Research Update from the Road: Trends in Biotech and more on Exon-skipping

May 7, 2010

I’ve been traveling pretty steadily for more than a week now—first out to Seattle to meet with AVI Biopharma at their headquarters, then to Chicago for the Biotechnology Industry y Organization meeting and finally to Ottawa for the “New Directions in Muscle Biology and Disease” meeting. I thought I would take this time to share with all of you what I’ve seen and heard.

First, it was good to put faces to names at AVI, the Seattle-based biotechnology company that is developing an approach to skip exon 51…they have a really good group of people there, many of whom I had emailed with but hadn’t met in person. I liked the fact that they only make regular coffee and “double strength” coffee in their kitchen—I think that’s a good sign. More on AVI later.

The Biotechnology Industry Organization meeting (or “BIO”) is a three ring circus that I’ve been attending since about 2004. BIO has always been pretty good to its non-profit constituents by providing free full access registrations to the meeting—worth over a thousand dollars—and in return, we have helped with certain advocacy initiatives in Washington when our agendas are aligned (for example, lobbying to remove lifetime caps for health insurance).

I met with one new company that has a drug they think might be applicable to muscular dystrophy. They wanted to understand the “lay of the land” before committing to a development program. They wanted to know how many people have Duchenne and how difficult is it to recruit for participants in clinical studies. I steered them to the DuchenneConnect registry, which I pointed out has over 1700 unique entries and contributes core data elements to the international TREAT-NMD registry so that you can actually understand at a global level how many people are eligible for trials. That’s why resources like DuchenneConnect are so important—not only do they allow us to contact families about participating in clinical studies, but really well-designed registries are a carrot for companies who are wondering if Duchenne is really a good disease area to be in.

I also spent some time talking to the acting CEO of Justin Fallon’s company. They’re working on “biglycan,” which seems to upregulate utrophin—you may recall that PPMD provided Justin Fallon with an “End Duchenne” GAP award when his first application to NIH didn’t make the cut-off line. He was later able to parlay the PPMD funding into a successful renewal at NIH.

Finally, trends in Biotechnology….I think what really stood out to me is how desperate companies are to streamline their operating models and become more efficient. They are starting to look at their internal resources and figure out how to recycle them. For example, a lot of companies are investing time and effort into mining the data they collect in those expensive phase 2 and phase 3 studies to see if they’ve missed anything, for example an unintended but ultimately useful drug effect. Viagra is a good example of a drug that was originally in development as a heart medication when trial participants started reporting some interesting side effects. They are also more interested now in reviewing all those compounds that have ended up on the shelf, some of them having made it as far as phase 3 studies before failing to meet endpoints for a particular indication. These phase 3 failed compounds are actually a really interesting group because they have millions of dollars worth of toxicology data and human clinical data attached to them already—if they can be repurposed it helps to reduce development costs for the new purpose. And there are other compounds that didn’t make it that far but might still be interesting for other uses. Rather than sitting on these, a lot of pharma companies, notably Pfizer, are actively looking for collaborators to find new purposes for these compounds. This is good news for our community and I made sure to highlight these resources for the muscle biology community at my talk at the “New Directions” meeting on Wednesday.

Which brings me back to exon-skipping. Eric Hoffman gave a detailed presentation at the New Directions in Muscle Disease meeting in which he reviewed his pretty stunning results using morpholinos (the particular type of antisense oligonuceleotides used by AVI to selectively skip parts of the dystrophin gene and bring out-of-frame mutations back into frame) in golden retrievers with dystrophin mutations. For more on Eric’s dog results see . He also reviewed the preclinical toxicology data for these morpholinos…it seems that in Europe both AVI and Prosensa were allowed to do this tox work in boys with Duchenne, but in the US the FDA wanted to see the animal studies first. Normally all new drugs are tested in animals first for tox issues, but these exon-skipping drugs are a bit different in that they could potentially give a healthy rat or mouse a Becker-like disease when exon 51 is skipped, and that might be interpreted as a toxicity by the FDA, even though that’s what they drug is designed to do. I know, it’s pretty messed up. But, now with some time and money (the money came from the Department of Defense, largely due to the lobbying efforts of Joel Wood and the Federation to Eradicate Duchene—big kudos to them!) a traditional animal tox package has been developed to submit to the FDA to get studies rolling in the US. Before you ask, no word on time lines. The good news is that in the animals, with weekly dosing you could go up to almost one gram/kg with no ill effects—this is considerably higher than the dose required in humans.

Eric bought up other exon-skipping issues we should all pay attention to—the three hundred pound gorillas in the room. First of all, what are we really talking about when we say that we might be able to convert a Duchenne-like disease course into a Becker-like disease course with these exon-skipping strategies? It seems there aren’t a lot of patients with in-frame deletions of exon 51, and those there are “aren’t so mild.” The prospects for skipping exon 45 and 46 look better from the standpoint of a clinical outcome. But I think the real take home message here is we don’t really know what we can achieve from a clinical standpoint—yes, we seem to be able to put some dystrophin back, but we shouldn’t lose sight of the fact that we aren’t putting back the full-length, fully functional protein. The same is true for gene therapy approaches in which we’re using a miniaturized dystrophin so that the gene will fit in the viral carrier, but in that case the mini-dystrophin has been thoroughly optimized to be as functional as we can possibly make it. With exon-skipping you take what you get when you remove that portion of the gene. Food for thought.

The other issue Eric brought up is something some of us have worried about for a while—that is that if you look at people with Becker who all have the same in-frame deletion (Eric looked specifically at ten patients with exon 45-47 in-frame deletions), you can find really huge variability in the amount of dystrophin they make and the severity of their disease. We don’t know the cause of this variability and whether or not we might see the same thing when you deliberately skip those exons to put out-of-frame deletions back into frame. Variability is the bane of clinical trials. It can be very hard to say definitively that a drug is working if the results are highly variable.

Ok, gloom and doom over now…I personally believe that exon skipping is a very viable therapeutic approach. The preliminary data from the human studies so far show that we really can stimulate dystrophin production and that we can do it systemically. So far both the AVI and Prosensa drugs appear safe. It might require some special handling from a regulatory standpoint and in the interpretation of the clinical results, but I don’t think these things are insurmountable. Everything we are trying out there has pros and cons like this, but you don’t really hear about the back stories in the press releases. There is such a fine line between hope and realism—I’d rather you all knew some of the concerns behind these approaches so that no one gets blind-sided.

In addition to exon-skipping there are many other therapeutic strategies in development out there. We heard more from Acceleron on their ACE-031 muscle-stimulating drug that is being tested for DMD in Canada (you can find details on and also on a parallel drug they are developing for age-related and illness-related muscle wasting called ACE-435. ACE-435 hits the same pathway as ACE-031, but with some specific optimization. Interestingly, in mice ACE-435 seems to dramatically reduce fat and increase lean body mass no matter what the mice ate. Accleron, if you are listening, I’m available to participate in the phase 1 study.

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Comment by Steve Dreher on May 12, 2010 at 5:19pm
Hi Sharon, I wonder if you could talk about your sense of the potential of ACE-031 after hearing Acceleron's presentation - I have been to the web page, but I'm interested in your perceptions as someone outside the company.
Comment by Sharon Hesterlee on May 10, 2010 at 8:08pm
Thanks Ofelia!
Comment by cheryl cliff on May 10, 2010 at 7:02pm
Good research Ofelia! Nothing gets by you. I REALLY needed and very much appreciate seeing there is an upcoming IND for 4658. Had given up on anything happening here with regard to exon skipping trials. BIG THANKS
Comment by Ofelia Marin on May 10, 2010 at 6:44pm
OK. I did listen to AVI's CC today. They DID send the GLP package for AVI-4658 IND to FDA. The answer is expected 30 days from the file date. As soon as the IND is open the trial can start, however when asked about start date the answer was not clear... they would like to see the results from the UK study 28 before the start, those will be available Q3 2010.
Comment by Sharon Hesterlee on May 10, 2010 at 12:15pm
Ofelia--my impression was that Eric was talking about evidence from the CINRG database, but I could try to clarify that with him. I agree absolutely that the best way to get this particular answer might be in the clinic. I think everyone is just trying to be prepared for all the possibilities.

Deb: one outcome that is being tested for clinical trials that might be more "natural" is a sort of pedometer that can measure steps taken in a day and falls. I suspect if the boys get used to wearing this device they will basically forget about it and just go about their business. Agree that MRI might be a good non-invasive biomarker--the NIH funding for that project (following the PPMD End Duchenne Award) is fantastic.

Dan: Joel is one of my favorite people--he can truly move mountains. You have a good team on your side!
Comment by Dan Carson on May 9, 2010 at 8:37am
Sharon ,good to have you with PPMD. Great article and insight on exon skipping and the reality of it all. You will be a critical catalyst for our boys and new treatments to come. Thank you for staying the course. You have a very broad and knowledgable history of Duchenne. Mark, my son, is 9 now and has Duchenne. We have been with Children's hospital in DC and FED with Joel Wood since 2004. Joel is a true champion for our boys and has raised incredible sums of money for research. Eric Hoffman is an compassionate, brilliant scientist that has alot of prayers betting he can pull off a miracle. Having you on board feels like our prayer starting to be answered. , sincerely, Dan Carson
Comment by Deb Robins on May 8, 2010 at 10:39pm
"perpetual " approval would make sense, please have a good chin-wag to Steve Wilton about that in Denver if you haven't already? By 21st century, I was thinking the MRI research that PPMD announced last week they'd given the End Duchenne funding for, but also more biomarkers. To me, clinical performances are unnatural unless behind one way glass; afterall a little horse with a big hear can win a race. We have so much technology, it makes sense to use it to measure small improvements, because a little improvement might feel a whole lot better than it looks to someone else with a stop watch and vice versa. Can functional tests be done without the person's knowledge for instance?
Comment by Ofelia Marin on May 8, 2010 at 12:51pm
Sharon, I am interested in the evidence Hoffman has. Are you talking about the paper where he presented graphs showing the prevalence and possible outcomes? If yes, that is based on Leiden database that contains a low number of BMD cases ending in 51 as opposed to a higher number ending in 45. Does he have additional data?

If we are talking about the same paper, one can read the "disclaimer" after the graph is presented as well:

“Not enough is known about dystrophin
structure and function, and the relative importance
of the protein sequence within the rod domain
remains entirely a matter of speculation. Historically, lack
of dystrophin expression has been used as the key criterion
for DMD diagnosis. This together with the presence
of theDMD clinical picture with such in-frame mutations
argues that other confounding variables such as
imprecisely defined mutation or aberrant splicing may
explain these “exceptions to the reading frame rule.” Thus,
it is anticipated that most or all patients with mutations
in the central rod domain would benefit from the production
of truncated dystrophin.”

It is hard to say how this will work out... in all fairness, I think that only the clinical trials will prove what works and what doesn't.
Comment by Sharon Hesterlee on May 8, 2010 at 10:33am
So, to Ofelia and Lisa's comments, yes, there is evidence from the literature that exon 51 deletions may be mild, but there is also unpublished evidence from Hoffman's database that it may not be...jury's still out. My only point in bringing up some of these concerns is that not everyone has heard them before--I get a lot of questions by email etc from people who really want to understand some of the pros and cons of this approach. I understand your frustration in wanting to know more specific information about time lines and strategies, but this information is not being shared by the companies until they have something definitive like an approved IND. I think what Eric shared at the meeting was encouraging in that a complete tox package has been done for the US regulatory application--it turns out that the oligos really don't get into the muscles very well in healthy rodents (in DMD the tears in the muscle membranes facilitate the entry of the oligos) so the concern that you might actually give a healthy rat BMD and that this would be interpreted as a toxicity was not a problem after all.

To your point, Deb, I'm not sure what you mean by "21st century outcome measures" but if you are talking about biomarkers, I agree wholeheartedly that this is something needed by our community. Well-validated biomarkers can dramatically reduce the time required for clinical development because most biomarkers are cheaper and more consistent that functional studies (although functional studies will still be required eventually for approval you can use biomarkers in Phase I and sometimes Phase II studies). We are working on expanding the strategic plan for research for PPMD and biomarker development will be part of that plan.

The other thing we are really interested in is new clinical protocols for extremely small patient populations--whether that's novel trial designs, or individual INDs. We are also exploring the idea of a "perpetual IND" in which a drug is never actually approved, but made available permanently under an experimental protocol. This might be the best option for extremely rare deletions in which the cost of a full development package is prohibitive.
Comment by Deb Robins on May 8, 2010 at 8:03am
Thanks for lovely info Sharon. Do you think small clinical outcomes will be better evaluated with technology research you have invested good to have some 21st century outcome measures so they can really see what may equate to a little function.

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