Full article reprinted from Start Up - September/October 2009
Start-Up -- The neurodegenerative disease R&D collaboration between RNA interference specialist Alnylam and device maker Medtronic--the first siRNA-oriented convergence opportunity--appears to be inching closer to the clinic. Key to the program's success to date are refinements in the Medtronic catheter and infusion -pump system used to deliver the Alnylam compund, in keeping with Medtronic's strategic goal of better understanding the mechanics of delivering chronic drugs into the brain. Read more...
siRNA Opening Up CNS Device Opportunities
Full article reprinted from Start Up - September/October 2009
Preclinical data from the neurodegenerative disease R&D collaboration between siRNA specialist Alnylam Pharmaceuticals Inc. and device maker Medtronic Inc. suggest that the first siRNA-oriented convergence opportunity is inching closer to the clinic.
It's early to claim validation of RNA interference as a therapeutic strategy, but not premature to suggest where the technology may have the best chance for success. One high-potential area is in the treatment of rare inherited disorders caused by well-defined and measurable expression of mutant proteins or protein overproduction. These include diseases of protein misfolding such as polyneuropathy and cardiomyopathy caused by transthyretin (TTR) amyloidosis, cystic fibrosis, and CNS diseases including Huntington's disease and, potentially, Parkinson's disease.
But to treat inherited CNS disorders you need to deliver the small interfering RNA (siRNA) molecules that silence disease-causing genes and thereby stop the damaging protein production at the source, directly to brain tissue--unlike those other settings, which call for systemic drug delivery. And that entails significant new device innovation.
A key to the Alnylam-Medtronic program's success to date appears to center around refinements in the Medtronic catheter and infusion-pump system used to deliver Alnylam's siRNA compound, ALN-HTT, at a high flow rate and with the requisite distribution in tissue. The new data, from non-human primate studies, was presented in September at the 2009 World Congress on Huntington's Disease. It showed that ALN-HTT delivered directly to the CNS using an experimental catheter and the commercially available Medtronic SynchroMed II pump targets and silences huntingtin, the gene responsible for Huntington's disease, and achieves broad tissue distribution at substantial distances from the infusion site.
"We are able to show that a Huntington's-like phenotype can be abrogated by delivery of siRNA to the appropriate region of the brain," says Akshay Viashnaw, MD, PhD, Alnylam's SVP, clinical research. "It gives us a very compelling case, given the compatibility and the ability to leverage the pump and catheter technology we have, to announce that Huntington's is clearly a disease of high unmet need and that we'd like to get to the clinic."
The collaboration began in 2005, five months after an earlier convergence program between Medtronic and Amgen Inc. was halted in Phase II. That earlier alliance aimed to treat Parkinson's disease by delivering glial-derived neurotrophic factor (GDNF) chronically to the brain, also with a catheter and a SynchroMed pump. Amgen's decision to stop supplying the drug was a controversial one that investigators still bristle over today because GDNF appeared to be working, leading to an ultimately unsuccessful petition to FDA to allow patients to continue to receive the drug after Amgen stopped supplying it to the investigators.
There were several varieties of catheters used in the GDNF program, including those that pulsed the drug at a high convection rate (convection-enhanced delivery, or CED) in the Phase I studies and then, in Phase II, point-source delivery catheters designed to keep the drug around the immediate area of the catheter tip.
As it turned out, the Phase I results were not replicated in Phase II. "Our sense was that the catheters were critical," says Don Gash, PhD, of the University of Kentucky, a long-time Medtronic collaborator who participated in the Phase I program for GDNF and who also led the non-human primate studies for the current Medtronic-Alnylam collaboration. "I think we've learned a lot from the GDNF trials. First of all, to go with CED."
Indeed, one of the main emphases of the work in Huntington's disease presented at the World Congress was that the companies have decided to use CED under relatively high flow rates to distribute Alnylam's drug over a broader brain region than would be accomplished with passive diffusion. "The results specifically showed that we achieved a knockdown of the huntingtin gene at a four millimeter distance from the infusion site, suggesting that we did achieve good convection-enhanced delivery," says Viashnaw.
For Medtronic, the Alnylam collaboration is part of its broad goal of better understanding the mechanics of delivering drugs into the brain. "This overall focus was not just put together in the context of the Alnylam collaboration," says Douglas Gwost, senior program manager for the collaboration at Medtronic. "To infuse drug into the CNS, especially intercranially, we need to better understand where the drug is going. It seems like a simple statement but it's really a basic premise you have to be able to know with some certainty."
One major challenge is to devise a system that creates enough flow in the catheter without causing backflow. Other hurdles include understanding the brain parenchyma itself as a medium in which to inject a drug and how that drug is going to flow and in which direction. To analyze these matters, Medtronic brought with it a wealth of experience from its interthecal chronic drug delivery efforts. "We were able to bring those things into play," says Gwost. "We wanted to measure things like the porosity of the tissue and what the distribution is going to be and the concentration of the drug based on that distribution."
The mechanics are especially tricky for chronic interparenchymal delivery, such as the administration of an siRNA to down-regulate the huntingtin gene. There are currently no catheter systems in commercial use for chronic drug delivery into the brain: Medtronic's goal is to create a platform for such delivery for a variety of drugs that cannot cross the blood-brain barrier. "We have a portfolio of drugs we are looking at for a variety of targets," says Gwost. But given they are all in the early stages of development, it's not possible to estimate what it might mean for Medtronic's neuromodulation business over all, he adds.
Medtronic wanted to work on interparenchymal delivery even before it settled on Huntington's disease as the lead indication with Alnylam--a decision announced in 2007, when they also converted the collaboration into a 50-50 partnership. "We weren't sure what the indication might be, but developing a chronic interparenchymal delivery system was a focus for us in the first two years," says Gwost. Huntington's disease turned out to be an ideal setting for several reasons: the molecular target is validated, and siRNA is attractive because it down-regulates the toxic production from the huntingtin gene, which is the undisputed and sole cause of Huntington's disease. It's also easy to identify individuals at risk and to have a general sense of when the disease may manifest. And there's a circumscribed anatomical region--the striatum--where the siRNA needs to go.
Although the companies will not give a timeline for an IND filing, they appear well along on that course. "There's clearly momentum in the program," says Viashnaw.
--Mark L. Ratner
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