Commercializing Neuroscience

Of the longstanding technical difficulties in the drug development business, few have proven more intractable than crossing the blood brain barrier – evolution’s elegant system designed to protect the brain from harmful chemicals. A molecule must cross this barrier in order to effectively treat some of the world’s most devastating neurological conditions, including ALS, Parkinson’s and Alzheimer’s.

The failure rate for drugs targeting diseases of the central nervous system (CNS) has been dauntingly high. Over the past 20 years, most drugs have been based on the “amyloid hypothesis,” which began with a simple observation: Alzheimer’s patients have an unusual buildup of the protein amyloid in their brains. Thus, drugs that prevent or remove the amyloid should slow the onset of dementia. Roche’s gantenerumab and Eli Lilly’s solanezumab are just a few of the more than 100 potential Alzheimer’s drugs that have flopped in pursuit of a solution.

The prevalence of failure in treating neurological diseases is a testament to their unique challenges. Uncertain diagnoses, long progressive burdens of disease, multiple etiologies and complicated clinical trials are just a few factors that are impeding success. Given the history of failure it may seem that you would have to be either stupid, crazy or charitable to invest in this space. However, given macro and societal drivers, such as the global rise in the incidence of mental illness and the aging of the population, particularly in western societies, the payoff could be enormous.

This represents a shift in recognizing that Beta-amyloid is just one protein that can mis-fold in the brain. Others, such as tau or alpha-synuclein, could hold clues to deciphering how Alzheimer's disease develops in the aging brain.

Tau, in particular, has intrigued many, earning recognition as another characteristic mark of Alzheimer's disease. Tangled clumps of the protein can stretch across regions of the brain, and its presence is correlated with worse cognition. Up to this point, the field could only diagnose Alzheimer’s when clinical symptoms were observed. This is a huge disadvantage akin to closing the barn door after the cows have left, because we now know that, by the time a patient has observable clinical symptoms, a lot of the neurons are already dead (estimates are that 70% of neurons are dead). The key then is to intervene when you still have all neurons intact. But up until today, this was not possible because there was no diagnostic means to identify people at risk. This has been one of the key developments over the past two years. We can now identify markers, such as phospho-tau 181 or phospho-tau 217, which allow you to identify people at risk, and begin treatment early on in the disease progression.

As an example, when you look at cardiovascular disease, a person goes to the doctor, gets checked for cholesterol and, if they have high cholesterol, then the doctor prescribes statins. The statins do not really treat heart disease but prevent it. There is now a recognition that risk markers for Alzheimer’s disease appear 10-20 years before the disease starts. By identifying these factors early on, a patient could receive a vaccine because it costs very little, it works for a long time and people would not lose their neurons, which is absolutely required in order to prevent the onset of the disease. This is where the field is headed today. Pfeifer continued: “This is precision medicine, which of course means specificity. It means safety, because you do not treat for something which you do not have, and it is cost effective because you do not treat something which costs a lot of money and does not really help you.”