On Monday, I attended the meeting in Washington, DC focused on AON. It was Elizabeth McNeil (OOPD) who suggested this meeting in Brussels last year, following the meeting with EMA (formerly EMEA - the European regulatory agency). Elizabeth suggested it would be important to open this dialogue with FDA and suggested that she would discuss this with Dr. Cote (OOPD) and leadership within FDA. The committee was organized and after numerous calls, discussions, the final agenda agreed upon. Unfortunately OOPD elected not to support the meeting and thankfully Janet Woodcock (FDA) and Anne Pariser (FDA) stepped in. With the leadership of John Porter (NIH), Ann Pariser, Emma Heslop (Treat NMD), and Abby Bronson (CNMC) and a number of organizations providing additional financial support (PPMD, MDA, FED, and CureDuchenne) the meeting was scheduled. I am hopeful many of you were able to watch as the meeting was streamlined, but for those who were unable, John Porter has provided the following information:

Increasing the level of interactions among the stakeholders in an emerging area is always a good thing, and I think we accomplished that. Moreover, I think there are some clear opportunities for moving forward on the regulatory science discussions, particularly in two areas—biochemical/muscle strength biomarkers and data sharing on AON backbone tox.

As follow-up:

• NIH will work with FDA and some of the participants to put together a brief meeting summary that I will try to get out to you very soon for your distribution or web posting.
• I will be seeking permission to post the presenters/working group PowerPoint presentations on an NIH website and will give you that link when available.
• And then there will be a more complete conference summary that at least will be posted on the NIH website with links for you—that may be written up for publication also—need to see what we have when the information is aggregated.
• I’ll try to make all of this happen as rapidly as possible; please remember though that I have to seek clearance on such releases.
• We did not archive the webcast.

I left the DC meeting to participate in discussions with industry and regulatory agencies in St. Louis and later the HRA meeting in Chicago. I discussed biomarkers with several individuals from FDA/CDER. And it was interesting to discuss biomarkers in general and the difficulty confirming biomarkers in any disease indication.

The major biomarkers are for common conditions, as in cholesterol. Low cholesterol means less stokes, less heart attacks. And it took years to get there. In our world, the community has read, listened to, and watched mouse studies where dystrophin is seen as a ‘halo’ around the cell and we all know, the more dystrophin, the better. But it is not quite that simple. We know that if a person is born with dystrophin, they do well. We also know that individuals born with truncated (shortened) versions and depending on the quality of that version, they may do well. (We have heard the story of the 65 year old playing tennis with Becker).

But what we do not know at this moment is what happens when you replace dystrophin in a person born without dystrophin. And to a large extent it will depend on WHEN you are able to replace dystrophin, the quality of the dystrophin protein (not all in-frame proteins are alike) and the cellular environment (how much fibrosis, how much fat) and at the end of the day, the biomarker has to be able to suggest that X% of dystrophin relates to X% improvement or X% slower degeneration or X% change in ability. There was considerable discussion about biomarkers: the difficulty, the lack of current knowledge, the urgent need. Several of the investigators said strength. It is all about strength. I think we would all agree.

Sharon and I are preparing a full report. We will do our very best to post by mid-week next week.

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Comment by cheryl cliff on October 6, 2010 at 12:05pm
Yes Sharon, you understood what I was asking. Keith, I was attempting to discern the difference in cost of each skipping compound with consideration to what Sharon identified as indirect vs direct costs. I realize the compound recipes exist in academia for different exons. Just not really sure of the "hard" or "direct" cost. It would be logical that costs should decrease for each exon skipping compound created after 51. Therefore, the rare exon compounds shouldn't cost as much as 51 to make.

So, the secret for success of all exon skipping compounds is making regulatory agencies see the paint bucket with different tints theory. This, of course, is what Pat & you are working very hard on. While I realize this stuff is brand new to FDA, I can't help but wonder if they can accept this theory, ever. Or at least in time to have some effect on this generation of boys.

Then, is there any way to determine the direct cost for regulatory processing with FDA, for exon skipping 51 vs 44 or 50, aside from other costs? I assume Prosensa/GSK & AVI have those numbers somewhere in their books, but are they willing to share that data?
Comment by Sharon Hesterlee on October 6, 2010 at 11:22am
Hi Cheryl, I think what you're asking about what we call "direct costs" ("indirect costs" do include things like keeping the lights on etc. that the Universities insist is necessary to keep things going) but I would consider the chemicals and equipment direct costs because they are essential to doing the work. Also, although the grad students in the US typically have some kind of stipend from the University or, more commonly, they teach to earn their salaries, it's the postdocs who do a lot of the work and they do have to be paid.
I'm not sure it is safe to assume AONs for exons 44 and 50 will be cheaper--there probably will be some savings through "economies of scale" in that you can use some of the same clinical infrastructure established for 51, but it's not clear that there will be significant savings unless the regulatory requirements are reduced. This has always been the elephant in the room for exon skipping--the technique looks encouraging, but the business model is going to be very tricky.
Comment by Keith Van Houten on October 6, 2010 at 11:00am
As I understand it - the AON's for all the skippable exons have already been created by academia.
Comment by cheryl cliff on October 5, 2010 at 8:14pm
Ok, thanks Sharon. You are so good with this info - I appreciate your opinions.

Now I am wondering what is the total investment in Exon Skipping compounds for 44 & 50 to date? Is it safe to assume they aren't as expensive as 51? And with the rough esti for academia & preclinical development does the $10 mil include just scientists time (in USA grad students work for free), chemicals & equipment or such things as keeping the lights on, clean up and toilet paper in the restrooms for 15 years, ect...

The reason I ask is it would be nice to have some numbers showing hard costs to create these compounds, not including everything Leiden Univ already had in place, such as up and running labs with lights already on, ect...
Comment by Sharon Hesterlee on October 5, 2010 at 5:26pm
Hi Cheryl, if you look at the whole field of exon-skipping and consider funds committed (if milestones are reached) as well as funds spent already, we are probably at or around $775 million (that includes $655 million in milestone payments from GSK to Prosensa if Exon 51 achieves all its milestones, $25 million up front to Prosensa from GSK, probably $20-30M spent by AVI--could be more, about the same for Prosensa before they handed off to GSK, and at least $10 million spent over the years by academia on preclinical development--and I think I may be leaving out ongoing develoment costs for Exon 51 by GSK, which could be another $30-$50 million). But some of those costs, like the preclinical development of the concept can be shared by any other AONs and don't just apply to Exon 51. That's my super rough estimate that doubtless is on the low side...
Comment by cheryl cliff on October 5, 2010 at 5:15pm
Does anybody have the total amount of money already spent on creating Exon Skipping compounds for 51 - to date?
Comment by Sharon Hesterlee on October 5, 2010 at 12:18pm
I should be clear that the IOM recommendations are big picture, big changes that need to be done, but organizationally, Pat and Lee and I are working on a plan to implement some new programs immediately that will get us better drug candidates in the clinic (so that we don't waste resources on the duds) and will allow us to conduct those phase I, II and III trials as quickly and efficiently as possible. We've been analyzing data about clinical trials to identify the typical bottlenecks that waste time and money and we are going to address those directly. Delays in patient recruitment is one example--a six month delay due to lack of enrollement might cost a company around $3 million dollars. We can help with that. It's almost like applying the Japanese six sigma business principles that allows factories to work efficiently--we need to shave off all of the fat and make sure these trials are lean and mean. We need to be smarter about how we do drug development.
Comment by Sharon Hesterlee on October 5, 2010 at 12:11pm
Cheryl, you are absolutely correct that there's not a lot of extra costs involved in actually making the variations of AONs with different sequences--the issues are with doing the preclinical tox package for each one (at least $300-$500K) and then doing phase I, II and III testing (about $500 Million). On the other hand, if we end up with an abbreviated approval process for additional AONs based on a clean safety profile of the first two, then that amount might be cut down to less than $10 million each....


It's also useful to keep in m ind that the AONs in testing now are based on about ten years and millions of dollars worth of basic research funded by a lot of different groups, including PPMD. The total cost to get a drug approved based on any single AON will be in the hundreds of millions of dollars. If you count post-surveillance marketing (a regulatory requirement) and the "opportunity costs"--what all that money might have earned if invested differently--then the cost can be over a billion. That's the reality of drug development in the US and Europe today. It's obviously not sustainable for rare disease. Pat recently participated in a prestigious Institute of Medicine Panel on Rare Disease that has made some recommendations about expediting therapies (http://www.iom.edu/Reports/2010/Rare-Diseases-and-Orphan-Products-A...). But it will take time to put those in place.
Comment by cheryl cliff on October 5, 2010 at 11:52am
I'm a bit confused. My perspective is that creating exon skipping compounds for mutations other than 51, 44, 50 should not be all that more expensive; and here's why-they will be using the same "basic recipe" but with slight alterations. Like Pat mentioned, it's similar making paint where one paint base is used to mix in various tints to reach the acheived color. If we already have a process to make the basic mix then the extreme cost is in what, making a couple of tints? Most likely I am over simplifying things so feel free to set me straight. I realize the number of end users decreases but do we know for sure there is going to be an over charge for a slightly different mix?
Comment by Keith Van Houten on October 5, 2010 at 10:23am
I can't argue with what you're saying, Ofelia - I think you have a better grasp of the science than I do.

All I know is that Wilson said that some of these other exons can be skipped with much higher efficiency and potentially better results than exons 50, 44 and 51, but there’s no business model to move them forward.

Whatever chemistry winds up being most effective (if any - never lose sight of that) - you're still left with same business case and regulatory approval problem for rare mutations in the end. Which is why I think a two prong approach is appropriate. Work the abbreviated path to approval, and work the non-profit perpetually open IND.

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