AVI BioPharma Announces Treatment of First Patient in Systemic Clinical Trial of AVI-4658 for Treatment of Duchenne Muscular Dystrophy

This is good news, even though the timeline is not that good -- 2 years for this Phase(?):

Estimated Enrollment: 16
Study Start Date: January 2009
Estimated Study Completion Date: December 2011
Estimated Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)

Let's hope that this will not delay the entry of the PPMO in trials.

http://www.clinicaltrials.gov/ct2/show/NCT00844597?spons=%22AVI+Bio...


http://www.avibio.com/pr/pr410.php

PORTLAND, OR — February 19, 2009 — AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA-based drugs, today announced treatment of the first patient in a clinical trial evaluating the systemic delivery of AVI-4658 for the treatment of Duchenne muscular dystrophy (DMD).

“We are very pleased to begin the systemic evaluation of our exon skipping drug — AVI-4658 — for the treatment of DMD,” said Stephen Shrewsbury, M.D., Chief Medical Officer and Senior Vice President, Clinical and Regulatory Affairs of AVI BioPharma. “We believe that this trial will build significantly on the data generated by the successful recent trial evaluating intramuscular administration of the same drug in DMD boys.” ...

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Ofelia - so, was there an actual request for a trial in the US by AVI that was put on hold by the FDA? I know you're really up to speed on research and trials - where can I look that kind of stuff up - specifically things that have applied for a trial? I would really like to learn more about this - especially about other potential therapies.
Ofelia,
Is AVI going to have trouble getting what I hope is an exon 50 skipping trial going in the US? Is the FDA going to hold that up? I know you said they had hoped to start that in 2010. This is of high inerest for me because it would potentially benefit my son.
Hi Karen,

I do not know if the FDA will hold the skipping trials for exon 50. All I know about that is that AVI is still working on the preclinical stuff and they hope to be done by the end of the year. It all depends on how those results will look.

Ofelia

Karen Barnett said:
Ofelia,
Is AVI going to have trouble getting what I hope is an exon 50 skipping trial going in the US? Is the FDA going to hold that up? I know you said they had hoped to start that in 2010. This is of high inerest for me because it would potentially benefit my son.
Keith,

During AVI's recent conference call about the DMD program the CEO (Leslie Hudson) said that FDA has put a clinical hold on skipping exon 51 using the PMO's from the UK trial. He did not give any details about why that is. He only said their hope is that the first results from the systemic delivery UK trial (which should be available during Q3 2009) will provide convincing evidence for the FDA to lift the clinical hold.

Reading an older presentation from September 2008 (http://www.avibio.com/downloads/AVI-2008-09-10-03-Leslie_Hudson_DMD...), on slide 16 I found this:

"US plans for Clinical Development of AVI-4658".

- Negotiated preclinical requirements with the FDA
- Have allowance for mechanistic toxicology study in mdx mouse model of DMD to support clinical testing of AVI-4658
– Evaluation of PMO-based exon 23 drug
– Initiate 3-month mdx toxicology study in 4Q 2008
- Anticipate that UK Phase 1b study results might impact FDA decision making prior to completion of planned pre-clinical GLP agenda for US-based studies
– Might allow immediate pivotal trial testing in US DMD boys

The question is: did they finish the "3-month mdx toxicology study" started in 4Q 2008? If not, that could explain why the FDA did not lift the hold, they are probably waiting to see these results before they allow the start of the trial... I do not know the answer to this question. I whish someone who has access could ask the CEO for more details about the US trails.

Then, there is Eric Hoffman's group using PPMOs. Last year, they did claim that they are ready to start clinical trials in the US this year. I am not sure what the problem is there.

Sorry, I do not have answers, only more questions unfortunately.

Ofelia



Keith said:
Ofelia - so, was there an actual request for a trial in the US by AVI that was put on hold by the FDA? I know you're really up to speed on research and trials - where can I look that kind of stuff up - specifically things that have applied for a trial? I would really like to learn more about this - especially about other potential therapies.
Does anyone know what happened to Eric Hoffman's research??
what particular research are you referring to?

I just spoke with Dr. Hoffman, and he is working like crazy to negotiate with AVI on their US exon skipping trials plans. They are also continuously testing promising compounds on their mice, although I'm not sure which ones they're currently working on.

I talked to the ombudsman at the FDA, and she said that the FDA can't share the reasons behind the clinical hold because it's proprietary information. But it's got to be a demand for either additional toxicology or additional efficacy studies...
Mindy,

I was talking about the PPMO work from Hoffman and collaborators. Do they have all the preclinical work completed to be able to start a clinical trial this year? Do they plan to start by skipping 51, other exons, parallel trials? Will AVI be able to support this on their own?

Ofelia

Mindy said:
what particular research are you referring to?

I just spoke with Dr. Hoffman, and he is working like crazy to negotiate with AVI on their US exon skipping trials plans. They are also continuously testing promising compounds on their mice, although I'm not sure which ones they're currently working on.

I talked to the ombudsman at the FDA, and she said that the FDA can't share the reasons behind the clinical hold because it's proprietary information. But it's got to be a demand for either additional toxicology or additional efficacy studies...
New AVI page about DMD: http://www.antivirals.com/duchenne_muscular_dystrophy.php

Information for Patients
DMD is an incurable muscle–wasting disease associated with errors in the gene that makes dystrophin, a protein that plays a key role in the way muscles work. Our drug candidate AVI–4658 is in clinical testing and has been designed to skip exon 51 of the dystrophin gene, allowing for restoration of the information in the mutated gene needed to make dystrophin from mRNA. AVI believes that restoring dystrophin might improve, stabilize or significantly slow the disease process, and might prolong and improve the quality of life for specific patients with DMD.

AVI is also evaluating a drug candidate AVI-5038, designed to skip exon 50, which is in preclinical development.

Mutations that could be potentially corrected by skipping exons 51and 50 are as follows:

Exon to be skipped Drug Candidate Stage Treatable Deletions
51 AVI-4658 Clinical Development Phase 1b 45-50, 47-50, 48-50, 49-50, 50, 52
50 AVI-5038 Preclinical Development 51, 51-53, 51-55


AVI is currently testing only two candidate drugs, AVI-4658 and AVI-5038, which have been designed to skip exons 51 and 50 respectively.
Interesting information during AVI’s conference call today (Q&A section). http://www.avibio.com/pr/pr412.php

About FDA’s clinical hold on 4658:

Patient advocacy groups (ActionDuchenne was mentioned) in the UK/Europe had a good relationship with the regulatory agency and that allowed the start of the UK trial w/o the full amount of safety data FDA is used to seeing. EMEA also took into account that PMOs were used in humans extensively.

The plan is to go back to the FDA with the mouse toxicology data (which is available at this point or will be soon) plus safety data in humans from both the UK IM and IV trials. They are revising a protocol plan now so they can go talk to the FDA during Q3 2009 when the safety data from the 3rd cohort of the UK IV trials becomes available.

About partnering with a big biopharma company for DMD program:

They feel that they can obtain a more attractive deal after clinical data is obtained. Discussions have been going on.

About the progress of the UK IV trial for 4658:

The first patient is in the 3rd dosing cohort.
They expect to have the predictive therapeutic range during Q3 2009.
After the 4th cohort, they will decide if the dose should be increased to >4 mg/kg.

About the PPMO for skipping exon 50:

Preclinical work just started this year, IND expected sometime during Q2 2010.
Great update, thanks for posting it.
That's a very good news,but I'm wondering after the FDA approval to begin trails,are we going to start from zerro or we'll continue from where the UK get to? since they already start the trails.
From what I've been told, much, possibly all, of the data generated in the UK can be used with the FDA, so it should be better than starting from zero.

djamel fathi said:
That's a very good news,but I'm wondering after the FDA approval to begin trails,are we going to start from zerro or we'll continue from where the UK get to? since they already start the trails.

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