I realize that this is a little premature, but since I have a 10 year old who is predicted to benefit from skipping either exon 43 or 45, but not 51, I am more than a little concerned that he'll be on a ventilator and gi tube before completion of clinical trials for a compound that will skip exon 43 or 44. I spent a godawful amount of money on a book on FDA law, and reached the conclusion that the FDA probably has discretion to treat the Prosensa compounds as one drug, even where they are designed to skip different exons, and the would apply to AviBioPharma's compounds. However, there is nothing in the law that would require the FDA to do so. Does anyone know whether these two companies or any of the patient advocacy organizations have begun talking to the FDA about whether they will require separate trials for each compound? I have heard a great deal of rumor and speculation, but I really want to know whether there is any reason to be optimistic, short of going to Congress for a legislative change. If we need a legislative change, then that ball needs to get rolling next year, assuming that the Phase I/II's for ProSensa and AviBioPharma come in as expected in December and are positive.

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Hi Paul,

I think they (Prosensa & AVI) suggested waiting until they see any sign of benefit in their systemic trials before the advocacy starts. I just discussed this with Steve Wilton and he seems to be pretty optimistic that only a few compounds need to be tested for this to be approved as a "platform" drug. I do not know what "few" means.

You might be aware that AVI has plans to conduct skipping 51 and 50 trials (51 UK is approved, they are waiting for approvals for 50 USA). Problem is that the 2 trials are not using the same chemistry, skipping 51 will be using PMOs that showed minimal effects on the heart in mice; skipping 50 will be using PPMOs that have great effects on the heart in pre-clinical studies. Since the chemistry is different, these 2 trials will be kept separate in case there are adverse effects with one or the other compound (ie peptide).

As I see it, this will not help speed up the approval process in case one of the compounds gives positive results...

Ofelia
Ofelia,

When you said skipping 50 using PPMO's has an effect on the heart is that effect considered good or bad?

cheryl

Ofelia Marin said:
Hi Paul,

I think they (Prosensa & AVI) suggested waiting until they see any sign of benefit in their systemic trials before the advocacy starts. I just discussed this with Steve Wilton and he seems to be pretty optimistic that only a few compounds need to be tested for this to be approved as a "platform" drug. I do not know what "few" means.

You might be aware that AVI has plans to conduct skipping 51 and 50 trials (51 UK is approved, they are waiting for approvals for 50 USA). Problem is that the 2 trials are not using the same chemistry, skipping 51 will be using PMOs that showed minimal effects on the heart in mice; skipping 50 will be using PPMOs that have great effects on the heart in pre-clinical studies. Since the chemistry is different, these 2 trials will be kept separate in case there are adverse effects with one or the other compound (ie peptide).

As I see it, this will not help speed up the approval process in case one of the compounds gives positive results...

Ofelia
PS
And...can we find out how much time is involved in what Steve Wilton referred to as a "few"? Ofelia- will he answer that question for you?

And...if, by chance, a "few" turns out to be a huge amount of time (again, our son just turned 10 and we want to keep him walking) does anyone out there know ways to speed this thing up?

cheryl
The bare Morpholinos (PMO) should work fine in the heart and lungs, the only challenge is delivering them into the cells. In mice, after systemic delivery, they noticed only very minimal dystrophin levels in the heart (I do not recall about diaphragm…might also be low). It is possible that by using ultrasound the PMOs might be introduced into cardiac and diaphragmatic cells, but they did not explore this method too much so far.

The delivery into the cells is a serious challenge and that is what the PPMOs are designed to overcome. A paper recently published showed PPMOs being very effective – using systemic delivery they obtained good levels of dystrophin in heart and diaphragm in mice.

It is not clear if PMOs or PPMOs have better effect on the skeletal muscles or if there are any side effects with one or the other compound. By using both chemistries in the 2 trials they plan to generate as much information as possible and hopefully answer these questions.

Ofelia
Hi Cheryl,

No timeline until they see any sign of benefit in children in the 51 and/or 50 systemic trials.

At the moment, they have approval from MHRA to conduct the systemic 51 (PMO) UK trail and they are sill waiting for approval from the UK gene therapy committee(I don't recall the exact name) before they can start; the 16 boys who will participate in this trial are already selected.

They are waiting for FDA's approval for systemic skipping 50 (PPMO) USA trial.
Ofelia,

Thanks for the information. I do get confused by the terminology. I think of ProSensa as the 2'O Methyl company and AviBioPharma as the morpholino company. Is PMO a different acronym for whatever enormous organic molecule ProSensa is using for its exon skipping and PPMO an acronym for AviBioPharma's process?

Ofelia Marin said:
Hi Cheryl,

No timeline until they see any sign of benefit in children in the 51 and/or 50 systemic trials.

At the moment, they have approval from MHRA to conduct the systemic 51 (PMO) UK trail and they are sill waiting for approval from the UK gene therapy committee(I don't recall the exact name) before they can start; the 16 boys who will participate in this trial are already selected.

They are waiting for FDA's approval for systemic skipping 50 (PPMO) USA trial.
Paul this is a post that I put on another website after the Advocacy meeting last year. I hope it helps.

Also, I have Steve Wiltons email address at home and will send it to you tonight. He is very approachable and willing to answer any of our questions. He responded to my emai within two hours which really surprised me.

We got to meet with someone from the FDA at the Advocacy Conference last week.

He said he didn't see any obstacles with lumping the "cocktails" together for exon skipping once it's shown that one works.

He said alot of other things. I was lucky enough to have him sit beside me to eat so by the time he got up to make his speech and take questions he knew what questions were in store for him because I had already asked them.

His name is Tim Cote, MD, MPH, Orphan Products, FDA and he spoke about regulatory issues. He just took over the position 4 months ago and he has two young kids that he had to bring with him because his wife was out of town so they sat with us while he spoke.

Lee Sweeney spoke after him and said that the FDA is not the hold up. There are still some issues with delivery that have to be addressed as well as some others.

I'm sure others on the board can elaborate better than I can.
Here is an article on Tim Cote.

FDA names orphan products development head

United Press International - September 19, 2007


--------------------------------------------------------------------------------
WASHINGTON (UPI) -- The U.S. Food and Drug Administration has named Dr. Timothy Cote as director of its Office of Orphan Products Development.
Cote will be responsible for promoting the development of products that demonstrate promise for the diagnosis or treatment of rare diseases or conditions.

A captain in the U.S. Public Health Service Commissioned Corps, Cote most recently served as the Centers for Disease Control's country director for the African nation of Rwanda. In Rwanda, he directed programs in HIV/AIDS, malaria and avian influenza, and was responsible for scientific and administrative leadership in patient care and research initiatives.

Cote -- who succeeds Dr. Debra Lewis, the office's acting director -- previously served as a CDC epidemic intelligence officer at the Maryland Health Department and as chief of the therapeutics and blood safety branch in the FDA's Center for Biologics Evaluation and Research.

The orphan drug program provides a seven-year exclusive right for a pharmaceutical company to market a drug designed to treat a disease that afflicts fewer than 200,000 people in the United States.


070919
Hi Cheryl,

Sorry for the confusion!

Both PMO and PPMO are morpholinos from AVI. PMO is bare morpholino. PPMO has a peptide attached so it improves the delivery into the cells (better penetration into cells of hard-to-deliver tissues). AVI will be conducting systemic delivery clinical trials for exon 51 using PMOs and exon 50 using PPMOs.

You are correct about Prosensa -- they use 2'O Methyl.

Ofelia
Thanks, I remember Dr. Cote from the Advocacy Conference, though I had forgotten his name. He seemed genuinely concerned.

Jacobs Mommom said:
Here is an article on Tim Cote.

FDA names orphan products development head

United Press International - September 19, 2007


--------------------------------------------------------------------------------
WASHINGTON (UPI) -- The U.S. Food and Drug Administration has named Dr. Timothy Cote as director of its Office of Orphan Products Development.
Cote will be responsible for promoting the development of products that demonstrate promise for the diagnosis or treatment of rare diseases or conditions.

A captain in the U.S. Public Health Service Commissioned Corps, Cote most recently served as the Centers for Disease Control's country director for the African nation of Rwanda. In Rwanda, he directed programs in HIV/AIDS, malaria and avian influenza, and was responsible for scientific and administrative leadership in patient care and research initiatives.

Cote -- who succeeds Dr. Debra Lewis, the office's acting director -- previously served as a CDC epidemic intelligence officer at the Maryland Health Department and as chief of the therapeutics and blood safety branch in the FDA's Center for Biologics Evaluation and Research.

The orphan drug program provides a seven-year exclusive right for a pharmaceutical company to market a drug designed to treat a disease that afflicts fewer than 200,000 people in the United States.


070919
Never mind. I figured it out. PPMO's = peptide conjugated morpholino, PMO's = some other kind of morpholino. This is the avIBIOPHARMA STUFF.

Paul Cliff said:
Ofelia,

Thanks for the information. I do get confused by the terminology. I think of ProSensa as the 2'O Methyl company and AviBioPharma as the morpholino company. Is PMO a different acronym for whatever enormous organic molecule ProSensa is using for its exon skipping and PPMO an acronym for AviBioPharma's process?

Ofelia Marin said:
Hi Cheryl,

No timeline until they see any sign of benefit in children in the 51 and/or 50 systemic trials.

At the moment, they have approval from MHRA to conduct the systemic 51 (PMO) UK trail and they are sill waiting for approval from the UK gene therapy committee(I don't recall the exact name) before they can start; the 16 boys who will participate in this trial are already selected.

They are waiting for FDA's approval for systemic skipping 50 (PPMO) USA trial.
Hi Paul,

This answer was for you...sorry.

Hi Cheryl,

Sorry for the confusion!

Both PMO and PPMO are morpholinos from AVI. PMO is bare morpholino. PPMO has a peptide attached so it improves the delivery into the cells (better penetration into cells of hard-to-deliver tissues). AVI will be conducting systemic delivery clinical trials for exon 51 using PMOs and exon 50 using PPMOs.

You are correct about Prosensa -- they use 2'O Methyl.

Ofelia

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