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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I agree. Assuming that all works well, by the end of the year they (AVI/MDEX) will know the therapeutic range (the appropriate dose level) besides collecting all the safety data. That therapeutic range can be used in the US trials, no need to go back and test the lower levels.



Paul Cliff said:
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.
This is a very good thing. If you go to Avi's website, you can listen to a tele-conference on the subject. The trial length lasts two years, but since they are now using these 16 boys to research IV drug delivery, results are expected by the third quarter of this year. I'm fresh from a meeting with Dr. Hoffman - and as you all know, he is the King on MD. He further says to NOT expect too much from this trial section as the dosing is way too low. The dosing at 0.9 with injections at the actual muscle site proved to have amazing results, but keep in mind that it was not IV delivery. This trial for the 16 is IV delivery. Our main goal at this point to to wait for the trial to come to the US - and that will more likely be at Children's in DC - luckily that's where I am. DC and Hoffman are already set up for the trials and since AVI just fired and hired new leaders, they too seem confident that within the next two years, trials will already be underway here. Hoffman was to seriously increase the dosage. Hoffman has dedicated his life to helping and is a wonderful person. Hang in there, it's coming.
The US still needs FDA approval and Hoffman has that all in order. Not a problem. There is a current hold on the process pending the outcome of the UK's current trial. But that will not stop or alter FDA approval.

Ofelia Marin said:
I agree. Assuming that all works well, by the end of the year they (AVI/MDEX) will know the therapeutic range (the appropriate dose level) besides collecting all the safety data. That therapeutic range can be used in the US trials, no need to go back and test the lower levels.



Paul Cliff said:
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.
I think there is some confusion here. AVI will be running the trials not Dr. Hoffman. AVI needs to get approval from FDA in order to start the trials. They are in discussions with the FDA as we speak.

CNMC in DC will be ONE of the trial sites. There will be other sites as well; for example AVI's people went to Dr Mendell (Columbus Childrens) a couple of weeks ago to discuss having them as a site for the trials. I am sure there will be several sites. The trial is expected to start this year.

Concerning the dose levels, they will be part of the protocol, AVI will decide how high they need to be using the experience obtained from the UK trial. We need to keep in mind that we cannot translate exactly the dose used in other species to humans, the most important results about safety&dosing will come from the UK trial.



irishgirl said:
The US still needs FDA approval and Hoffman has that all in order. Not a problem. There is a current hold on the process pending the outcome of the UK's current trial. But that will not stop or alter FDA approval.

Ofelia Marin said:
I agree. Assuming that all works well, by the end of the year they (AVI/MDEX) will know the therapeutic range (the appropriate dose level) besides collecting all the safety data. That therapeutic range can be used in the US trials, no need to go back and test the lower levels.



Paul Cliff said:
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.
This is Steve Wilton's replay to my question about the huge discrepancy b/w dose levels in Hoffman's dog experiments and UK trail skipping 51.

Hi Ofelia, the Hoffman canine AOs were not optimized and they relied on high concentrations to make it work. The UK trials have to be safe, hence doses will be much lower. They may not work, but they will be safe.

Hope this helps

Cheers Steve


irishgirl said:
The US still needs FDA approval and Hoffman has that all in order. Not a problem. There is a current hold on the process pending the outcome of the UK's current trial. But that will not stop or alter FDA approval.

Ofelia Marin said:
I agree. Assuming that all works well, by the end of the year they (AVI/MDEX) will know the therapeutic range (the appropriate dose level) besides collecting all the safety data. That therapeutic range can be used in the US trials, no need to go back and test the lower levels.



Paul Cliff said:
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.
AVI BioPharma Announces Department of Defense Funding to Accelerate Development of AVI-4658 for Duchenne Muscular Dystrophy

http://www.avibio.com/pr/pr416.php

For Immediate Release
PORTLAND, OR — May 6, 2009 — AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA-based drugs, today announced a $2.5 million contract with Children’s National Medical Center (CNMC) in Washington, D.C. to support preclinical studies in the development of AVI-4658 for treatment of Duchenne muscular dystrophy. The work will be conducted with CNMC collaborators Eric Hoffman, Ph.D., an authority on DMD and Professor of Pediatrics, and Edward Connor, M.D., Director, Office of Investigational Therapeutics and Professor of Pediatrics. AVI will serve as a subcontractor to a grant awarded to CNMC by the U.S. Department of Defense.

“We are pleased to collaborate with Dr. Hoffman, a distinguished researcher and expert in the field of DMD, and advance AVI’s efforts toward the development of therapeutics utilizing exon skipping for the treatment of DMD,” said Steve Shrewsbury, M.D., Chief Medical Officer and Senior Vice President of Clinical and Regulatory Affairs of AVI BioPharma. “Through this collaboration, AVI hopes to provide the additional data as requested by the FDA to allow clinical studies with AVI-4658 to begin in the U.S.”

The collaboration will support a series of GLP toxicology studies for AVI’s exon skipping drug candidates based on phosphorodiamidate morpholino oligomers (PMO) chemistry. The funding is part of the Department of Defense’s Congressionally Directed Medical Research Program to identify and pursue research with the most promise for treatment of DMD.

“Exon skipping represents one of the most promising investigational approaches for the treatment of Duchenne muscular dystrophy, and it is imperative to accelerate the clinical development of therapeutics that could improve the care and quality of life for boys with this disease,’ said Dr. Hoffman. “We are excited to be collaborating with AVI, both a pioneer and a leading developer of RNA-based drugs.”

“A strong pre-clinical GLP toxicology package is a critical part of a robust drug development program, and this new grant is designed to help enable both intravenous and subcutaneous clinical trials in DMD patients in the U.S.,” said Dr. Connor.

AVI is currently evaluating AVI-4658 in human clinical trials in Europe. The drug is designed to skip exon 51 of the dystrophin gene, allowing for restoration of the reading frame in the mRNA sequence. By skipping this exon, a truncated, yet potentially functional form of the dystrophin protein is produced, which could ameliorate the disease process and possibly prolong and improve the quality of life in these patients. Results from a Phase 1 proof-of-concept trial showed that injection of the drug into the muscles of a series of DMD boys successfully induced dystrophin production in a dose-responsive manner. Further, the drug was well tolerated, with no significant drug–related adverse events reported. The clinical trial was conducted in collaboration with the MDEX Consortium in London UK. AVI is currently sponsoring an ongoing clinical trial in the UK evaluating the systemic delivery of AVI-4658. This is an open label, 12 week safety trial, which includes measures of drug efficacy and pharmacokinetics, being conducted in London UK at the UCL Institute of Child Health / Great Ormond Street Hospital NHS Trust facilities by members of the MDEX Consortium.

About Duchenne Muscular Dystrophy (DMD)
DMD is the most common fatal genetic disorder to affect children around the world. Approximately one in every 3,500 boys worldwide is afflicted with Duchenne muscular dystrophy with 20,000 new cases reported each year. It is a devastating and incurable muscle-wasting disease associated with specific inborn errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fiber function. Symptoms usually appear in male children before age six. Progressive muscle weakness of the legs and pelvis eventually spreads to the arms, neck, and other areas. By age 10, braces may be required for walking, and most patients are confined to a wheelchair by age 12. Eventually, this progresses to complete paralysis and increasing difficulty in breathing. The condition is terminal and death usually occurs before the age of 30. The outpatient cost of care for a non-ambulatory DMD boy is among the highest of any disease. There is currently no cure for DMD, but for the first time in decades, there are promising therapies in or moving into development.

About AVI BioPharma
AVI BioPharma is focused on the discovery and development of RNA–based drugs utilizing proprietary derivatives of its antisense chemistry (morpholino-modified phosphorodiamidate oligomers or PMOs) that can be applied to a wide range of diseases and genetic disorders through several distinct mechanisms of action. Unlike other RNA therapeutic approaches, AVI’s antisense technology has been used to directly target both messenger RNA (mRNA) and its precursor (pre-mRNA), allowing for both up- and down-regulation of targeted genes and proteins. AVI’s RNA–based drug programs are being evaluated for the treatment of Duchenne muscular dystrophy as well as for the treatment of cardiovascular restenosis through our partner Global Therapeutics, a Cook Group Company. AVI’s antiviral programs have demonstrated promising outcomes in Ebola Zaire and Marburg Musoke virus infections and may prove applicable to other viral targets such as HCV or Dengue viruses. For more information, visit www.avibio.com.

About Children’s National Medical Center/Children’s Research Institute
Children's National Medical Center, located in Washington, D.C., is a proven leader in the development of innovative new treatments for childhood illness and injury. Children’s has been serving the nation's children for more than 135 years. Children’s National is proudly ranked among the best pediatric hospitals in America by US News & World Report and the Leapfrog Group. For more information, visit www.childrensnational.org Children’s Research Institute, the academic arm of Children’s National Medical Center, encompasses the translational, clinical, and community research efforts of the institution. Learn more about our research programs at www.childrensnational.org/research and www.wickerproject.org.
Why would the Dept of Defense be interested in funding this research?
They were interested for long time. http://www.wellstone-dc.org/Default.aspx?alias=www.wellstone-dc.org...
It is not the first grant received by them for research work on muscular dystrophy.

Karen Barnett said:
Why would the Dept of Defense be interested in funding this research?
Some info here:

http://www.avibio.com/downloads/AVI-2009-05-19-Annual_Shareholders_...

•AVI-4658 -PMO -designed to skip exon 51 in certain DMD patients
–Phase 1b/2 trial underway in Europe
–Toxicology package to release the US IND from clinical hold is underway
•AVI-5038 -PPMO -designed to skip exon 50
–A collaboration with Charley’s Fund
–Data for IND package being generated
•Discovery research work underway to skip exons 45, 53 and 44
•Together these 5 drugs could treat approximately half DMD patients
This looks REALLY REALLY GOOD!!
We've been waiting for 45 skipping.

Ofelia Marin said:
Some info here:

http://www.avibio.com/downloads/AVI-2009-05-19-Annual_Shareholders_...

•AVI-4658 -PMO -designed to skip exon 51 in certain DMD patients
–Phase 1b/2 trial underway in Europe
–Toxicology package to release the US IND from clinical hold is underway
•AVI-5038 -PPMO -designed to skip exon 50
–A collaboration with Charley’s Fund
–Data for IND package being generated
•Discovery research work underway to skip exons 45, 53 and 44
•Together these 5 drugs could treat approximately half DMD patients

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