Unlike the significant strides cancer research has made over the last few years, the field of neuroscience is often seen to be lagging behind. Although the prevalence of neurodegenerative disease such as Alzheimer’s disease and other cognitive dementias are high and growing as the population ages, current treatments are severely inadequate. Attempts made by pharma in drug discovery for neurodegenerative diseases have often led to spectacular losses with a 99.6% failure rate in clinical trials for Alzheimer’s disease alone.
There are often cited reasons on the challenges of drug discovery for neurodegenerative diseases which include:
- Poor animal models (mice do not get Alzheimer’s)
- Blood-brain barrier preventing drug entry
- Poor understanding of pathophysiological disease processes (People are still arguing about whether tau tangles or amyloid beta plaques cause Alzheimer’s)
- Poor diagnosis methods (dementia scoring is based on interviews with patients which can be rather subjective and you cannot do this with mice)
- Focus on receptor-ligand model (the typical drug discovery approach which may work for other diseases but you never know with the brain, many compensatory activities can occur… it is an important organ.)
- Patient selection for clinical trials (due to poor diagnosis methods, patients selected for clinical trials may not really have Alzheimer’s, or may be too far along in the disease for a drug to take effect).
Recently however, Biogen has reported pretty impressive results in its latest Phase Ib clinical trial for aducanumab, a human monoclonal antibody that targets amyloid beta (both soluble and insoluble forms) in Alzheimer’s disease. The trial had 166 patients that were split into groups assigned placebo or the drug at different dosage levels. Amyloid beta plaque levels were monitored by positron emission topography and at 54 weeks post-treatment, levels of amyloid plaques were significantly reduced in the mid to high dose-level groups. More significantly, patients in the highest dose group achieved a 5-fold improvement in the Mini Mental State Examination and Clinical Dementia Rating scores compared to those on placebo, suggesting treatment slowed the cognitive decline seen in Alzheimer’s. However, some severe side effects such as brain swelling were reported that led to discontinuation of treatment in some patients. Why Biogen has succeeded while others have failed may lie in their more careful enrollment of clinical trial participants. They made sure to exclude patients with other forms of dementia often misdiagnosed as AD and included those only in early stages of the disease. Aducanumab now advances to Phase III trials and if these positive results keep up, it would be a massive breakthrough for Alzheimer’s disease treatment and a humongous paycheck for Biogen.
In an effort to advance neuroscience research, several large funding initiatives have been launched in many countries including the US, Europe, China, Japan, Australia and Israel. They all have ambitious goals of creating a computer-simulated human brain, or establishing the functional connectome (in other words, mapping which electrical signals between neurons leads to specific changes in behavior). The European Commission has dedicated 1.19 billion Euro to its Human Brain Project over a 10 year period. President Obama has granted $100 million USD to the US BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative for the year 2014 with a projected spending of up to $3 billion over 10 years. The jury is still out though on how effective these programs will be. In contrast to the Human Genome Project where the goal was clear (sequence the full human genome) and processes established, these programs simply consists of collecting large amounts of data in the hope that a pattern emerges which may reveal some fundamental principles of brain function or structure. Already, there has been some criticism that these large programs are limiting the availability of funds for other smaller research groups.
But clearly, understanding the brain is not a one-man task and an integrated approach may be what is needed to create some real advances. I suppose only time will tell.
*the cool image above is a scanning electron micrograph of cultured mouse hippocampal neurons (tan) on a layer of glial cells (brown) forming synaptic boutons from Thomas Deerinck and Mark Ellisman, the National Center for Microscopy and Imaging Research, UCSD