharon Hesterlee on April 6, 2011 at 2:20pm
Hi Michelle:  the boys discussed at the meeting were 11 and 13. 
Comment by Michelle on April 6, 2011 at 10:39am

For those unfamiliar with the terminology of NDA:


For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization.  The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S.  The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND)1 become part of the NDA.

The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decisions:

  • Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.
  • Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.
  • Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.

The documentation required in an NDA is supposed to tell the drug's whole story, including what happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged. 

Comment by Michelle Scaglione on April 5, 2011 at 3:51pm

Dear Pat

How old were the boys you are writing about?


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