Today we completed the Phase 2 trial running at Nijmegen with the intermittent regime. The trail continues since the last participant was on boarded in Aug 2011. Doc tells that results should be published by late this year. No other information available except for the few readings we took along the year.

We lost quiet some mts in the 6MWT over the year. The way my kid has slowed down; I am pretty sure that we were on placebo. Over that there were nothing but a few instances of bacteria and WBC in the urine samples. 

However we start on the extension study in a month from now. The gap is needed to ensure that data for extension is isolated from the original study. A new baseline for the extension study, and we start with weekly shots. This time its for sure that we will gets the meds. NO MORE PLACEBO.

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Hi Andrea--I'm not as familiar with the system in Canada, but I know that at least some drugs have been approved faster there than in the US.  I think it's probably easier to recruit people for trials in Canada because things are more standardized with the national healthcare system.  I have some contacts at the Marigold Foundation, which is a Canadian MD organization headquartered in Calgary--they are primarily focused on myotonic dystrophy but have done some work on all the dystrophies and are a pretty active organization.  The regulatory issues will affect drug development in myotonic dystrophy just like it does in DMD.  If they have a strategy on this topic I will let you know.

Sharon

Sharon,

Conditional approval after phase 2 still requires the company running the trial to submit papers to regulators, right? What's their motivation to do so? PTC chose not to. How do we know AVI or GSK will?

-David

 

Hi David, there is usually a time limit on that conditional approval--it's not meant to be permanent so the company does have to conduct studies leading to a final approval or risk losing the ability to market the drug at all.  The real question is how do you recruit for a phase III placebo-controlled study if the drug is already available?  Who's going to be in a study where you might get assigned a placebo if there is any possible way to get the drug outside of the study?  That's where a "natural history" control arm instead of placebo might come into play, but those are controversial as well.

 

Sharon

I'm sure it's not this simple, but seems the major factor here is age / ambulation / short term prognosis. An active 4 year old will not suffer from a year of placebo.

A prone 17 year old on a respirator is in a whole nother world.

How does compassionate use fit in here? Or does it?

Finally words I am happy to hear: “"natural history" control arm instead of placebo”

A couple of years ago I did buy the need to placebo controlled studies although doctors like Mendell did have historical data on DMD boys, but I did buy the fact that the progression is slightly different due to steroids started as early as age 3 (as Cincinnati pushes these days, although osteoporosis and fractures might stop these boys from walking as early as years ago), heart meds started early, ventilation, maybe even some vitamins like D3 or supplements etc. Now companies like GSK collected years of data in these boys. Their plan is to run these trials up to 2014. So they will have years of data in hundreds of boys in placebo groups. I think we are getting closer to be able to make a good point on “natural history”. I find it harder and harder to swallow that these boys on placebo and their families need to travel weekly to be injected with saline and need to biopsied when they are higher risk for malignant hyperthermia. I would understand when a study is truly blinded and no one knows who’s on the drug or placebo, but come on, many of us now saw the pictures of the boy’s injection sites while on the GSK drug…only a blind person doesn’t know that these boys are on the drug. :(

Thanks.

A.

Sharon Hesterlee said:

 

Hi Andrea--I'm not as familiar with the system in Canada, but I know that at least some drugs have been approved faster there than in the US.  I think it's probably easier to recruit people for trials in Canada because things are more standardized with the national healthcare system.  I have some contacts at the Marigold Foundation, which is a Canadian MD organization headquartered in Calgary--they are primarily focused on myotonic dystrophy but have done some work on all the dystrophies and are a pretty active organization.  The regulatory issues will affect drug development in myotonic dystrophy just like it does in DMD.  If they have a strategy on this topic I will let you know.

Sharon

Re: Biopsy and malignant hyperthermia,

I realize this was not the point of your comment, I just wanted to clarify that  Simon's muscle biopsy was just a local anesthetic. Are others having general anesthesia?

Ofelia Marin said:

Finally words I am happy to hear: “"natural history" control arm instead of placebo”

A couple of years ago I did buy the need to placebo controlled studies although doctors like Mendell did have historical data on DMD boys, but I did buy the fact that the progression is slightly different due to steroids started as early as age 3 (as Cincinnati pushes these days, although osteoporosis and fractures might stop these boys from walking as early as years ago), heart meds started early, ventilation, maybe even some vitamins like D3 or supplements etc. Now companies like GSK collected years of data in these boys. Their plan is to run these trials up to 2014. So they will have years of data in hundreds of boys in placebo groups. I think we are getting closer to be able to make a good point on “natural history”. I find it harder and harder to swallow that these boys on placebo and their families need to travel weekly to be injected with saline and need to biopsied when they are higher risk for malignant hyperthermia. I would understand when a study is truly blinded and no one knows who’s on the drug or placebo, but come on, many of us now saw the pictures of the boy’s injection sites while on the GSK drug…only a blind person doesn’t know that these boys are on the drug. :(

If natural history of the current trial ready generation has been affected by steroid/ D3, then by the same logic general usage of CoQ10 will be impacting the natural history of the next trial ready generation. I dont think GSK is naive enough to think that they get some benefit from maintaining the placebo group for natural history. Placebo group is practically increasing the cost of the trial by 33%. I dont see why GSK will spend this much to gather data not useful 3 to 4 years down the line.

Even without the trials I have already signed up for collection of all possible data. If I remember correctly this data was to be archived for future reference for 18 years. This includes videos and genetic information. Hospital not part of any trials are already gathering natural history data and making them available for research.

The only value placebo adds is to give a exact comparison on a week by week basis. Weekly data from Urine and blood work, is where the placebo adds value to this particular phase of the trail. If the same weekly pattern is observed say with Exon 44 trial also then we have a case to not have placebos in subsequent trails. I strongly feel that without this first set of controls we will be only trying our luck for not having placebos. 

@ Andrea,

 It was local anesthesia for us too. A sedative was used to clam down. That was one of the lighter moment ;my kid was talking like a drunk person all through the 10 min procedure of biopsy. I was a bit surprized to see the nurses and doc coming out of the OT smiling and joking about the talkative boy.

Sam's wasn't general either. Just local with something relax him. He ended up sleeping through it but woke up as soon as I came back in. He said it made him feel "comfy".

Andrea Cleary said:

Re: Biopsy and malignant hyperthermia,

I realize this was not the point of your comment, I just wanted to clarify that  Simon's muscle biopsy was just a local anesthetic. Are others having general anesthesia?

Ofelia Marin said:

Finally words I am happy to hear: “"natural history" control arm instead of placebo”

A couple of years ago I did buy the need to placebo controlled studies although doctors like Mendell did have historical data on DMD boys, but I did buy the fact that the progression is slightly different due to steroids started as early as age 3 (as Cincinnati pushes these days, although osteoporosis and fractures might stop these boys from walking as early as years ago), heart meds started early, ventilation, maybe even some vitamins like D3 or supplements etc. Now companies like GSK collected years of data in these boys. Their plan is to run these trials up to 2014. So they will have years of data in hundreds of boys in placebo groups. I think we are getting closer to be able to make a good point on “natural history”. I find it harder and harder to swallow that these boys on placebo and their families need to travel weekly to be injected with saline and need to biopsied when they are higher risk for malignant hyperthermia. I would understand when a study is truly blinded and no one knows who’s on the drug or placebo, but come on, many of us now saw the pictures of the boy’s injection sites while on the GSK drug…only a blind person doesn’t know that these boys are on the drug. :(

I also believe these first trials need a placebo arm. And GSK is in phase 3 now so there will be no conditional approval after phase 2 in this case. I was referring to future trials. And honestly I am not even that optimistic to hope for no placebo controlled Phase 3. I just hope these drugs, if effective, are approved after phase 3 but before the years of extension trials end. Well, we first need to prove they are effective and we are not there yet.

Tulika said:

If natural history of the current trial ready generation has been affected by steroid/ D3, then by the same logic general usage of CoQ10 will be impacting the natural history of the next trial ready generation. I dont think GSK is naive enough to think that they get some benefit from maintaining the placebo group for natural history. Placebo group is practically increasing the cost of the trial by 33%. I dont see why GSK will spend this much to gather data not useful 3 to 4 years down the line.

Even without the trials I have already signed up for collection of all possible data. If I remember correctly this data was to be archived for future reference for 18 years. This includes videos and genetic information. Hospital not part of any trials are already gathering natural history data and making them available for research.

The only value placebo adds is to give a exact comparison on a week by week basis. Weekly data from Urine and blood work, is where the placebo adds value to this particular phase of the trail. If the same weekly pattern is observed say with Exon 44 trial also then we have a case to not have placebos in subsequent trails. I strongly feel that without this first set of controls we will be only trying our luck for not having placebos. 

@ Andrea,

 It was local anesthesia for us too. A sedative was used to clam down. That was one of the lighter moment ;my kid was talking like a drunk person all through the 10 min procedure of biopsy. I was a bit surprized to see the nurses and doc coming out of the OT smiling and joking about the talkative boy.

My comment about natural history data referred to older data other doctors have collected before these new trials. Years ago when steroids were not introduced as early as today, coq10, heart meds, vitamins and supplements were not used as often today, the progression of the disease might have been different with boys losing ability to walk earlier on the average etc. CoQ10 was excluded in the GSK trial due to blood coagulation right? I remember reading something like this. Moreover, none of the supplements are proven to increase strength or slow progression, however early treatment with steroids might or high doses of VitD3 from an early age might help their bones, who knows. The assumption is that this generation's progression is somewhat better hence the scientific community might reject use of older data. Of course, the hope is that the next generation's progression will be different the more we learn about the pathology and introduce some treatment. 

Tulika said:

If natural history of the current trial ready generation has been affected by steroid/ D3, then by the same logic general usage of CoQ10 will be impacting the natural history of the next trial ready generation. I dont think GSK is naive enough to think that they get some benefit from maintaining the placebo group for natural history. Placebo group is practically increasing the cost of the trial by 33%. I dont see why GSK will spend this much to gather data not useful 3 to 4 years down the line.

 

So, we are actually getting beautiful and current natural history data from the placebo arms of all these trials--if we could aggregate that data we would have a large sample size.  There is some precedent for doing this kind of thing.  The Coalition Agains Major Disease at the Critical Path Institute has put together a consortium of government funders, academicians and industry to aggregate the placebo arm data from trials in MS, Alzheimer's and Parkinson's disease (separately for each disease).  They have a lot of the major pharmas signed on and they have "mapped" the data from one trial to the next so that they can compare apples to apples.  I had a long discussion with the staff at CPath who are running this consortium and they are interested in using the template they have developed in other disease spaces--I think Duchenne would be an excellent place for them to expand. Will work on this!

Sharon

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