World Muscle Society Congress & ACE-031 news

The Duchenne community has been eagerly awaiting news about a Phase 2 Randomized, Placebo-Controlled, Multiple-Ascending-Dose Study of ACE-031 in ambulant, steroid-treated boys with Duchenne (A031-03). We were all disappointed to hear the study was terminated and hoping to understand what were the results of the study in terms of safety and pharmacologic effects and what expectations we might have with regard to next steps for ACE-031. We needed a therapeutic dose of HOPE!


This week at the World Muscle Society Congress in Portugal, Acceleron and investigators presented summary data from this Phase 2 study, which was conducted in Canada.


In the context of trials, the participants are referred to as subjects. To begin, 24 subjects participated in the trial. For inclusion into the trial, the subjects had to be ambulant boys with Duchenne who were age four or older and currently on a stable dose of corticosteroids. The average age of participants in the study was approximately ten years old.


The primary objective of the study was to evaluate the safety and tolerability of multiple escalating doses of ACE-031 in ambulatory steroid-treated boys with Duchenne. Several secondary objectives were also investigated.  


In each cohort, subjects were randomized (randomly assigned) to receive placebo or ACE-031. In the first cohort, nine boys received 0.5mg/kg q4 weeks (0.5 mg ACE-031 per kg of body weight given every four weeks) over a period of 12 weeks. Safety data was reviewed prior to the start of the second cohort. The second cohort of 12 boys was randomized to receive 1.0 mg/kg q2 weeks over a period of 12 weeks. Subjects were followed for 12 weeks after the treatment period was completed. 


There were no serious or severe adverse events (AEs) in the study, nor did any AEs lead to discontinuation. There were no clinically significant changes observed in safety lab results. The most frequent adverse events were injection site redness (occurring in approximately 50% of ACE-031 or placebo-treated subjects); mild nosebleeds (occurring in 0%, 11% and 56% of subjects given placebo, ACE-031 0.5 mg/kg q4 weeks and ACE-031 1.0 mg/kg q2 weeks, respectively) and telangiectasias (small, dilated blood vessels within the skin), occurring in 5 out of 9 subjects in the ACE-031 1.0 mg/kg q2 weeks group only. 


There was a significant increase in average total body lean mass (which includes skeletal muscle, measured by DXA) that appeared to be dose-dependent, indicating the amount of increase may be correlated to the dose of ACE-031.  The maximum average increase was 5.4% after 24 weeks, noted in both ACE-031 treated groups. With the small number of subjects in this study, there was inadequate statistical power to detect a difference in the 6-minute walk test (6MWT), however, the trends showed the average 6MWT distance was maintained in the boys on ACE-031 over the 24 weeks, but declined in the placebo group (i.e., those not on ACE-031).  


Bone mineral density of the lumbar spine (lower back) as determined by DXA scan, showed a significant increase at day 169 as compared to the baseline measurement in the 1 mg/kg every 2 week dosing cohort. Additionally, there was less gain in total body fat mass for the subjects on ACE-031 and this correlated with the distance walked in the 6MWT.


As mentioned last June, Acceleron and Shire remain committed to the development of ACE-031 and are working hard with regulatory agencies. As their partnership moves forward, Acceleron and Shire will continue to explore the relationships between adverse events, multiple clinical outcomes and ACE-031 dose exposure in their clinical and non-clinical programs. 


The Duchenne community wishes Acceleron and Shire Godspeed.

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Comment by cheryl cliff on November 9, 2011 at 12:34pm

Yes, it sure would be a great thing if we could hold big pharma to a reasonable standard of openess.  Not a bad idea for all big corporations actually.   Would have had a preventative element regarding Enron a few years back.  But since that goal is very, very far off (if not impossible) we are lucky to have organizations who can focus on what is obtainable sooner.  

Still, there is work we can do.  I urge everyone who can no longer tolerate patience or complacency to attend the PPMD winter DC conference coming up.  It really, really makes a big impact on duchenne in America.       


Comment by David on November 8, 2011 at 11:57pm
Not shooting the messenger. Just trying to hold these companies to a reasonable standard of openess. The market forces applying pressure on these companies to open their programs is minimal, it is quite necessary for advocacy organizations to play this role.
There is fine line between patience and complacency. I can only assume that these companies, and their lawyers, already understand this community will not tolerate complacency. If we at times appear impatient to prevent complacency, I say go for it.
Comment by cheryl cliff on November 8, 2011 at 11:18pm

I think, but could be wrong as it wouldn't be the first time, that there are little legal elves running around in the background of companies like Acceleron and Shire, GSK, Prosensa, AVI...  These elves are most likely advising pharma companies they can not say anything in public until specific benchmarks have been reached.  Wouldn't make sense for a company to pay lawyers for advice and then not take it. 

Sure frustrates me constantly, but no one individual controls the attitude and practice of big pharmas.  This attitude isn't brought  upon or controlled by Pat or anyone else heading up Duchenne non-profits.  

Shooting the messinger doesn't eliminate this problem. 




Comment by David on October 28, 2011 at 12:46pm

I don't think any parents really expect a company like Acceleron/Shire to share actual specific details like dosing issues, etc. And after only a few years living with Duchenne most of us come to realize that nothing will move as fast as we would like.

But as Ofelia suggested, why is it too much to ask - "what is the hold up?" Are more animal studies being conducted? Is the company just waiting for some response from regulators? Has the company put aside the program until a later date due to funding?

Responses may give parents something to move on. We can lobby regulators, for example. We can raise funds. And these responses don't seem to give away any details that might jeapardize the companies precious stock value.


Comment by Pat Furlong on October 28, 2011 at 9:47am

Hello again,  I do understand and I know they are very interested and willing to share, once they work out all of the issues.  For so long, I have heard the 'bench to bedside' term, but the reality is that it is inaccurate.  Seems to me it is bench to bedside, sometimes back to bench and hopefully back to bedside.  Acceleron/Shire is very willing to share details, but they are still working on questions such as 'is this a dosing issue?  is it the regimen? (higher dose less frequently, lower dose more frequently, different dose all together, regimen that includes taking an x week or month holiday)  clearly the compound it 'hitting' a vascular pathway.  is this a minor or major vascular pathway and likely to lead to more serious consequences?      what additional tox studies are needed/required?  what will it take for fda/health to lift the clinical hold?

 I have spoken with several individuals from Acceleron and Shire.  They are anxious to communicate with the community, but not until they have the full story in terms of what they learned and what the future looks like for this compound.  They won't give us a blow by blow and in some ways, it makes so no sense for all of us to live through their day to day issues.  

I don't disagree waiting is frustrating.  I'm not sure about you, but when my sons lived and I was waiting, I could drive myself nuts.  When there was no news, I find myself making all sorts of senarios in my head.  So, I get that completely. I understand the way all of us look at our sons, worry about tomorrow, about the future and I also understand that information, knowing something, having some news - so that in our head we can plan, find hope, look forward to something, have expectations.   Every day I used to make calculations in my head.  If this, then Chris and Patrick would be x age, they would have x function, and this could.....      


Acceleron/Shire will update us and hopefully before the end of the year.  I just know they will want to have the opportunity to lay out their strategy so that families interested and potentially willing to participate in a future trial, have sufficient information to make an informed decision.      

Comment by Ofelia Marin on October 28, 2011 at 9:19am

Pat, of course I understand that they are not required to tell us anything. I just thought that there should be a partnership b/w them and us. After all, they cannot test their drugs if our boys do not enroll and they cannot make money if they do not test their drugs. Until a drug is approved it doesn’t help our sons. During clinical trials, our sons are just subjects who experience those “minor” or not side effects AND we all make financial and personal sacrifices to participate only to advance these treatments. Many of us know that, if approved, some of them will only help the next generation and not our own sons. Hence, it would be nice if they would keep this community informed with more than “working hard with regulatory agencies”. I also think that you and a few other people have access to a lot more information than the rest of us. You can write blogs and talk about it from a totally different perspective than the rest of us. We are left with asking these questions and receiving 5 word answers. Not sure about anyone else but I appreciate companies willing to provide that information although they are not required to.

Comment by Pat Furlong on October 27, 2011 at 11:38pm

Hello Ofelia.   I'm sorry if I sound frustrated.  I am not a shareholder in either company and therefore cannot speak for them. But I have met with individuals in both companies and found them to be honest brokers.  

 What I have learned about the drug development process over the years is that it is a frustrating process all around.   As you have heard 8 out of 10 fail for one reason or another.   Companies invest money and time.  We invest our children and in that, have the highest stakes. 

 Acceleron/Shire did all of the due diligence around the compound, sufficient to have approval for the safety/dose finding trial. And  while animal data is useful and certainly informative, it cannot predict what will happens in kids.  This is the reason Phase I and Phase II trials focus on safety and dose finding.  The nose bleeding/gums bleeing etc. were signals and these signals were taken very seriously.  They stopped the trial and went back to the bench to figure it out.  This is exactly what we can expect will happen. 


They are not required to tell us what they are learning or what obstacles they are encountering.  When they have something to say, they will.  I trust that and have had these conversations with them.  Seems to me Acceleron and Shire are good and responsbile partners in the Duchenne community.  They are being thoughtful and careful, exactly what we want to see.  And once they get to the point of the green light to move forward, they will communicate with the community about next steps. 

And once they explain where they are and what their next steps will be, families will be able to make thoughtful, informed decisions about their willingness (or not) to participate.


Comment by Ofelia Marin on October 27, 2011 at 11:01pm

I thought about you and your son Jason when I read what they said about the "minor bleeds" and the fact that your son's bleeds were not minor at all. It would definitely be difficult to see my son walking around with serious nose bleeds on top of everything else.


Pat, it is very frustrating to hear the "working hard with regulatory agencies" for months. I hope they communicate more to the patients they will need to test their drug on before they start asking them again to enroll in their trials, miss school and work days, put their lives on hold, pay for travel, go through the difficult days of injections and testing...they seem to be very vocal when they need to test their drugs on our boys, not so much now. It is not exactly fair.


Comment by Pat Furlong on October 27, 2011 at 9:26pm

Hello Everyone. 
I realize this is incredibly frustrating, devastating and painful.    Every company, biotech and pharma, has their own corporate culture. What they are willing or able to share and when they are able to share information  will have significant variability from company to company.. .   The bottom line is that Acceleron/Shire has to address the safety concerns raised during the dose finding/safety study.  They are currently on clinical hold and until/unless they are able to satisfy FDA and/or Health Canada's concerns related to safety, they cannot move forward.. None of us are privy to this information.    All of us would like to see this compound move forward and all of us should be thankful they are working hard to understand the issues related to safety and address them.  I realize this has been their mantra for 8 mo.+/-, but my guess is that it isn't a simple question and will take some time to sort out.


Comment by Jason G on October 27, 2011 at 6:34pm

My son was involved in the study and had some pretty heavy nosebleeds.   It is extremely frustrating to have things come to an abrupt halt, especially when it was showing positive results  .... it is also extremely important to know the dangers of a drug that we are injecting into our son.

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