ATALUREN - confused about the information given from PTC Therapeutics and Genzyme

 

Hi Sharon and Pat

or anyone else who can help

 

Can someone PLEASE help me understand the information given from PTC Therapeutics and Genzyme, regards to Ataluren. Our son can use Ataluren, and he is about to stop walking. He didn’t participate in the
previous clinical trials, because the enrollment was closed before our son
could enter the trial. I know there are many other boys ”out there” in the same
position.

I am asking for several other parents coming from Norway,but also parents coming from other contries.

 

First we had this article from the Annual Meeting of the American Academy of Neurology, published

April 13th. This article didn’t say anything that this is going to be a follow-on clinical study of Ataluren, so I thought ohhhhh finally Ataluren will be on the market in the USA (if approved by the FDA):

 

 

AAN 2011: Ataluren Reduces Decline in Ambulation in Duchenne Muscular Dystrophy

Based on these results, PTC Therapeutics, the company that developed ataluren, is planning to seek approval for its use in DMD from the United States Food and Drug Administration. Because of
the mechanism by which the drug overcomes the effects of the mutation, it would
be appropriate for only about 13% of DMD patients, according to study presenter
Ted Abresch, Research Associate in Neuromuscular Disease at the University of
California at Davis.

 

The whole article published April 13th 2011

http://www.hcplive.com/conferences/aan_2011/Ataluren-Reduces-Declin...

 

Then today, this article was publised by Genzyme. They are talking about a follow-on open label clinical study for previous trial participants, in Europe.

 

Ataluren update from Genzyme

Follow-on open label clinical study announced for previous trial participants

As part of our continuing assessment, Genzyme plans to initiate a follow-on clinical study of ataluren in nmDBMD patients who previously participated in the clinical trials in Europe, Israel and Australia.
All patients who have previously participated in the clinical trials with
ataluren in nmDBMD, irrespective of their current clinical status, will be
eligible to participate.

We believe that this clinical study will allow for the collection of additional information on ataluren in nmDBMD while providing access to ataluren to all patients who have been involved in earlier clinical trials.
Currently we are working to develop the timelines and design for this clinical
study and we plan to update the community, with these additional details in the
very near future. We are reaching out to the original trial investigators to
make them aware of this new development and they may be in touch with eligible
families directly as well.

The whole article posted May 2nd 2011: http://www.actionduchenne.org/viewarticle?news=175

 

When/if Ataluren is approved by the FDA in the USA, is this an approval for all Stop-codon-boys in the USA ? Also those who didn’t participate in the previous clinical trials ?

When/if Ataluren is approvad by the European regulatory authorities, is this an approval for all Stop-codon-boys in Europe, also those who didn’t participate in the previous clinical trials ?

 

Can someone please help.

 

BeritSofie

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i very much agree with u ofelia. so frustrating. Yes we all are aware of the safety issues involved but unfortunately with this illness our boys do not have the luxury of "the waiting game".We are all raising money for the same end, research and clinical trials. But we need to change the game plan in relation to time scales for approval. The fda and ema in europe need to think outside the box. This is the nature of the illness we are dealing with.  I do not hope that all the effort we are all putting in for our children will have retained the status quo in another five years! Time for change in regulatory mindsets.

I think this is exactly why the meetings with the FDA are necessary.

They have a group of boys that can be measured against the performance of ataluren boys with no ethical concerns - everyone who doesn't have a stop codon.


Why can't we persuade the FDA to do a long-term study measuring boys on ataluren against boys with other mutations. The burden on this untreated arm wouldn't be too high - just the same physical testing they do at most check-ups, plus a 6 minute walk.

 

For a drug that appears safe, I cannot for the life of me understand why they need to accept the collateral damage of a placebo arm when they can compare against an untreated group. Yes, it will not be double-blind, but it doesn't involve the tolerance for the sacrifice of any boys who could potentially be helped.

 

Why are they OK with not doing everything they can to potentially help this generation of boys?

 

If one of our kids was on the second floor of a burning building, and the fire department had a ladder that was sturdy, but might not reach all the way to the window, would you want them to try and use it, or should they just watch the kid burn, citing ladder height regulations?

Pat - why does ataluren not meet the criteria for accelerated approval? it seems to more than meet them, since we're talking about actual clinical benefit rather than surrogate measures.

 

It is just not enough improvement? Some improvement, but not enough?

 

Thanks.

The process of drug development is difficult, labor intense and expensive.    We do not want the rules relaxed actually.  We do need SAFE and EFFECTIVE medicines.  We are in need of perhaps a greater degree of flexibility on the part of FDA, to understand that indeed Duchenne is 'tricky', that a specific drug or biologic may have different effects on different sub populations of patients.   We have learned a great deal from the ataluren study that PTC has thankfully and graciously shared with industry.   

We cannot pitch 'our boys are dying now' as they actually are not dying 'now'.  Clearly they have a progressive, debilitating life-limiting disease, but death is not imminent or it would be an outcome measure!   We can discuss and promote the fact that no change in the outcome (stabilization) means benefit.  We can work with FDA to discuss alternative design for trials and are currently working with the community on outcomes research, measures for  non-ambulatory boys, measures that are sufficiently sensitive to demonstrate change.  I disagree that it will be 100 years, though I agree it sometimes feels like it.  I think we are at a pivotal point in time, when there are a number of drugs/biologics in trial or in development.  We now have a better understanding of the 6mwt and the U. Florida  (U. Penn, Portland Ore) collaboration on MRI may well become our first biomarker in terms of muscle imaging.  PPMD is sponsoring a biomarkers study with SomaLogics and there are other studies underway.  Seems to me, as  trial designs improve  we will be better able to understand the impact of a specific drug using existing tools and some that are moving forward.   I think FDA /CDER/Neurology has a better grasp of the issues as well.   The first trial felt like entering a dark room with no light switches.   We have learned a great deal and i expect we will  continue to learn.  We need drugs that provide benefit and we need FDA (or EMA) to approve them and sponsors have to meet requirements.. Keep in mind there is a ripple effect to this.  If the drug is determined NOT to be beneficial, it is unlikely the payers will cover the costs. 

Exon skipping is moving forward as are other drugs, one example is the CAT 1004 described this afternoon by the Catabasis folks - pathway pharmaceuticals.    I think it is a matter of time before we get the first drug through the process and that will be a real turning point.  Say tuned and don't give up the ship.   Who said 'things looks the darkest just before dawn' or something like that.   We keep marching forward....  pat

What do you mean they are not dying now? You are aware of the boys we lost recently and in the past years, aged 3 to 17 right? Whose boys are you referring to when you say that they are not dying? The ones that do not right now ignoring the ones that do?

And are you referring to the CAT-1004 when they made it very clear that it is 'EARLY' days? For our boys there are no early days, their progssion does not stop so we can wait for these drugs to go past early days.

I am sorry but this is not the message I want FDA to hear. If the communication is that there are drugs in the pipeline and our sons are not dying, it is ridiculous. Maybe the parents who recently lost teenage or young boys should make it clear the urgency, since the rest of us apparently have time since our boys are not dying today.

Safe and effective is what we all want but articles show that this drug is effective, just not effective enough?Than this is the point where someone talks about the risk of not having these boys on this drug and waiting for them to die instead. Not sure why we try to beat around the bush again, this is a terminate disease, boys are dying as they did before and it is not acceptable to tell the parents losing their sons that they are not dying now.



Pat Furlong said:

The process of drug development is difficult, labor intense and expensive.    We do not want the rules relaxed actually.  We do need SAFE and EFFECTIVE medicines.  We are in need of perhaps a greater degree of flexibility on the part of FDA, to understand that indeed Duchenne is 'tricky', that a specific drug or biologic may have different effects on different sub populations of patients.   We have learned a great deal from the ataluren study that PTC has thankfully and graciously shared with industry.   

We cannot pitch 'our boys are dying now' as they actually are not dying 'now'.  Clearly they have a progressive, debilitating life-limiting disease, but death is not imminent or it would be an outcome measure!   We can discuss and promote the fact that no change in the outcome (stabilization) means benefit.  We can work with FDA to discuss alternative design for trials and are currently working with the community on outcomes research, measures for  non-ambulatory boys, measures that are sufficiently sensitive to demonstrate change.  I disagree that it will be 100 years, though I agree it sometimes feels like it.  I think we are at a pivotal point in time, when there are a number of drugs/biologics in trial or in development.  We now have a better understanding of the 6mwt and the U. Florida  (U. Penn, Portland Ore) collaboration on MRI may well become our first biomarker in terms of muscle imaging.  PPMD is sponsoring a biomarkers study with SomaLogics and there are other studies underway.  Seems to me, as  trial designs improve  we will be better able to understand the impact of a specific drug using existing tools and some that are moving forward.   I think FDA /CDER/Neurology has a better grasp of the issues as well.   The first trial felt like entering a dark room with no light switches.   We have learned a great deal and i expect we will  continue to learn.  We need drugs that provide benefit and we need FDA (or EMA) to approve them and sponsors have to meet requirements.. Keep in mind there is a ripple effect to this.  If the drug is determined NOT to be beneficial, it is unlikely the payers will cover the costs. 

Exon skipping is moving forward as are other drugs, one example is the CAT 1004 described this afternoon by the Catabasis folks - pathway pharmaceuticals.    I think it is a matter of time before we get the first drug through the process and that will be a real turning point.  Say tuned and don't give up the ship.   Who said 'things looks the darkest just before dawn' or something like that.   We keep marching forward....  pat

Pat,

 I want the rules to change.

Lets consider clinical trials specially for ambulant kids

A very very simple step would be to eliminate placebo from DMD related trials.  We have enough medical history from a huge population that we dont need to comparison under strict observation. A Win win for the research companies and the patients. WHY is FDA still insisting on placebo controls in DMD trials.

For the non ambulant population or the seniors why cant we have rules that have been applied for Prochymal from Osiris. In this case even marketing rights are given with a commitment to let the clinical trials continue. Why cant FDA device something like this for our seniors. Most of them are well informed and well educated to make a good sound judgement for themselves. Why does FDA not give the seniors in DMD community the structure to make their own risk vs reward judgements. Or in other words having a choice of taking a calculated risk as as compared of risk of doing nothing.

Sorry, rules have to and should change. FDA has a moral right to control drugs entering the market. It should focus on strengthening Phase 3 and Phase 4 of the trails. Instead FDA works on making the entry point as difficult as possible. 

Pat,

You as our representative should make constant pressure on the regulatory organs to adopt the rules to the actual situation. I strongly support the idea of talks with FDA suggesting that so may data has been gathered that no double blinded studies are necessary at least in majority of situations, the natural history is known well enough. Secondly as mentioned earlier in case of Ataluren the stop-codon group may be compared to other groups. Last but not the least, we should remember that DMD is a fatal disease, it is not like a cold. I agree that medications for a non-fatal disease should be verified precisely but for DMD the risk should be accepted for the benefit of this generation of boys. I am sure that very many of us (parents) and the DMD boys as well will take some risk against the risk of doing nothing.

Furthermore, please urge PTC to accept other boys who didn't participate in the previous trials to be admitted to current one.

Dear Pat,

There was said a lot of information, thank you very much. But I didnt understand on thing. Now is in the USA and Europe, Izrael and Australia the programme for boys who had been in previous clinical trials. In the USA is the clinical trial III with preliminary results in July 2012. Will be these safety results as the basis for negotiations with FDA or no? Why you spoke about next clinical trials?
 
Pat Furlong said:

Proces vývoje léků je těžké, intenzivní práce a drahé. Nechceme, aby se uvolnily pravidla skutečnosti. Potřebujeme bezpečné a účinné léky. Jsme potřebují možná větší míru flexibility ze strany FDA, aby pochopili, že opravdu Duchenne je "složité", že určitý lék nebo biologická mohou mít různé účinky na různých dílčích populací pacientů. Naučili jsme se hodně ze studie ataluren, že PTC naštěstí a milostivě sdílené s průmyslem.   

Nemůžeme hodit "naši chlapci umírají nyní", jak ve skutečnosti jsou sice umírání "teď". Je zřejmé, že mají progresivní, oslabující život limitující onemocnění, ale smrt není bezprostřední, nebo to bude výsledkem opatření! Můžeme diskutovat a prosazovat skutečnost, že k žádné změně ve výsledku (stabilizace) znamená přínos. Můžeme pracovat s FDA diskutovat alternativní návrh k pokusům a jsou v současné době pracuje s komunitou na výsledky výzkumu, opatření pro non-ambulantních chlapců, opatření, které jsou dostatečně citlivé k prokázání změny. Nesouhlasím s tím, že to bude 100 let, i když souhlasím s tím, že se někdy cítí jako to. Myslím, že jsme v klíčovém okamžiku, kdy existuje celá řada léků / Biologics v hodnocení nebo ve vývoji. Nyní máme lepší představu o 6mwt a U. Florida (U. Penn, Portland Ruda) spolupráce na MRI může dobře stát naší první biomarker, pokud jde o svalové zobrazování. PPMD sponzoruje biomarkery studii SomaLogics a tam jsou další studie v plném proudu. Zdá se mi, jako zkušební návrhy zlepšení, budeme moci lépe porozumět vlivu konkrétního léku s využitím stávajících nástrojů a některé, které se pohybují vpřed. Myslím, že FDA / CDER / Neurologie má lepší pochopení problémů také. První zkušební pocit, že vstupem do tmavé místnosti bez světla přepínačů. Naučili jsme se hodně a myslím, že budeme pokračovat v učení. Potřebujeme léky, které poskytují výhody a my potřebujeme FDA (nebo EMA) schvalovat je a sponzoři musí splňovat požadavky .. Mějte na paměti, je dominový efekt v této oblasti. Pokud lék není určen jako přínosné, je nepravděpodobné, že plátci pokryje náklady. 

Exon skipping postupuje stejně jako jiné léky, jedná se například o CAT 1004 popsal dnes odpoledne podle Catabasis lidí - dráha farmaceutických. Myslím, že je otázkou času, kdy dostaneme první lék prostřednictvím procesu a že bude skutečný zlom. Řekni naladěný a nevzdávejte se loď. Kdo řekl, že "věci, vypadá nejtemnější těsně před svítáním", nebo něco takového. Držíme pochodující vpřed .... pat

Thanks for your comments.   Drugs have to be safe and effective.  We can discuss trial design for the rest of our lives, but ultimately the decision of the sponsor and FDA to agree to a path forward.  Like you, I believe we should have a strategy to include all eligible individuals once safety has been established.  This is an ongoing discussion with sponsors and regulatory authorities.

 

  Placebo controlled trials are done in most circumstances and done for very good reasons.  There is ALWAYS a placebo effect.  There is considerable documentation (in other conditions)  that the placebo effect in some cases has lasted 12 -18 months.  And it is clear that patients participating in clinical studies improve because of a variety of factors to include more frequent visits with the clinical team, potentially (in our case) more aggressive/frequent pt, better nutrition, and HOPE.  We all know and understand the decline in DMD will ultimately be visible if the individual in on placebo (depends on the length of the clinical study), but as we all have seen there are days when our sons look better or worse and there are plateau's, when things looks fairly stable, sometimes for a relatively long period of time- see 6mwt comments in previous post.  For this reason, placebos are an important tool and help us understand the clinical effect of a drug over time.   And as you learned from the AVI trial, trials (depending on the drug target/subjects studied) may require more time than 48 weeks +/_) And while we have natural history which is amazing and growing, we still have a lot to learn about Duchenne - better understanding each mutation and associated binding sites,  how the protein folds and genes that modify disease course.   Clearly steroids, improved respiratory care, cardiac interventions, pt/stretching have changed the natural history of Duchenne.  We all know that each individual with Duchenne is unique and we know there are subsets of individuals with congnitive and behaviors that make testing difficult.  And we know that care is highly variable across the US and across the world.  All of these variables make it difficult to tease out the effect of a certain drug or biologic.  And for this reason, I suspect RCT (randomized, placebo controlled clinical trials ) are here to stay, at least for now.

 I also understand you want the rules to change.  This requires legislation. There are 7000 rare diseases.  FDA will not make rules for each condition - FDA does not have sufficient resources -people, expertise, money - for this to happen.  THis is why we advocate for additional resouces for FDA.   We are actively, aggressively working on the PDUFA  (which is the legislation that provides guidance to FDA and is reauthorized and amended every 5 years.   This is why you should care and get engaged with our advocacy agenda.  There are specific provisions in both the House and Senate versions that would directly impact Duchenne.

 

We are working on the risk/benefit issue as well.  It is easy to say parents are willing to 'risk anything' but it is very difficult to define.  Are you willling to risk more rapid progression?  another comorbid condition?   death?  And the risk is likely to be different or vary depending on the target (nonsense mutation, exon skipping, anti-fibrotic, anti-inflammatory, etc)   Risk tolerance is an issue that FDA is very interested in and we are working on a strategy to understand risk tolerance in the DMD community and intend to provide data to FDA.  You will be hearing more about this soon.  I also understand and agree, doing nothing is doing harm.  Rolls off the tongue pretty easily but pretty difficult to put concrete data around it.  What are we (as a communty) willing to tolerate.  What  is your son willing to sign onto?  Keep in mind, they will be signing an informed consent document as well, giving their permission, accepting risk.  What are they willling to toerate? Are you aware that less than 5% of individuals actuall typically participate in trials?  Why? Because they are a pain in the neck, require loads of accomodation for families and often, families without resources (money, babysitting, jobs, etc) or teenage boys who have school, friends, plans -find it very, very difficult.  We need everyone to be willing to participate.  We are in the lucky circumstance of having a number of trials. If the recruitment is slow or insufficient, we will not have sufficient patients (subjects) to power the trial, will not reach statistical requirements and will not see approvals.

   As you know, FDA /EMA are data driven.  Opinion - 'i think...we wish....we believe...' just won't hold up.  They need data, this means fulfilling recruitment, compliance with the rigor of trials and (cross fingers here) approvals.

 

The focus has to be to design a study that will get us to the endpoint - approval.  Once approved, the drug will be available for all.  Sponsors (biopharmaceutical companies) make the decisions (guided by steering committees comprised of clinicians and advocates) about what the trial will look like and FDA or EMA approves the study.  We all want everyone -all eligible boys, ambulatory or not  - to be included, but this is sometimes not the easiest or fastest way to approval.  I am well aware of the feeling that the loss of ambulation feels like you are sitting in the back of the bus in so many ways (trials, treatments, clinics -transition to adult) and am working on all of these issues. 

 

We need approvals.  payers need to pay for the drugs.  this means private insurance and government insurance. In the US it is 'guesstimated' that 40% of the boys are on Medicaid.   Medicaid reimbursement depends on state budgets, so this is another area we are working on - actually with the international community.  

 

I know well DMD is fatal.  You don't have to convince me that DMD is more than the common cold.  

 

  I wish this was simple and there is never a day or a minute of the day when I am not trying to figure out what we might do to accelerate the process.  

Ofelia--

Interestingly, pharmaceutical companies now feel the key reason that so many drugs fail in clinical testing is that they are moved into the clinic too quickly--before the mechanism of action is understood well enough to plan better trials--and that fast does not equal efficient.  We have to make sure that we focus on "pushing" where there is truly wasted time in the system and not push on the things that will ultimately slow us down.  To my mind, things that are absolutely unnecessary wastes of time in clinical testing are multiple IRB approvals, multiple site contracts, and recruitment delays--these are the primary things that slow down the process and add no value.  Things that take time but shouldn't be skimped on are validating the preclinical data and rationale and spending time to truly understand natural history and endpoints when planning a trial.  So, PPMD is planning to partner with NIH's NeuroNext network to encourage trial sponsors to use that mechanism, which has a single central IRB and a master site contract.  We operate the Connect Patient Registry and provide participant travel grants for studies to help speed recruitment for clinical trials and we support the TREAT-NMD TACT committee to help companies plan better trials.  Finally we support Lee Sweeney's lab at UPenn to double-check results that are published in the literature so that we don't spend a lot of time and money testing drugs for DMD that are not likely to work.  PPMD has also been supportive of the new PDUFA legislation that pushes the FDA to be more flexible and proactive in rare disease and we have been in independent talks with the FDA. I think we have to apply the boyscout motto about "proper, prior planning" and then, as Pat pointed, keep in mind that PTC Therapeutics was really trying to blaze a trail here--there was no path for regulatory approval for a DMD drug established and to some extent they and we are paying the price for that. Trials that follow will benefit from this learning experience.

 

And I think you are absolutely right when you say this is a nightmare--Duchenne is a nightmare and drug development is a nightmare.  I don't know why anyone does it who doesn't have a personal stake in it.  Very few drugs ever really make money and it's hard, hard, hard.  But with all that being said there are 10 companies coming to the Connect Conference in Fort Lauderdale, all with candidate therapeutics for DMD.

 

Let's push where we can to be the most constructive--a little community activism never hurts.  Go to the Advocacy conference if you can, or write letters or visit your local representatives if you can't go to Washington. 

 

Sharon

And just one more word...I think Pat is in the awkward position here of trying to explain the FDA's point of view--you should all know that Pat is the one person in the community who spends A LOT of time meeting with the FDA, pushing the FDA and strategizing about how to change the rules that make sense to change.  This has been a consuming focus for her and that's why she is able to explain in so much detail all the issues.  Storming the gates without a well-considered plan is rarely constructive--sometimes it works better to push for change from the inside.  She is doing battle for your sons with the FDA, day after day--there should never be an concern from anyone about that.  My own son has autism and I would sleep better if the autism community had a champion like Pat.  My ten cents.  :)

 

Sharon

Pat has given us this voice and this venue. I respect her and sincerely thank to all those who are committed to the cause so dear to me. However one thing that I have learnt from this situation is I will not rest till I find the cure. I will question and evaluate every option. Debate is out of this intent and not to question the judgement of folks much more informed.

Continuing the discussion...

Bieke is conducting a trial on DMD with Human Mesenchymal Stem cell (trial id NCT01610440 on clinical trails website). Phase 1b/2a completes Primary phase in 1 year on Oct 2012 and final completion by Oct 2013. Key points to note

  • No Placebo
  • Inclusion criterion is practically anyone with DMD of age 5 to 12

I know Bieke does not follow the prevalent value system. Their representative in India was eager to poke my kid with stem cell injection for a cost (about 30K in 2008). With the value system I have I cannot entirely trust this company or this trial. However this is a approved trial and findings will be accepted by FDA.

I am not able to understand why is FDA having a different standard for trials run in Europe or US.

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