Prosensa has completed their Phase II systemic delivery. AVI’s dose escalation trials are still in progress in the UK. Both companies are expected to discuss progress to date during the annual World Muscle Society meeting in Geneva, Switzerland, September 9-12, 2009. Both companies have targeted skipping exon 51 and trials were done to prove safety and to determine therapeutic dose. In both cases biopsies were performed before and following delivery of the exon 51 skipping chemistry.

Next steps include multi-centered trials. Prosensa is in discussion with regulatory agencies and has plans to open trials skipping exon 51 and exon 44. These multi-centered trials are expected to be Phase IIb trials. AVI has announced plans for trials skipping exons 51 and 50. The multi-centered trials will concentrate on efficacy, paving the way for exon skipping as a potential therapy for Duchenne.

Many of the Duchenne specific foundations are providing financial support to academic laboratories collaborating with Industry partners and/or to AVI or Prosensa – Action Duchenne (UK), AFM, Charley’s Fund, Cure Duchenne, DPP (Italy, the Netherlands), MDA, PPMD (USA) and UPPMD.

As always, we will keep you up-to-date as information becomes available.

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Comment by Teresa on August 27, 2009 at 5:50pm
I don't understand if my sons deletion is 42 would he qualify... And if one sons deletion is 42 would all my sons delitions be 42???

Comment by Pat Furlong on August 27, 2009 at 11:58am
It certainly feels like a new day for our sons... dawn and the sun coming up.
Comment by cheryl cliff on August 27, 2009 at 11:54am
Muchas gracias Pat and Ofelia for the current update :). Paul and I live for optimistic DMD information. Information we can pass on to both our sons so we, as a family, know good things are happening to solve the DMD puzzle.

It is getting closer and what a beautiful sight to see !!

Comment by Pat Furlong on August 26, 2009 at 10:40am
As suggested in the blog, AVI will release results during the World Muscle Society Meeting.
AVI BioPharma Phase 1 Proof of Concept and Safety Data for AVI-4658 in Duchenne Muscular Dystrophy Featured in Lancet Neurology
AVI-4658 Demonstrates Compelling Proof of Concept and Safety Profile for Pediatric Patients with DMD; Findings Support Progression to Current Systemic Use Trial
For Immediate Release
BOTHELL, WA — Aug. 25, 2009 — AVI BioPharma, Inc. (Nasdaq: AVII), a developer of RNA-based drugs, today announced that the results and scientific findings of its Phase 1 clinical trial assessing the "proof of concept" and safety of AVI-4658 in patients with Duchenne Muscular Dystrophy (DMD) have been published online in the journal, Lancet Neurology. DMD is an incurable muscle-wasting disease associated with errors in the gene that makes dystrophin. These findings, which show that treatment with AVI-4658 was safe and effective in inducing dystrophin expression, suggest that AVI-4658 could have promise as a drug for the treatment of DMD. The paper will be published in the October print issue of the journal.
The paper, "Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study," was authored by AVI and a group of preeminent DMD researchers including Professor Francesco Muntoni, the principal investigator of the UK MDEX Consortium. The publication was featured in the journal along with commentary and review from scientists at the Leiden University Medical Center. This external review explored AVI's data in comparison to similar recent antisense technology findings, with an alternative chemistry, and ultimately underscored the overall therapeutic potential of antisense technology in this indication and, importantly, the need for a safe antisense therapy that could be dosed at effective levels for lifelong use in pediatric patients living with DMD.
"We are extremely excited by these promising data for AVI-4658 in patients with DMD, which further validate the excellent safety of our extensively studied core chemistry around phosphorodiamidate morpholino oligomers, or PMOs," said Dr. Stephen B. Shrewsbury, Chief Medical Officer and Senior Vice President of Preclinical, Clinical and Regulatory Affairs of AVI. "We believe that these data and our additional findings to be presented at the upcoming 14th Annual International Congress of the World Muscle Society will provide the DMD community with the opportunity to fully understand the promising safety and efficacy of the PMO therapies being developed for chronic, lifelong use in children living with DMD."
The Lancet Neurology publication details AVI's Phase 1 study, in which Professor Muntoni and his team conducted a single blind, placebo-controlled, dose escalation study in DMD patients to assess the safety and proof of concept of a single intramuscular administration of AVI-4658 into a small foot muscle - the extensor digitorum brevis (EDB). Biopsies of placebo and drug-treated muscles from each patient were conducted approximately three to four weeks following this intramuscular injection. The primary endpoint of the trial was to determine safety and tolerability, especially in terms of the potential for an immune response to newly expressed dystrophin induced by the ability of AVI-4658 to skip exon 51 and so enable protein expression. The findings of the study show that there were no drug related serious adverse events in the study, no adverse event signal related to the administration of study drug AVI-4658 and no observed immune response to the newly expressed dystrophin. This PMO therapy induced detectable exon skipping at a very low drug dose of 0.09 mg and at the 0.9 mg dose the skipping of exon 51 led to high levels of dystrophin expression, compared to the placebo-treated muscle on the other foot. It is important to note that the dystrophin levels achieved per cell - up to 42 percent of those found in healthy muscle - exceeded the levels reported from a recent 2'O-Methyl-oligonucleotide (2'O-Me) DMD clinical trial referenced in the external review by the Leiden University Medical College researchers.
"The growing body of promising data for potential treatments for DMD is a significant milestone in and of itself and one that we are extremely encouraged to see realized," said Nick Catlin, Chief Executive Officer of Action Duchenne, a leading UK charity dedicated to increasing awareness, engendering action and raising funds to find a cure for DMD. "Action Duchenne believes that these results from AVI are promising and we are excited to be working with the company and supporting its research through Action Duchenne funding. We are pleased that DMD patients and their families are beginning to see long-awaited movement toward a potential safe, well tolerated and effective therapy for this devastating disease."
AVI also announced today that it will present these Phase 1 data at the 14th International Congress of the World Muscle Society, along with late-breaking, preliminary data from its currently ongoing Phase 1b/2 clinical trial evaluating the systemic administration of AVI-4658 in boys with DMD. These preliminary findings from the ongoing trial continue to confirm the excellent safety record of PMO therapy, validate AVI's novel approach to treating DMD with this PMO class and show that AVI-4658 has been very well tolerated by DMD patients in the first two completed dosing cohorts in the trial. There have been no serious adverse events or drug-related adverse events identified and the independent Data Safety Monitoring Board has approved each of the AVI trial's dose escalations. Dosing at 4mg/kg is ongoing. In the coming weeks, AVI expects to escalate to two higher doses - 10 and 20 mg/kg - which, at 12 weeks duration, will exceed both the dose levels and the duration of dosing previously studied elsewhere with the alternative 2'O-Me approach. AVI believes that this encouraging and growing safety profile, duration of exposure and approved dose escalations are extremely important clinical advances for its PMO chemistry approach as any dose-limiting toxicity, especially after only short-term exposure, could severely limit the effectiveness of a DMD therapy in this chronic condition where treatment must continue for life.
"These data are both important and timely and we at AVI believe that we could be at a critical juncture in the treatment of this debilitating and fatal disease," said Dr. Leslie Hudson, President and Chief Executive Officer of AVI. "We are pleased to have the support of Action Duchenne and other research and patient organizations that are committed to accelerating the development of safe and effective drugs for DMD patients. Further, we are eager to continue our work with our clinical collaborators and the U.S. and European regulatory authorities as we work to develop AVI-4658 - which has both orphan drug and fast track status - as safely and expeditiously as possible."
The currently ongoing Phase 1b/2 dose-finding clinical trial is evaluating the systemic delivery of AVI-4658. This is an open label, 12-week safety trial, which includes measures of drug efficacy and pharmacokinetics and is being conducted in London, UK at the UCL Institute of Child Health / Great Ormond Street Hospital NHS Trust facilities and at the Royal Victoria Infirmary, Newcastle-Upon-Tyne, UK which is the coordinating center for the European Treat Neuromuscular Diseases (Treat-NMD) initiative. The clinical costs for the trial are provided, in part, by the UK Medical Research Council.
Comment by Ofelia Marin on August 25, 2009 at 9:15pm
New info here:
Comment by Tricia Ferrell on August 15, 2009 at 8:23pm
Hi Pat,

We always love to hear good news! Skipping Exon 51 will work for my boys and we too would like to them to participate in the upcoming trial. We look forward to future postings.
Comment by Panayiotis Voskos on August 14, 2009 at 4:42pm
Thanks for the news Pat. Hope that in October will hear more interesting ones.
Comment by Ofelia Marin on August 14, 2009 at 3:18pm
A couple more details about AVI 4568 trial from AVI's 2nd quarter financial results conference call. They are in the highest dose level group (4 mg/kg) group BUT they submitted and received EMEA approval to increase the dose to 10 mg/kg and 20 mg/kg so the UK trial will continue until Q2 2010. They did not look at any data about dystrophin expression at this point so nothing can be said about the dystrophin produced. Safety looks fine so far at all levels up to 4 mg/kg. They plan to present something at the Geneva conference in mid September.

About the US trials, they are working on the mouse and primates preclinical additional data requested by FDA in order to lift the clinical hold. It is hoped that the data will be sent to FDA Q1 2010 so the trial will not start before Q2 2010. Of course, no enrollment is done at this point as Pat mentioned. The hope is that the therapeutic dose range found working during the UK trial will be used in the US trial.

Comment by Pat Furlong on August 14, 2009 at 9:42am
A couple of things:
Dr. Mendell is working with AVI and will be the initial site for the clinical trial (avi/4658), but he is not recruiting patients and the trial is not open. All clinical trials in the US are listed on the site Here is a url to the DMD specific trials:
I am sure Dr. Mendell and staff are excited about the trial and are probably talking about it with patients, but they are not accepting patients into the study. In addition, I am sure the first patients to be screened be local, that is live fairly near to the site (Columbus, Ohio) This is very typical in trials because of safety. Should there be side effects or concerns, it is good if the patients live in the area as there are often some things that occur that need to be figured out in the first days and with the first patients. No patient recruitment can occur at this time. AVI is still on clinical hold and until the FDA lifts the hold and approves moving forward, nothing can happen. And once FDA approves, Dr. Mendell and in the near future other sites will need IRB (institutional review board) approval from their local institutional board.

AVI vs Prosensa. There are rumors upon rumors about what trial to join and what chemistry might be more efficient. The truth of the matter is that we simply do not know. You all know Prosensa has completed the safety and dose escalation trial. Their press release said they have ‘promising results’. What is not yet released by the company is the quantity of dystrophin expressed. And further what is still unknown in the world of Duchenne is how much Dystrophin (or in the case of exon skipping – how much of the shortened version) is needed to improve function – that is, for clinical benefit. Researchers are making guesses based on the mdx mouse and a few dog studies, but what that means in terms of an individual boy, your son for instance, is likely to be different. How much will your son need to stabilize or to improve? And it will probably have a significant variation based on degree of muscle damage present and a number of other factors (genetic modifiers). The AVI dose escalation trial in the UK is nearly complete as well. AVI has suggested the same ‘promising results’ which means the shortened Dystrophin was expressed. The quantity of Dystrophin on biopsy has not been released. And keep in mind, none of the trials were looking for clinical benefit. They were limited to safety (and found to be safe) and dose escalation (to determine therapeutic dose) and efficacy in the context of amount of dystrophin expressed.

Both companies are moving forward. Trials are trials. They have a beginning and an end. Because neither chemistry has been in DMD boys in the US, I would assume they will start with a 2A, (safety, dystrophin expression, functional testing - proof of concept) evaluate the results and, if positive, move to the 2b where they will need a significant number of boys and multiple sites, testing for clinical benefit/efficacy.

At the moment, the jury is out on which chemistry will be better and it just may be that they both work (think prednisone/deflazacort-both work, some boys respond better to one or the other) or that one works for certain mutations where skipping 51 results in an in-frame mutation and the other works in other instances. I think it is premature for anyone to suggest one is better than the other and to be honest, a bit unfair. This is the work of clinical trials.

And last, if your son is screened and is accepted into a clinical trial, it is unacceptable to quit one trial and join another because you think it might be better. It will be important to think carefully and critically about participation, what it may mean for your son.

I wish this was easier. Please do not listen to rumors. The field is full of them. If someone promises you something, please understand those are words. There are no promises but there is reason to have a great deal of hope.

I am currently in DC, a member of an Institute of Medicine Committee on rare disease. One of the members of the panel said “feels like trials and potential therapies are raining down on Duchenne”. I smiled and said “from your lips to God’s ears”. There are any number of trials moving forward from exon skipping, to myostatin inhibition (acceleron) to Losartin (multi-site trials), IGF-1, and other. In addition, care and interventions are improving continuously. There is no one therapy that will be ‘magic’, erasing the word Duchenne from your heart and your son’s life. But a combination of aggressive care and therapies will help your son life a long and productive life.
Comment by Julie Hathaway on August 12, 2009 at 9:16pm
I've heard that boys have already signed up for Dr. Mendel's trial through AVI and wondered where I can go to do this. Also, what are your thoughts on the progress of Prosensa vs. AVI and will our boys be able to sign up for both? We are still so new to the Duchenne community and I'm a little confused. I don't want to miss out on any opportunities. Brandon has a deletion of 51. Thank you.

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