This is Part II of a 2-part series from the Neurotech Investing & Partnering Conference. Read Part I here.
A nearly impermeable endothelial boundary called the blood brain barrier separates the central nervous system (CNS) from the bloodstream. The BBB is essential for maintaining stability of the CNS microenvironment and ensuring that toxic substances are kept out of the brain. However, it also presents an insurmountable hurdle preventing many beneficial drug and biologics from reaching the necessary therapeutics targets in the brain and spinal cord (see June 2011 news story). At The Annual Neurotech Investing & Partnering Conference in San Francisco on April 7-8, 2015, four promising companies presented their creative approaches for drug delivery across the BBB in the exciting session on “Crossing the Blood Brain Barrier”. For more on new therapeutic approaches for multiple sclerosis and neuroinflammation, click here.
Jacqueline Grant, Manager Business Development Neuroscience, Genentech,opened the session by underscoring the critical importance of developing methods to penetrate the BBB for neurotherapeutics, as evidences by a long string of failures of clinical trials for neurological diseases, likely in many cases due to failure of these drugs to ever reach their targets in the CNS.
First to present was Michael Hite, CEO of Impel NeuroPharma, a company developing methods to deliver drugs across the BBB by intranasal delivery (see April 2013 news story). The company’s Precision Olfactory Delivery (POD) device is designed to deliver pressurized aerosolized drugs (small molecules and biologics) to the upper nasal cavity olfactory epithelium, where they are rapidly distributed in the CNS. This delivery system confers advantages over intravenous drug delivery, due to dramatically lower drug doses needed, and fewer side effects. In non-human primates, a therapeutic dose of F-18 deposited into the nasal cavity by a POD device, achieved rapid distribution to multiple brain regions, including olfactory bulb and prefrontal cortex. The company is currently pursuing 10 active programs spanning different therapeutic indications, including two Phase II clinical studies in Alzheimer’s disease.
A very different approach for bypassing the BBB was presented by James Callway, CEO of ArmaGen. The company’s technology leverages the body’s natural active transport systems present on BBB – the transferrin, insulin or LRP1 receptors – and fuses a therapeutic to an antibody that binds these receptors. The antibody-drug protein is then transported across the BBB in a process known as receptor-mediated transcytosis. The company’s current therapeutic focus is lysosomal storage diseases (LSDs) and neurodegeneration. ArmaGen’s lead candidate for Hurler’s syndrome (MPS I), called AGT-181, is a fusion protein of iduronidase (IDUA), the enzyme lacking in the disease, and an antibody that binds the insulin receptor. In animal models of MPS I, AGT-m181 reduced lysosomal inclusion bodies in the brain by 73% as compared to saline-injected mice (Boado, RJ et. al, 2011). In the neurodegenerative disease space, Armagen has developed an inhibitor of tumor necrosis factor (TNF), a proinflammatory substance that has been implicated in as ALS and AD. Preclinical validation studies are ongoing in ALS, as well as in AD, Parkinson’s disease and stroke.
Jim Stice, CEO of Twin Star Medical, presented another original approach to shuttle drugs across the BBB. The company has developed a porous hollow fiber catheter technology for local delivery of therapeutics. These catheters provide several significant advantages over existing drug delivery mechanisms: delivery is independent of intact microcirculation, which may be disrupted due to injury (such as trauma), there is no need for systemic delivery when toxicity of the agents is a limitation, and the size of the pores can be adapted for each tissue and agent, improving drug delivery and reproducibility. In the neurodegenerative disease space, the company is focusing on delivery of small interfering RNAs (siRNA) and adeno-associated vector (AAV)-based therapeutics.
The final presenter, Frank Walsh, CEO of Ossianix, showcased another twist on the Trojan Horse approach presented earlier by Armagen, in this cases using transferrin receptors (TFR1) to shuttle drugs across the BBB. Ossianix’s has developed a single domain antibody platform modeled on the shark variable new antigen receptor (VNAR) structure, a platform particularly suitable for designing high affinity antibodies to epitopes that are not recognizable by traditional antibodies. As a candidate therapy for Alzheimer’s disease, the company has developed a beta-secretase (BACE1)/TFR1 antibody, which significantly reduced brain amyloid beta levels in preclinical studies. The company is also developing a therapeutic approach for ALS based on a myostatin antogonist to increase muscle mass, with funding from the ALS Association. In the questions that followed the presentation, Dr. Walsh emphasized that, based on data from non-human primates, there is little concern of immunogenicity of these VNAR bispecific antibodies.
These exciting new possibilities for efficiently delivering therapeutics into the CNS will likely advance drug development for all neurodegenerative diseases, including ALS, where drug delivery to the primary site of degeneration is critical for success.- Sara Shnider