Prize4Life recently attended the annual Neurotechnology Industry Organization (NIO) Annual Neurotech Meeting in San Francisco. For those unfamiliar, NIO is a non-profit trade association for neuroscience-focused companies founded in 2006 to accelerate the development of treatments and cures for brain and nervous system illnesses. While there were many provocative sessions, two stand out as having particular relevance to ALS included one on exciting progress in CNS delivery and another specifically on the promise and peril of pursuing the development of drugs for orphan diseases (covered in Part II here).
While much focus has been placed on identifying therapeutic agents that modify disease progression and improve patients outcomes, there has been a growing recognition that devising efficient delivery mechanisms for these promising therapeutics is as important for successful CNS drug development as the therapeutic itself.
As many a disheartened drug developer knows, it has long been harder to get drugs into the brain than to break into Fort Knox, given the existence of one of the brain’s many levels of protection, a system known as the Blood Brain Barrier (BBB). It is estimated that up to 95% of drugs can not penetrate the brain.
A session entitled: Beyond the BBB: Gene Therapy, Cell implants, Drug Delivery, showcased a variety of promising strategies to surmount this formidable obstacle. Starting things off was a presentation from the CEO of Canadian company AngioChem, Dr. Jean Paul Castaigne. AngioChem’s clever approach is to use a sort of Trojan Horse trick and envelop a potential drug of choice with a protein sequence recognized by the ubiquitous receptor, LRP1, essentially tricking the brain into actively transporting the drug across the BBB. AngioChem is specifically focusing on tackling brain cancer, Parkinson’s Disease, and pain, but the approach could potentially be relevant for numerous other CNS disorders. The degree of delivery presented (milliliters per gram per minute) was impressive and Castaigne showed some visually powerful images of a brain cancer patient with an aggressive tumor (that had previously grown back twice following surgery) remaining cancer free in the presence of one of AngioChem’s drugs, which was recently licensed to Geron for the treatment of patients with primary and metastatic brain tumors. Of potential interest to the ALS community, one of the compounds AngioChem is currently interested in developing is a modified form of GDNF, a trophic factor known to promote powerful survival effects for motor neurons and currently being explored by Clive Svendsen’s group at the Cedars-Sinai Regenerative Institute, in combination with cell-based delivery, as an ALS therapeutic.
Next up was Dr. Erich Mohr, CEO of MedGenesis Therapeutix to discuss their approach to overcoming the dreaded BBB. Highlighting the difficulty of delivering drugs to the brain, Dr. Mohr reminded the audience of GDNF’s long and checkered history as a potential treatment for Parkinson’s Disease, first in the hands of Amgen, then Biovail (MedGenesis’ pharma partner), before MedGenesis finally solved the delivery issues that had been plaguing the sticky protein. Using a delivery approach called Convection Enhanced Delivery, Mohr showed that MedGenesis was able to deliver GDNF at high and sustained concentrations to its dopaminergic brain targets, eliciting remarkable benefits for Parkinson’s patients, as illustrated in two videos. MedGenesis is preparing to launch a Phase II placebo controlled clinical trial in Parkinson’s Disease, and is also interested in epilepsy and deafness.
Next at bat and focusing on GDNF’s sibling rival, Neurturin, CEO Dr Jeffrey Ostrove presented Ceregene’s strategy to harness gene therapy to deliver protein therapeutics to the brain. Using a modified adeno-associated virus as a delivery mechanism, Ceregene is currently preparing for a Phase IIb study in Parkinson’s patients. Of particular promise, in the 60 subjects who have previously received Ceregene’s drug, none have experienced significant safety issues or adverse events.
Last to present, Lars Wahlberg, CEO of the Danish company, NsGene, described their innovative efforts to bypass the BBB by implanting cellular sources of trophic factors directly into the CNS. Among the factors being pursued are the aforementioned GDNF, as well as another member of the family, Artemin/neublastin, and of course the trophic factor that started it all, Nerve Growth Factor or NGF. Wahlberg described NsGene’s approach as akin to developing “biotrodes” (like an electrode but formed from a combined device + cells), which when implanted, act like small local bio-factories to make and deliver directly to the brain anything a cell line can make, from antibodies to growth factors. NsGene is the heir to efforts begun long ago with a company spun out of Brown University called CytoTherapeutics
During the question and answer period, of all the companies in the group Ceregene was the most open to exploring ALS as an indication for their approach, but considering the enticing opportunities in orphan drug development (discussed here in part 2 of this series), perhaps these (and other) companies will consider getting onboard the ALS bandwagon in the future.-Melanie Leitner.