This feature is part of a series focused on Alzheimer's disease. To view other posts in the series, check out the spotlight page.
Pharmaceutical researchers usually have more weighing on their shoulders than white lab coats.
Their jobs are to find cures for disease, meaning they may be tasked with identifying new molecules that can destroy cancer cells or with creating clinical trials that adequately test a cholesterol-lowering drug's safety and efficacy. Underlying all that work is the science of drug development.
Across all therapeutic areas, the science is difficult. But it has been especially challenging in Alzheimer's disease (AD), which costs the healthcare systems hundreds of billions of dollars annually and has offered up some of the industry's biggest clinical let downs.
The modern era of AD research began about four decades ago, anchored by the discovery of beta-amyloid and tau proteins and the roles they play in the progression of the illness. More recently, investigators have recognized gene therapy and agents non-pathogenic mechanisms of action (MOAs) as possible avenues for AD treatment. Some drugmakers were even able to bring medicines that alleviate AD symptoms to market.
But in spite of the advances, the Food and Drug Administration hasn't approved any disease-modifying products. Developing a treatment that can accomplish such a feat, and knowing the science that allows it to work, appears to be the next frontier for neuroscience drugmakers.
Mechanisms of action
As of early 2017, there were 105 agents being tested as treatments for AD across nearly 140 in-human clinical studies, according to a review published in May by the journal Alzheimer's & Dementia: Translational Research & Clinical Interventions. Seven out of ten of those agents were disease-modifying therapies while the remainder addressed symptoms.
Though a small percentage of the trials didn't disclose the MOA for their investigational drugs, those that did showed MOAs targeting a protein known as beta-amyloid accounted for about 40% of the agents under investigation — with 12 in Phase 1, 14 in Phase 2 and 15 in Phase 3.
Three agents in Phase 1, four in Phase 2 and one in Phase 3 had MOAs directed at another protein, named tau. Roughly 25 more potentially disease-modifying therapies spanned across early- to late-stage testing and reflected a variety of MOAs, from inflammation reduction to metabolic process regulation.
Researchers for decades have considered beta-amyloid protein integral to the onset and development of AD. The protein is born when a pair of enzymes, beta- or gamma-secretase, cut up an amyloid precursor protein (APP). Studies suggest APP, while not completely understood, helps to repair communication between nerve cells.
Beta-amyloid protein production occurs in patients both with and without AD. Backed by extensive investigations, scientists have found that what often differentiates the two groups are mutations in APPs that spur excess beta-amyloid protein synthesis. Over time, the proteins can misfold and congregate on the surface of blood vessels and, most notably, the brain, forming sticky plaques that many believe are the root of the neurodegeneration associated with AD.
Tau proteins follow a similar pattern. They aid in the construction and stabilization of microtubules, yet also pose health risks if mutated. Mutations may prompt the proteins to breakdown or get loaded up with phosphoryl groups, which in turn can cause the proteins to lose function or form neurofibrillary tangles that impair nutrient transport and signaling across the cell.
Therapies aimed at tackling tau and beta-amyloid protein pathogenesis are numerous. They include Eli Lilly's solanezumab, a monoclonal antibody that attempts to bind to soluble, monomeric beta-amyloid protein and usher it away from the brain so plaques don't form in the first place, and Biogen's aducanumab, another monoclonal antibody that binds to plaques and flags abnormally folded beta-amyloid protein for the immune system to destroy. Treatments inhibiting beta-secretase (BACE) are also fairly prominent, fleshing out the neuroscience pipelines of AstraZeneca, Eisai and other large drugmakers.
Conversely, some biopharma players are exploring non-pathogenic routes to solve AD, such as epigenetics. Biogen-backed Rodin Therapeutics, for instance, is a preclinical biotech focused on creating histone deacetylation inhibitors, which studies have demonstrated keep the switch on for genes correlated with improved cognition.
But why amyloid?
In addition to comprising a sizeable portion of global pipeline for AD treatments, amyloid-targeting drugs represent some of the space's biggest trial blow ups.
In November, Lilly revealed its highly anticipated solanezumab had failed a third Phase 3 trial. A few months later, Merck halted a late-stage study of its BACE inhibitor verubecestat after an independent data monitoring committee said the candidate had "virtually no chance of finding a positive clinical effect." Roche, Johnson & Johnson and a slew of other drugmakers have reported clinical setbacks for their beta-amyloid-reducing candidates as well.
Nevertheless, pharmaceutical developers remain committed to the amyloid hypothesis, as well as the promise of regulating tau. Part of the reasoning behind the loyalties to those proteins lies in the history of Alzheimer's research, according to Howard Fillit, MD, chief scientific officer for the Alzheimer's Drug Discovery Foundation.
"Research really didn't start until the 1980s, and it started based on the pathology because those were the primary clues that we had about the disease — the plaques and tangles," Fillit told BioPharma Dive.
As a result of that headstart, researchers know more about amyloid and tau than most, if not all, other potential MOAs for AD. Drugs directed at the proteins have also been effective in preclinical mouse models.
"My favorite quote is that 'we've cured Alzheimer's disease in mice a few hundred times already, we just haven't figured out how to do it in human brains yet,'" Phyllis Ferrell, head of Lilly’s global late-stage Alzheimer’s therapeutic and diagnostic team, told BioPharma Dive in an interview.
Obviously, there are plenty of hurdles left to clear.
For starters, animal models haven't really translated over to in-human tests, according to Ferrell. And compared to other therapeutic areas, researchers haven’t had as many years to investigate AD, meaning many of the ways to optimize drug discovery or treatment haven’t been fully puzzled out.
"We think we know the processes behind plaques and tangles, but we still don't know which part of the process to hit; if we have to hit multiple processes and test combinations, and even what stage do we have to treat," Lilly’s head of early phase neurosciences, Michael Irizarry, said in an interview. "Do we have to treat before there's symptoms — before there's even pathology — or can treatments work later?"
A maturing science
What is clear, however, is that the science is progressing.
Identifying AD patients, which had for years only been possible through autopsies or highly invasive biopsies, is now easier thanks to amyloid tracers — ligands used in positron emission tomography scans to detect the presence of amyloid plaques.
Lilly's tracer Amyvid (florbetapir) was the first to reach the U.S. market back in 2012, but was quickly followed by GE Healthcare's Vizamyl (flutemetamol) and Piramel's NeuraCeq (florbetaben). A medley of tau tracers, meanwhile, are currently in early-stage development.
The wider breadth of diagnostics is helping to optimize clinical trials. To that end as well, investigators have gotten better at identifying potential therapies and drugable targets and testing to see whether they support the underlying theories surrounding amyloid and tau proteins.
"Pharma and biotech are now testing molecules with really strong target engagement and pharmacodynamic effects that can test ... therapeutic hypotheses well," Irizarry said.
But beyond amyloid and tau, the industry and academia are looking deeper into agents with MOAs that work on non-pathogenesis factors associated with Alzheimer's disease, such as epigenetics, oxidative stress on brain tissues, inflammation and neuroprotection.
"What the field is coming around to is the recognition that aging is the leading risk for Alzheimer's disease," Fillit said.
"If we try to translate what we know about aging — what's called biological gerontology — we can really synthesize a whole number of approaches to understanding the aging brain, how aging of the brain can lead to neuronal dysfunction and the pathology that ultimately occurs from it, as well as how that relates to the symptoms of a disease," he added.