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 http://insciences.org/article.php?article_id=3331
. 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 clinicaltrials.gov) 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.