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 www.clinicaltrials.gov 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 www.clinicaltrials.gov 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: http://www.acceleronpharma.com/content/products/ace-031.jsp.

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 Jacobs Mommom on April 16, 2010 at 11:14am
Thanks Sharon for posting in a way that everyone can understand. I too hope that the "get lucky" phase is in the past but just incase I too will keep everything crossed like Cheryl and continue with the prayers:)
Comment by Ofelia Marin on April 16, 2010 at 9:13am
Sharon, I really hope that we are passed the "get lucky" phase. Scientists worked on exon skipping for DMD for years and years, 8-10 (?). They did see functional improvement (at high doses) in large animals. Prosensa/GSK moved from Phase I to II and now (hopefully before the end of the year) to Phase III. AVI is also starting the next phase of the trial. We do not know how much dystrophin is required for functional improvement in humans (10-15% obtained by Prosensa at 6 mg/kg dose 12 weekly injections is promising, lower than what Wilton and Muntoni think it "might" be needed but promising), how high a dose is required to get there and many other questions need to be answered BUT there is progress. One would hope that things progress mostly based on the knowledge accumulated during the past 10 years and not so much on luck.
Comment by Donna Taylor on April 15, 2010 at 8:20pm
Thanks so much for the detailed post Sharon. We are so fortunate to have you there to update us with the very latest information.
Comment by cheryl cliff on April 15, 2010 at 7:18pm
What beautiful news! Thanks so much Sharon!! Hope it will keep on coming.
Going to keep fingers, eyes, toes, arms & legs crossed while repeating prayers asking God to remove Duchenne from the planet, 2010.
He/She probably thinks I'm a freak but that's OK :)

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