Live Report from the American Academy of Neurology

Sharon Hesterlee, Ph.D.

Senior Director Research and Advocacy

Parent Project Muscular Dystrophy

At the American Academy of Neurology meeting in Toronto this week, so far, three different companies have presented data from therapeutic trials for Duchenne—I think that is probably a record for this disease area. When I first started managing research projects for MDA in 1998, there were no companies interested in the disease and gene therapy was the hot topic (just coming down from the myoblast transplant disappointment). Now we have many companies working in this space and three with encouraging data—it definitely shows progress.

AVI-4658, Exon-skipping

First, AVI presented the results of their systemic administration of AVI-4658, designed to skip exon 51 in boys with DMD. This is the study that took place in Europe and was led by Dr. Francesco Muntoni. Basically there were six different groups of boys and each group received a different dose of the drug (0.5, 1, 2, 4, 10 or 20 mg/kg) in weekly IV infusions for 12 weeks. The study is not yet complete as the last participant just underwent his muscle biopsy, but Dr. Muntoni shared data from the first four groups (doses 0.5, 1, 2 and 4mg/kg). Boys participating in the trial had to have a deletion that could be brought back into frame by skipping exon 51—this eligible group included boys with deletions of exons 45-50, exons 47-50, exons 48-50, exons 49-50, exon 52 and exons 52-63. There were no serious adverse events associated with the drug at any dose and all but one boy completed the study (the boy who dropped out developed further cardiomyopathy which was deemed not related to the study drug).

As predicted, the boys who received the lowest dose of the drug did now show evidence for dystrophin protein n production or other evidence of exon skipping, but boys in groups who received the higher doses did show evidence of dystrophin production in a dose dependent manner—that is, as the dose increased, so did the amount of dystrophin produced. The “best responder” seemed to produce dystrophin in about 21% of his muscle fibers when evaluated by immunostaining from his final muscle biopsy. The full clinical results should be available at the end of summer or early fall and the company predicts that the two final groups, who received the highest dose of the drug, will demonstrate greater levels of dystrophin production.

GKS 2402968 (aka, PRO051), Exon-skipping

We had previously agreed with GSK to distribute a single unified report on this data, so I’m including that report, in the form of a Q&A based on questions submitted in advance by several groups:

( sent on Behalf of John Kraus, MD and Giles Campion, MD)

Q. How many boys and what ages participated? Were all of the boys ambulatory?

12 boys participated in Study PRO051-02. The age range was 5 – 13 years. One boy was non-ambulatory.

Q. Were all boys on open label at a certain moment and what was the regimen?

After the dose escalation portion of this study was completed, all boys entered an open-label follow up phase and all received PRO051/GSK2402968 6mg/kg once a week.

A. Did you see any serious side effects? Did any of the patients/participants have to stop because of side effects?

No serious adverse events, considered drug related, were observed in Study PO051-02. No patient discontinued from the study. Injection site reaction was the most commonly reported adverse event.

Q. Did any of them complain or refuse to take the injections?

No child refused the weekly injections.

Q. Do you have any data or insight into the potential toxicities of long term systemic delivery?

Small amounts of protein were present in intermittent urine tests during Study PRO051-02 and need to be investigated further. Longer term placebo controlled studies are needed to understand long term systemic delivery of this investigational drug.

Q. What do the results of this trial show in terms of dystrophin expression, changes in blood work (PK)? Was Dystrophin expressed in all boys? Were you able to quantify the amount? Were you able to correlate dystrophin expression to functional improvement?

Does Prosensa plan to show or have data to show dystrophin as a surrogate market for clinical benefit?
In the dose escalation part of Study PRO051-02, stable dystrophin was measured in all treatment groups in a dose related manner. These results are compatible with dystrophin levels of approximately 10 – 15%, although the dose escalation portion of this study was not long enough for the drug to have reached steady state. Longer term placebo controlled studies are needed to determine if these dystrophin levels are associated with improved muscle function.

Q. While we understand this was a Phase 1/2 safety/dose escalation trial, do you believe you now know the therapeutic dose?

It is too early to know the therapeutic dose of this investigational drug. Placebo controlled trials and regulatory approval are needed to determine the therapeutic dose.

Q. Did the 6mwt show any significant changes? And if so is this enough to approve the drug? Do we, with the results of this trial in hand, still need placebo controlled trials? And if so why?

Statistical significance was not determined in Study PRO051-02, as the study was small and did not have a control group for comparison. Most, but not all, boys had variable improvement in the 6-Minute Walk Distance measured after 12 weeks at a dose of 6 mg/kg. Larger placebo-controlled studies are needed for regulatory approval.

Q. Will you consult the patient population in an effort to understand what outcomes measures they believe carry the most significance?

The selection of outcome measures for clinical trials is based on discussions with clinical experts and regulatory authorities.

Q. Because the trial included several different mutations wherein skipping exon 51 would restore the frame, did you see variability in terms of expression across mutations?

This study was not large enough to answer this question.

Q. What are your plans for further development of exon skipping as a viable treatment for DMD?

New studies for PRO051/GSK2402968 are planned to start mid-2010, pending regulatory feedback.

Q. Which secondary outcome measures were tested during this trial?

Did you look at other biomarkers?

Secondary endpoints from this study will be included in the scientific publication.

Q. Which outcome measures will be used in the next trial(s)?

Study endpoints will be posted on when study plans are completed.

Q. Are you planning to include non-ambulant patients in future trials? Are you able to share that timeline?

It is anticipated that the next series of clinical studies with PRO051/GSK2402968 will include studies for ambulatory and non-ambulatory boys with a mutation correctable by skipping exon 51. These studies are planned to start in mid-2010, pending regulatory feedback. Clinical trial details will be posted on when study plans are completed.

Q. What does the outcome of this trial mean for the next steps in development of AO's to skip other exons?

These results support starting new PRO051/GSK2402968 studies in mid-2010, pending regulatory feedback.

Q. Are you able to provide details with regard to future plans in terms of what exons will follow? At what stage will 44 and 51 need to get to before further exons can be rolled out?

What timeline does Prosensa see for getting each further Exon to Market assuming 51 and 44 get passed next trial stages? Will these be run in parallel? What is the plan to get rarer exons to market (community scheme etc)..

Compounds currently in clinical development are being studied in mutations amenable to skipping exon 51 (GSK) and exon 44 (Prosensa). Compounds suitable for targeting other dystrophin mutations are under investigation in the laboratory setting.

Q. Are you considering expanded access programs and/or compassion for individuals who are unable to participate based on the inclusion criteria?
Not at this time.

Just to clarify a one point about the amount of dystrophin production reported by AVI vs. GSK/Prosensa, it’s important to note that AVI reported the percentage of muscle fibers that were positive for dystrophin in a given section of a muscle biopsy (21%) while GSK/Prosensa reported the percentage of dystrophin in a given section of a muscle biopsy compared to normal levels (15%). You cannot directly compare these two numbers. Both reported their best results—for AVI in a single patient, and for GSK/Prosensa, the average of the response on the group that got the highest dose.

ACE-031, muscle building compound

Acceleron reported the results of their compound ACE-031, which stimulates muscle production by inhibiting members of the TGF-beta superfamily (myostatin is a member of this group) from binding to and signaling through the Activin Receptor Type IIB (ActRIIB), in a safety study of healthy volunteers. The study was randomized, placebo-controlled and double-blinded with escalating doses. Other than some reports of headaches and injection site irritation, the drug was generally safe and well-tolerated.

The company found, in addition to being safe, that the two highest doses of the drug caused significant increases in lean muscle mass (3.3% when measured 29 days after the injection), and thigh muscle volume increased by 5.1%. Markers for bone formation were increased and some markers for fat formation were decreased. There was a trend for improved grip strength.

A dose-escalation clinical study for DMD has been launched in Canada and other indications are planned. For more on this approach, check out this informatin on Acceleron's Web site:

Final Thoughts

There's more to come at AAN (PTC presents tomorrow--Friday) and I haven't covered Dr. Mendell's gentamicin results here, but I will try to add that information tomorrow. I think the data from these three studies are encouraging, but caution that we really don't know, at the end of the day, how much dystrophin is required to improve muscle strength and reduce fatigue, and we really don't know, at the end of the day, if making muscles bigger will impact the course of Duchenne. The upcoming studies will help answer those questions but we might not have a straight path from phase I to II to III to approval for any of these drugs...or we might get lucky. It is good to see these three drugs in the pipeline and to know that other strategies like Biomarin's utrophin upregulator are also in clinical testing. The more shots we take the better our chances of a success.

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Comment by Sharon Hesterlee on April 18, 2010 at 7:15pm
Hi Steve:

I think we just don't guess is that it would likely be a stop-gap measure and something that could ultimately be combined with other approaches that seek to correct the underlying defect to get an additive effect. We also don't know about the non-ambulatory encouraging thing is that ACE-031 seems to reduce fibrosis (scarring) which is a big problem as the boys lose muscle. The results of the first clinical study in Duchenne should help to answer a lot of these questions.
Comment by Steve Dreher on April 17, 2010 at 8:44pm
Hi Sharon,

There is a discussion strand going on about ACE-031. In the best case, if it works as Acceleron hopes, is it primarily going to be a stop-gap (even considering the utrophin upregualtion)?

Also, what implications would it have for non-ambulatory boys? Could they conceivably build enough muscles to become ambulatory again?

Comment by Pat Furlong on April 17, 2010 at 10:38am
Thanks Sharon for the great report. I agree with your view about 'luck' and see this as maybe a bit broader than the human element, but human nevertheless, as it has to do with picking the right dose, stratifying the trial (subset of individuals), choosing primary/secondary outcome measures, selecting the right sites, who do things the right way, and so on... and then it has to do with the human response - that everything leading up (Iining all the ducks in a row to the extent possible) to this moment is replicated as predicted in the boys. And then dealing with the variability of the boys, degree of function, degree of fiber/fat in the muscle, etc and hoping,hoping, hoping that what you believe is exactly what you get in the end.

Again, Sharon, Thanks for everything.
Comment by cheryl cliff on April 16, 2010 at 7:23pm
Very helpful- thanks Sharon!!
Comment by Ofelia Marin on April 16, 2010 at 3:52pm
Wow! Very interesting Ataluren results! So low dose "works" but not high.
Comment by Jimmy Mooney on April 16, 2010 at 1:43pm
Thanks for the excellent updates.
I agree that we need a bit of luck as well.
A few years back I was convinced that Myodur would treat our sons as it seemed to have strong animal data at the time and it dissapeared.
One of these approaches surely make market approval.
Comment by Sharon Hesterlee on April 16, 2010 at 12:27pm
Cheryl, those are really good questions (lots of discussion among scientists at the AAN meeting on the same topics). Acceleron is developing additional preclinical data to answer some of those questions, but whether or not you can make enough muscle to cope with muscle loss in DMD is what we will find out with the clinical study. The animal studies suggest that you can improve strength, even though the new muscle mass lacks dystrophin. Normally those fibers without dystrophin are more susceptible to injury and they eventually die, leaving you with less muscle and less strength. There may also be some strength loss even in undamaged fibers due to the lack of dystrophin, but I think most people think the major cause of weakness is loss of the fibers themselves. So even though the increased muscle mass doesn't contain dystrophin, you might be able to stay ahead of the curve a bit just by building new muscle as fast as it's lost due to damage. Does that help answer your question? It's all pretty theoretical until you test it in humans, but the compound really does seem to increase muscle mass. Again--good questions. Lots of discussion about these same issues at the meeting.
Comment by cheryl cliff on April 16, 2010 at 12:01pm
Hi Sharon-
Opps, didn't finish asking questions before I hit the add comment button accidently...
Is there any info on how kidneys & liver will cope clearing extra nuscle necrosis?
and regarding satallite cells that generate extra muscle cells - will they enter early senesence from extra workload?
Comment by cheryl cliff on April 16, 2010 at 11:58am
With regard to ACE-031:
How much benefit can there be without dystrophin present in increased muscles?
Comment by Sharon Hesterlee on April 16, 2010 at 11:23am
Ofelia--of course the tremendous amount of scientific effort and funding put into these new technologies is the reason we are where we are, but a bit of luck is always appreciated, as anyone in the biotech industry knows. It's a hard slog...these trials are big and complicated and a million things can go wrong. I think we (scientists, funding agencies, companies and families) have done everything in our power to give these therapeutics the best shot and I'd like to think that we will beat the industry average with new drugs approved, but we also have to be prepared for the possibility that we might not go in a direct path from phase I to II to III...sometimes you have to go back to the drawing board and then move forward again. The more compounds we put into the pipeline with good solid data behind them, the better our chances will some extent it's a numbers game. VC's will typically make 20 investments from a single fund hoping that one or two will hit. If you get lucky, the first investment is the one that hits, not the last. That's what I meant by "luck." :)

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