Phase I/IIa study on Antisense Compound PRO051 in patients with Duchenne (van Deutekom)

Eight years in the drug development of AON. PRO051 is a 2’o-Me-PS RNA antisense oligonucleotide introducing exon 51 skipping. It demonstrated proof of concept with up to 95% dystrophin fibers in treated muscle area in Duchenne patients. 6 month safety data on PRO051 was available in monkeys and longer term studies in progress. Extensive safety data available for this class of compounds. 12 patients/4 sequential groups from .5 to 6mg/kg – dose escalation trial, completed in May 2009. This was a safety trial with extensive safety parameters. Plasma and tissue PK profile analyzed. Muscle biopsies at two time-points. RNA and protein effects. CK levels were drawn. Muscle strength and performance measured.

12 patients admitted to the study and treated. Mean age 9.1 years with different clinical status in the disease process. All were on a stable dose of steroids. PRO051 was safe and well-tolerated. No SAE detected. Only difficulty was localized pain at the injection site. None of the patients discontinued the study. No safety concerns. Dystrophin antibodies were checked, none found. Because the study is not published, full data is not available.

PK – 6mg/kg. Measuring levels demonstrated : Rapidly cleared from plasma, rapidly distributed to muscle tissue. Half life is 19-56 days.

Dystrophin was detected in all biopsy samples. The protein was sequenced and was found to be expressed as the result of skipping.

Even in the low dose group, dystrophin was detected.

Clinical effects: after 5 weeks. (patient has not reached steady state) trends in functional improvement and drop in CK. In the highest dose groups, there is a trend toward decreased CK levels and early signs of functional improvement as determined by 6 minute walk test and functional testing.

There is some confidence that with longer studies, they will be able to demonstrate safety and efficacy.

This was the first study to show successful administration of antisense oligo in Duchenne. Extension study has started and is ongoing in all 12 patients at the highest dose (6mg/kg). Safety data up to 6 monts is being collected. Phase II/III pivotal 12 month study is in preparation. They expect to start the study within the next year.

MDEX- AVI exon skipping - F. Muntoni

Current trial: 7 patients, ages 10-17 years of age. This was a dose escalation study and the first systemic administration of AVI 4658 in Duchenne.

There were 6 cohorts in a dose escalation. Dose level 0.5 to 20.0mg/kg IV. The infusion was given over a period of 1 hr, weekly X 12 weeks. The initial subject in each cohort was treated for 3 weeks. If there were no serious concerns, they would move to the next patient. All patients were ambulant and were biopsied to confirm the absence of dystrophin. All mutations were confirmed. Patient and family had psychiatric adjustments, supportive psychosocial services and full understanding of the study aims, process, and likely outcomes.

Primary outcome was safety and tolerability.

Secondary outcomes were PK (urine and blood), molecular efficacy (dystrophin on biopsy), and functional testing.

Psychiatric adjustments: Process
• Parents and children seen separately as part of the trial preparation procedure
• Interviews and questionnaires
• Level of risk conveyed to the research team.

Patient recruitment took place in London and Newcastle. Patients were referred through advocacy groups and registries.

Status to date: Last cohort of patients in process. Genotype of patients is represented – those with mutations where skipping exon 51 will result in an in-frame protein. No drug related adverse events. One patient had a worsening cardiomyopathy and had to be excluded, but this was not related to the compound. CK levels demonstrate a decreasing trend. Dr. Muntoni would not comment on functional improvement. He said it was too early to discuss.

General comments: Antisense is well-tolerated, given IV. Some of the patients have now received a considerable amount of drug without appreciable side effects. Last patient will complete in March at which time full analysis of the data will begin.

More to come from Brussels...

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Comment by JUAN PEDRO ARBULU on November 19, 2009 at 6:46pm
we should head for 2012 for sure, it´s possible and we will keep pushing until we do it.
Thank you Pat.
Comment by RAKTIM SINGH on November 19, 2009 at 12:27am
This is great. Prayer and Hard work pays. Let's hope for the best.
Comment by cheryl cliff on November 18, 2009 at 9:04pm
Wow, pumpkin gnocchi! Jerry, can I have the recipe?
And although, at Pat's request, I will keep the pitchfork stored away I would like to reserve the right to using voodoo should this nice lady with FDA go sour. ;D
Comment by Jerry Dallapè on November 18, 2009 at 8:42pm
I've got plenty of sugar, Pat. Tell her I make a killer pumpkin gnocchi and would be more than happy to make it for her. I can also get her my discount at Bed Bath & Beyond if she can facilitate this thing. ;-)
Comment by cheryl cliff on November 18, 2009 at 7:22pm
Ok Pat, I'll keep the tools in the shed for now :)

Comment by Pat Furlong on November 18, 2009 at 5:42pm
I think we have a friend in FDA, she is here and attended the EMEA meeting. She agrees that DMD is at a pivotal point and if we get this right, other rare conditions will benefit based on what we learned in terms of outcome measures and trials with small populations. No need for a pitchfork at the moment as sugar is better than acid. Advocacy - consistent messages and consistent pressure.
Comment by cheryl cliff on November 18, 2009 at 5:05pm
Jerry, our pitchfork is still in the garage and still sharp. It may be time to consider going medieval in DC. Probably no better time than the present...
Comment by Jerry Dallapè on November 18, 2009 at 3:06pm
The better the news, the more impatient I become. Faster, faster! More, more!

I sense that we should start making preparations to descend en masse on our elected officials and the regulatory bodies to push this therapy through as a class of drugs and to expedite it even faster to our sons. We've had great success coming together as a community in recent months. Let's start ramping up our advocacy and reaching out to other Duchenne groups to make exon skipping a reality by 2012.
Comment by Jacobs Mommom on November 18, 2009 at 2:17pm
Thumbs Up!
Comment by Ofelia Marin on November 18, 2009 at 2:00pm
This is great, best news we can expect at this point. Thank you!

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