There’s often a fine line between “out-of-the–box” and “out-in-left-field.” I guess when my blog about Duchenne research starts with that statement you know I’m probably going to come down one way or another about something, but it might not be the direction you’re expecting.

This community lives with a lot of hope and hype. Many of you have learned that when you hear something too good to be true that it’s probably not. You know the principles of scientific experimentation, you understand the need for placebos (even if you loath the idea), and you know that progress tends to come in little baby steps and not giant leaps. You may have even found yourself in arguments with people who want to try unproven exotic devices or cell therapies.

But I think it’s also important to remember, at the end of the day, that nothing about the scientific method dictates a priori what answer is right and what is wrong. The true spirit of science is the ability to embrace anything for which there is evidence. Galileo was branded a heretic and imprisoned for supporting what he felt the evidence told him about the planets revolving around the sun and Lister’s theory of germs as a source of infection was mocked for years in surgeries where people left sicker than they arrived. For many years I’ve had a scrap of paper taped to my computer with the quote “I am too much of a skeptic to deny the possibility of anything” (from Thomas Huxley, a contemporary of Charles Darwin).

So all of that being said, I just returned from a visit to the MDA Western Australia meeting in Perth and I want to address some of the elephants in the room surrounding the technique of exon skipping. Just for reference for those of you who are geographically challenged like me, if you get on a plane in LA and fly through five feature films, two meals and a variety of turbulence and finally land in Sydney…you are still five hours from Perth. It’s a lovely city nestled on the West side of Australia along a river and the Indian Ocean and, I understand from the locals, it’s the most isolated state capital in the world. It’s also the home of a thriving group of researchers and clinical investigators focused on Duchenne muscular dystrophy and other muscle disease, including Steve Wilton, Sue Fletcher, Nigel Liang and Miranda Grounds. In addition to the science, I heard some fantastic talks from parents and young men with DMD.

Dr. Steve Wilton, as many of you may know, was one of the pioneers who developed the technique of exon skipping that we are now following so closely as the Prosensa/GSK and AVI trials progress. Most cases of DMD occur when a piece of the gene is deleted and when the number of nucleotides that makes up that missing piece is not a multiple of three--this throws the three letter “words” of the genetic code out of sync or “out-of-frame” and the protein produced from this transcript is just gobbledygook. When, about a third of the time, the missing piece of genetic code is made up of a multiple of three nucleotides you get an “in-frame” deletion, which is usually associated with milder symptoms. Guys with Becker often have in-frame deletions.

As early as 1999 Wilton’s group had published its first evidence that you could “trick” muscle cells into carving out a carefully measured extra piece of the code that is normally left in, called an “exon” (in addition to the already missing piece) during the normal trimming process of the dystrophin RNA, bringing the sequence back into frame so that a protein could still be made. It’s the equivalent of tidying up the rough edges of a cut by removing more material before putting the clean edges back together. Although a Japanese group actually published the first report describing the use of antisense oligonucleotides to alter the reading frame of dystrophin in cultured cells in 1996, Wilton’s group was responsible for much of the early work to perfect the technique in muscle cells. PPMD and MDA were early funders and supporters of the technology during its development.

Unfortunately, the very large dystrophin gene is susceptible to losing pieces of its genetic code at any point along its length, although there are deletion hot spots where such mutations are more common. This means that different exons would need to be carved out or “skipped” to accommodate deletions in different parts of the gene—this is not a one-size-fits-all solution. AVI Biopharma and GSK both have exon 51 skipping strategies in the clinic ( the GSK exon 51 program originated at Prosensa and was funded, in part, by Cure Duchenne) and Prosensa has started a phase I study to look at skipping exon 44. At the meeting, Sue Fletcher, Wilton’s long-time collaborator on this technology, described their efforts to look beyond exon 51.

The area around exon 51 is one of the hot spots for deletions in the dystrophin gene. According to Fletcher and Wilton, approximately 6000 boys worldwide have deletions that could probably be addressed by skipping exon 51—these include deletions of exons 45-50, 47-50, 48-50, 49-50, 50, and 52. Next on deck for AVI is skipping exon 50, a project supported by Charley’s Fund, which could potentially address deletions of exons 51, 51-53, and 51-55 and Prosensa’s PRO044 oligos could address deletions of exons 43, 45, 38-43, 40-43, 42-43 and 45-54 (about 6% of boys with DMD). Clinical results from both exon 51 skipping programs have been promising with some evidence that dystrophin can be produced and potentially some trends (not statistically significant) in improved 6 minute walk tests.

AVI and Prosensa have plans to follow up with AONs to skip additional exons, but at this point, it looks like each pair of oligos will be treated as a new drug from a regulatory standpoint and require the full pharm/tox package along with phase I, II and III testing. The AON technology used in this way is very new and regulatory agencies worry about toxicity developing if the AONs bind to inappropriate pieces of the genetic code for other genes, potentially disrupting their function. No exon-skipping trial has yet begun in the US.

Although collectively, the ability to skip these three exons might benefit a fair proportion of boys with DMD, there are actually 77 “skippable exons” according to Fletcher and Wilson. In some cases, skipping one of these other exons to correct a rarer deletion might only be applicable to a handful of boys, or even a single boy. The irony, Wilson says, is 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. How do you spend $1.4 billion to develop a drug for one boy? And if technology looks really promising and is potentially life-saving, how do you not?

So Wilton’s group has been wrestling with this problem and has proposed a solution that is either “innovative and out-of-the-box” or “out-in-left-field” depending on how you look at it, and, to a certain extent depending on how they choose to go about it: the “N=1 Study.” “N” is the number of replicates you use in a study—in a clinical study “N” usually represents the number of participants.

Wilton is proposing to manufacture and test oligos for the rarer mutations in very small studies of one to a handful of participants. These studies will likely not be powered appropriately to ever get a drug approved based on the results, but one solution would be to maintain a “perpetually open IND” and continue to treat the boys with what would be categorized as an experimental therapy. A major shortcoming of this approach is that without marketing approval, there is no way to get insurance to pay for the drugs, so Wilton is proposing to set up a manufacturing facility that will be run as a nonprofit foundation to supply oligos to the boys for the rest of their lives at no cost. He would donate all of the intellectual property (IP) around the other exons to this foundation and if anyone ever did want to license the IP to market one of these oligos, the proceeds would go back to the foundation to continue to help supply other oligos to boys who need them. Sue Fletcher mentioned that the labs are focusing now on skipping exons 8 (9 comes out with 8 so you skip both), 16, 46, 43, 53, 41 and 74. They would like to tailor a strategy to each boy’s individual mutation.

So, I like some things about this approach. I like the fact Wilton’s group has recognized that you don’t actually have to have marketing approval to make a drug available—you just need to meet the regulatory requirements to open an Investigational New Drug application, or IND. For the less common deletions, this might be the only approach that ever makes exon-skipping feasible. I like the fact that he’s thinking ahead about the need to supply oligos for an entire lifetime, which could stretch on many additional years if the oligos work like we all hope they will (adding the caveat that we don’t yet know how effective AONs will be if they work and this efficacy will very likely vary with different exons and AON pairs).

I have a lot of concerns as well, starting with the fact that efficacy may be difficult or impossible to demonstrate in such a small number of boys—can you justify keeping an IND open if you can’t show efficacy? One potential answer to this question is that if the boys can stay on drug for several years you might be able to measure the effect over time even in a small group of boys. The other potential answer is that maybe some of the oligos might work well enough that you can measure definitive changes with very small numbers. At the very least, you should be able to see if the AONs are triggering dystrophin production even with smaller numbers of boys. If there are only five boys in the world that might benefit from skipping a certain exon and two respond and three don’t, it doesn’t mean the drug fails, it just becomes a two person drug—it’s like the difference between quantum and classical physics. The rules are different when you are dealing with very small numbers.

Next concern—is it really realistic to think that you can raise enough funds to build a manufacturing plant and then supply an expensive oligo for the life time of these boys pro bono? This question is complicated by the chicken-and-egg nature of the issue. If you do a study with a set of AONs and there is a dramatic positive response, ethically you have to be prepared to continue to supply the oligos in perpetuity, so you need a manufacturing source. At the same time, it’s hard to convince people to put up money to build a manufacturing plant before you even know if the approach is viable. What I think is likely to happen in reality is that any oligos that produce a dramatic positive response probably could be licensed to one of the drug companies to develop for marketing and the licensing fees could go back into the kitty to help support the manufacturing facility. It’s the manufacturing of oligos with more subtle results that would need to be supported on the proceeds of any oligos that could be licensed for marketing. That’s if any of the oligos do produce a dramatic response without limiting side-effects (let’s not forget the potential for side effects).
And finally, can Wilton pull it off? He admits that he’s not a “business guy,” at least not by choice. He knows he needs help but sees this n=1 strategy as the only way forward for the less common deletions whether it’s realistic or not.

Personally, I think it’s probably worth knowing if mutation independent approaches like Acceleron’s muscle building compound might not have a greater impact and it’s also worth knowing if AVI, GSK and Prosensa can show any functional results with exons 50, 51 and 44. But as personalized medicine gets more and more personal, the $1.6 billion model of drug development is untenable. Somehow, some way, the costs to develop a drug will have to come down and maybe the perpetual IND with a nonprofit payment system is one way to go. At this point I’d call it “innovative.” The execution will prove whether or not it’s out-in-left-field.

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Comment by Sharon Hesterlee on November 29, 2010 at 2:06pm
Hi Cheryl:

I think those are all quite reasonable concerns.

1. I worry about an n=1 trial failing because it sets the bar higher for the next group/company who attempts to skip the same exon; there are already steep economic hurdles to developing drugs for the rarer deletions and a failed attempt might put off some companies. It shouldn't, but it might--just psychology. Happens in gene therapy all the time.
2. I don't know if oligos will be a permanent fix, a temporary fix or a fix at all. But if they do manage to slow progression or even reverse it to some extent, you really want to make sure there's a reliable supply of them.
3. We don't know every speck of mystery about any drug, even asprin. I think we just need to know enough to know if the drug is relatively safe and that it's benefits are worth the time, emotional commitment and financial commitment--and don't get me wrong, I don't think it's even possible to set a value on a life-saving drug, but if you are never really able to establish the drug works at all, then what is it worth in those terms?
4. As for the wheel-spinning, I guess I was making the point that a lot of energy could be expended with no result. Sure I think we have to try things because we don't know what will work, but we don't have unlimited resources---every dollar that goes into one project is a dollar that doesn't go into another project. Every trial in which your son participates means there are several others recruiting at the same time or near future in which he will not be allowed to participate. I always try to think of things that way--sure, we could do this, but if we do, what else won't be we able to do? This analysis doesn't have to be paralyzing, but it's worth at least asking before every decision.

I support David's decision and hope that he reports back frequently. There are pros and cons to all of these things--my pointing out some concerns doesn't mean I think he shouldn't do it. Everyone should just go into all of these situations with their eyes open about the potential outcomes.

Comment by David on November 29, 2010 at 1:47pm
Sharon -

My eyes are wide open. I expect my chances of success are lower than I want to admit. But I also suspect they are higher than my chances "inside" they system.

And to be honest - now that I feel I understand the landscape - I can't at least try.

Comment by cheryl cliff on November 29, 2010 at 1:33pm
Hi Sharon,

I don't mean to sound critical but I do have a couple of issues and questions,

Regarding #1) If any big pharma conducts a one-kid-trial and it fails, becase of the variable ou mentioned, wouldn't they (and regualtory agencies) be taking that into consideration? I mean, how in the world could they morally justify cutting off life saving medicine for others with the same rare mutation, should it not work for just one kid in a private trial, especially if big pharma had no additional cost (privately funded) to run the one-kid-trial?

#2) How can we see oligos as a permanent fix? Aren't they best viewed as a solid option for now? If my son had to take oligos for a few years, even 5, it most likely will buy more time until a cure or better treatment, is found. I am in the business of buying time.

#3) Does it really matter if we uncover every speck of mystery as to why something works? If scientists can't fully explain how/why steriods work for our guys should we as parents really care or shouldn't we just try it and see? This is all a leap of faith.

#4) Frankly, I'd rather all people spin their wheels to help keep things moving, and in all directions. Scientists have taken amazing steps just in the few years I've been following DMD (now 3). But they can't explain a lot and there is something to be said for searching the corners that scientists can't or won't look into. I thought a lot of advances in our society come unintentionally, by accident or surprise discovery.
Comment by Sharon Hesterlee on November 29, 2010 at 10:29am
David--I admire your courage. These "outside the box" approaches only seem crazy until someone succeeds and then they are lauded as the clear path forwards. I think contacting the Hempel's about their experience is a great idea--they might have some ideas about a consultant. I would just caution that you choose any paid consultant carefully because there are no end of people out there willing to prey on a parent's hope, but I'm sure you know that. I spoke briefly with Dr. Wilton a few weeks ago at the Action Duchenne meeting and he says he's still working on the logistics of it all, but he thinks things are coming together. He's trying to identify a manufacturer who can make clinical grade oligos for a price that makes this whole project feasible.

Things to keep in mind:

1. If your son doesn't respond to the oligos, that particular oligo combination may never be tried again in humans even though it might have worked for some other child (remember the variable response that AVI got that they still are still trying to understand?)
2. If it does work, your son will need treatment for life and you will want to make sure that this manufacturing issue is really sorted out.
3. The most likely outcome by far will be that the oligos do may be doing something for your son but no one is completely sure because it's hard to see definitive results in one child--for example, even thought it's clear now that prednisone actually has pretty dramatic results, you couldn't be sure of those results in a single child. Then you will expend more time and money trying to get some definitive evidence, but afraid to stop in case they are helping. In the meantime, your son will not be able to participate in other studies because of his exposure to these oligos (at least until a considerable wash out time has passed).
4. The obvious concern--a lot of people could spin their wheels spending time and money and this approach may never be feasible for all the reasons mentioned in my blog above.

So, I'm definitely not saying don't do it, just go into with your eyes open and be prepared for the possible outcomes. You may want to predetermine how great of an effect you would want to see in your son to justify continuing to put money into the oligos and their further development. Write that down now on a piece of paper before you are totally invested mentally, emotionally and financially in this endeavor, and put it in a sealed envelope to be opened down the line.

I absolutely agree that the current model for drug development is broken--it's not working for anyone, including the biotech and pharma industry. I've spent a lot of time researching what parts of the process are really necessary and what parts are just red tape and wasted time (multiple IRB approvals for multi-site trials, for example). At PPMD we've developed a pretty detailed plan to tackle the clinical trials process head on (will be up on our Web site by the end of the year) but there are many possible solutions. N=1 trials may be part of that solution. Please keep us all posted!

Comment by David on November 28, 2010 at 2:17pm
If anybody else is interested, a truly brilliant vision is described here, which sounds a whole lot like Dr. Wilton's vision in a broader context.

I am setting out on a similar path as Chris Hempel (Addi and Cassi's) mom, to start a virtual biotech firm that will engage in a N=1 study for my son who needs to skip 17/18. I sat 10 feet from Dr. Wilton in Denver as he demonstrated in-vitro results of successful skip of these exact exons in June 2010. How long will it take Big Pharma to get that skip to market? I suspect we all know the answer is "not fast enough" despite our hopes that somehow all oligos will be treated as a class. My son is 12.

I am a scientist too (computer science). I realize N=1 studies aren't "true" science to many in the industry. And for traditional treatments I can surely see how this might be seen as unethical. I've read and re-read the article in Science Direct that was co-signed by Pat Furlong which repudiates n=1 trials, and I fully appreciate the risks.

But I reject those arguments, and not because of my emotions as a DMD parent. The entire article rests on the statement:

"[P]arent and patients cannot invoke "compassionte use" to receive treament with anti-sense oligonucleotides, as no conclusive proof has been obtained yet that the treatment will work at longer term with acceptable safety."

The whole argument of risk here relies on that word "conclusive." The word "conclusive" in medical science could not be more impossible to define with a consensus that spans all treatments. I reject the premise that the medical community somehow owns that definition.

I'm committed to sharing all information I can obtain with PPMD and any other parents who are interested. I will continue to support PPMD to the greatest extent my finances will allow. I still believe this is the best organization in the entire community for DMD. However, with all due respect to the great people of PPMD, I just don't see how a traditional advocacy organization can help kids who aren't in the magic 44-55 range. I'm not interested in waiting a minute longer.
Comment by David on November 25, 2010 at 12:45pm
Sharon - did some reading on Addi and Cassi, very inspirational. I want to start working towards an Individual IND for my son with DMD who needs exon 17 skipped. Of course I will ask my clinicians for help, but honestly, they will give me lip service and not much more. I need to drive this, they can play their part.

Do you know of any consultants who do this sort of thing? - somebody who ALREADY KNOWS how to do this? I have money. I don't have time nor expertise. I have reached out to Addi and Cassi's mom too. Any suggestions are welcome.
Comment by Keith Van Houten on September 30, 2010 at 10:30am
Sharon - I think we're mixing comments from this blog post and Pat's.

Didn't this conversation with Wilton take place at the MDA Western Australia meeting in Perth? Was this something he presented formally at the meeting or a side conversation? You posted this before the FDA/NIH meeting took place, so it wasn't from that meeting.

You say Wilton says he's not a business guy and needs help. Let's get him some help. Maybe it's not a consultant. Maybe it's funding a graduate student. Seems like you could at least flush out some rough numbers and build a business case with that level of expertise. Would not be very costly.
Comment by cheryl cliff on September 29, 2010 at 12:21pm
Thank you Sharon. Having FDA listen and comprehend is all we can do for this week. We live within margins of hope and this is another, hoping they will eventually come around and fast. I do understand the issue from their perspective.

I was very pleased at the portions of the 2 day conference I was able to see. Specifically when Dr Flanigan said exon skipping could possibly have a "curative" reaction for those with point mutations. As well as listening to Dr Muntoni as he shared pictures of the two California cousins who recently participated in a clinical trial for melanoma. FDA & the families of these young men watched in horror as Roche, a Swiss biopharm, gave meds to one cousin, which reduced his tumors by half . The other got a placebo, was then refused meds by Roche, for the "greater good" they said. He quickly got worse and died. A very telling story specifically related to how it was handled by FDA, who tried to convince Roche they would allow meds for the dying cousin before the trial was finished.

The fate of our sons isn't just in the hands of the FDA.
Comment by Sharon Hesterlee on September 29, 2010 at 8:57am
Hi Keith--no, this wasn't an MDA conference. It was organized by the FDA and NIH and supported in part by PPMD, Cure Duchenne, FED and MDA. MDA was at the conference but they didn't comment on this issue, specifically. The idea of hiring a consultant (would have to be the right one--my experience with consultants has been mixed) is an interesting one. The meeting ended with several people questioning whether or not there was a realistic regulatory path forward for the more rare deletions and if not, what should we do about it.

Cheryl, in answer to your question, Chuck Riesebeck, who has a son with Duchenne, made a really impassioned plea to the scientists and regulators to keep things moving and remember the boys who are the ultimate beneficiaries. People in the audience were wiping their eyes. He was very fair, but he definitely laid the burden squarely at their feet.

And the FDA reiterated their willingness to be flexible but also reiterated that until they saw the data from the first couple of exons they couldn't say up front what course they would recommend. If it turns out there is some sort of weird toxicities in any of these studies, it might not make sense to go straight to a shorter approval process so they wouldn't commit to that now. They have committed to listening to the community and the scientists and working with us to get good drugs approved as quickly as possible. They aren't going to go beyond that. But there were a lot of FDA staffers in the room and they were all taking notes and taking the proceedings very seriously so I think that was a positive sign. The more we can engage them, the faster I think things will move in the long run.
Comment by Keith Van Houten on September 28, 2010 at 8:18pm
Sharon - if FDA winds up being flexible on approval for small populations, that really is the best case scenario. FDA approval brings insurance dollars. That goes back to the non-profit, they develop more compounds, etc etc.

You say Steve is trying to work out the costs. Does he need help? Can we hire support personnel to get that answer quicker? Fund a research assistant? Hire a consultant?

This was at an MDA conference, right? What's MDA's reaction to the concept? They've got the financial resources to do something like this. It's conceivable they could fund the startup costs. They're at least a good target to lobby for funding it.

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