Alzheimer’s disease (AD) probably the last frontier of man’s battle with diseases, is a progressive brain disorder that damages and eventually destroys our brain cells leading to memory loss and a gradual decline in other brain functions. The Alzheimer’s Association states that every 71 seconds someone in the US develops Alzheimer’s and by 2050 it’ll be every 33 seconds. By 2050 nearly million people will be affected by the disease that will create an economic burden running to a trillion dollars. Clearly, the world stands amidst an epidemic, and this is not new news.
A Very Brief History of AD
Dr. Alois Alzheimer first described the disease in 1906 based on his observation of a patient at the Frankfurt Asylum whose behavioral symptoms and loss of short term memory became his obsession for the next several years. By 1910 Emil Kraepelin a German psychiatrist named the disease as Alzheimer’s disease in the eight edition of his book called Psychiatrie. It took another 60 years for the US Congress to establish the National Institute of Aging (NIA) as a primary federal agency to fund the research on the disease. The year 1983 saw the month of November being designated as a national Alzheimer’s Disease month. By 1984 beta-amyloid (Abeta) – a prime suspect in triggering the disease was identified by George Glenner and Caine Wong eventually leading to the beta-amyloid hypothesis –the basis of several recent clinical trials. Tau-the microtubule-associated protein was identified in 1986. The year 1987 saw two breakthroughs, 1. The identification of the first gene on chromosome 21 that codes for the amyloid precursor protein (APP). 2. The clinical trial of tacrine, the first drug that targeted the symptoms of Alzheimer’s. Alzheimer’s Association, NIA, and Warner-Lambert Pharmaceutical company (Pfizer) collaborated to run the trial. Since then there have been numerous clinical trials, and almost every one of them has failed to find the cure for the disease.
Next Generation Drugs of AD
Next Generation Drugs that are being tested now are mostly based on the beta-amyloid hypothesis. The fundamental reasoning behind the hypothesis is based on the gene mutations responsible for the synthesis of beta-amyloid that have been associated with early, onset, familial AD. The 42-mer peptide derived from the Amyloid precursor protein (APP), a protein thought to be involved in synapse formation, and neuronal cell adhesion is responsible for brain amyloid plaques-the pathological hallmarks of the AD. Therefore, the strategies to defeat the disease are now based on immunotherapy (monoclonal antibodies, therapeutic vaccines), secretase (enzymes that can cleave APP) inhibitors and aggregation inhibitors.
The second camp of believers in the war against the AD, however, believes that the neurofibrillary tangles composed of an abnormally high phosphorylated microtubule-associated protein called tau are a better target to tackle the disease. Among the companies that have significantly invested in this approach are Merck, Biogen, and Roche.
The Monoclonal Antibody Trials
Both approaches have met with significant setbacks and failures. The latest to fail is Lilly’s Solanezumab. The result from the EXPEDITION3 trial of Solanezumab, a humanized monoclonal antibody that has been designed to clear soluble Abeta has just been published in the New England Journal of Medicine a week ago. Sadly, the trial failed to replicate the findings from an earlier trial where secondary analyses had shown a modest effect in slowing the cognitive decline. The current trial was a double-blind placebo control that involved patients with mild dementia due to AD (Mini-Mental State Examination of 20-26). The results of the primary outcome measure (ADAS-cog14) showed no significant difference between the treated and the untreated (placebo group) in reducing the cognitive decline in the patients.
The study hinted that the administered dose of Solanezumab might not have been sufficient to reduce the deposited cerebral amyloid, neuronal atrophy or other associated pathology of the disease. The drug penetration in the CNS ranged from 0.1% to 0.3% of the plasma level, that may be too low to produce a clinically meaningful effect. Secondly, even though the drug cleared more than 90% of the free plasma Abeta, the florbetapir PET imaging data suggested that the antibody failed to reduce the fibrillar amyloid burden in the patients. Though the study puts a yet another dent in the amyloid hypothesis, it pins our hope on the two ongoing Phase III trials with Biogen’s Aducanumab known as ENGAGE and EMERGE for reasons that are specified below.
Biogen’s study (A 2016 double-blind placebo-controlled phase Ib PRIME study that was reported in Nature on Sep 2016) is based on a monoclonal antibody that recognizes the pathological Abeta aggregates involving patients with mild dementia. Unlike Solanezumab, the penetration of Aducanumab through the blood-brain barrier was reported to be 1.3% (nearly tenfold more). The drug based on the florbetapir PET imaging test showed a reduction in the Abeta plaques in both dose and time-dependent manner. Clinical assessment of the study even though exploratory (that is the study was not powered to detect clinical change) showed a dose-dependent slowing of clinical progression at one year. On Nov 2017 Biogen released their result from their long-term extension of the ongoing Phase Ib study of the Aducanumab that showed a continued reduction of the amyloid plaque and suggested benefit on the clinical decline for the patients in Phase Ib. Analysts have vetted that Biogen’s Aducanumab is perhaps the best anti-amyloid antibody currently available with more than 50% chance of success. Only time will tell whether Aducanumab will be able to achieve the efficacy required to bring a possible drug to the market. For now, the world has to wait.
The Road Ahead
However, the pursuit to find a new and diverse target continues and that itself is hope for millions of families globally. The US federal Government’s effort through National Institute of Health (NIH) has been persistent in funding the disease area, and the share of funding has increased in several folds compared to other disease areas in recent years. The funding spree has created a tsunami of information about the disease process both macroscopically and at a molecular level. Just a search on “Alzheimer’s Disease” at the clinical trial.gov shows more than 200 active trials that are currently running. The target repertoire includes Abeta to cholinergic neurons to kinases to lipid and glucose metabolism to growth factors to protein homeostasis to the biology of mitochondria, etc. At par with oncology, AD therapy is seeing a trend towards precision medicine, mostly because of our better understanding of the genes and genetic pathways involved in the disease process today.
The war against neurodegeneration has recently seen an encouragement from venture funding too (This speaks a lot about the health our biotech venture ecosystem). LifesciVc remarked a 40% increase in the central nervous system (CNS) venture funding over the last 5 years. There have been several venture-backed neuro focused startups that have promising pipelines. The star among them is, of course, Denali which closed a 1.2 billion dollar valuation last year. Some of the other startups that are worth looking forward to are Cortexyme, Cerevance, Alzheon, Voyager, Yumanity to name a few.
Even though the future of drug discovery in the AD seems uncertain but so was the journey to the moon. I think tomorrow will be exciting and someone from this generation will write how through collective efforts, the battle of Alzheimer’s was won in the coming decades. I sincerely wish I can read that book in my lifetime.
Author: Ananda Ghosh
Acknowledgement: The blog resulted from a discussion with Sadhana Chitale, PhD, Director, Life Sciences, NYU Technology Ventures and Partnerships over an article on Alzheimer’s research.
Editor: Sadhana Chitale, PhD
Image: The Persistence of Memory, Salvador Dali, 1931
Obsession & Opinions Cartoons: Manasi Pethe, Ph.D. San Diego
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