It may seem ungrateful to say that medical progress has a downside, but the growing toll from Alzheimer’s disease might tempt one to that conclusion. As new therapies have helped patients live with diseases that were more deadly in decades past, more people are surviving to an age where the risk of Alzheimer’s increases precipitously. In the U.S. alone, the number of seniors with Alzheimer’s is expected to climb 40 percent to 7.1 million patients in the next decade1. The number of people affected swells when you factor in the spouses, children, and others whose lives are also severely impacted by this disease.
“It’s a horrible disease,” said Rob Lenz, vice president, Neuroscience Global Development. “It really strips you of your identity and takes away who you are as a person. It’s not just dehumanizing for the patients, it’s dehumanizing for the families as well. There’s a huge unmet medical need for additional therapies.”
In an effort to accelerate the arrival of effective Alzheimer’s treatments, Amgen and Novartis have launched a global neuroscience collaboration. Under the terms of the agreement, the companies will be co-developing and co-commercializing new BACE (beta-site APP-cleaving enzyme-1) inhibitors for Alzheimer’s disease.
For Amgen, the collaboration advances a long-standing goal of finding a way to target beta secretase. This enzyme plays a critical role in creating amyloid plaque, a sticky and toxic substance that accumulates in the brains of Alzheimer’s patients. The plaque is composed of amyloid beta, a peptide derived from amyloid precursor protein (APP). Beta secretase helps produce amyloid beta by snipping APP at a particular site on that protein, hence the protein’s other name, BACE (beta-site APP-cleaving enzyme-1).
BACE Inhibitors: A Tough Target
Amgen’s interest in BACE dates back to the late 1990s, when scientists at the company led the first successful effort to clone this key enzyme.2 The cloning capped a search of nearly two decades in the broader research community for the mechanism behind the formation of the amyloid plaque that is one of the hallmarks of the disease. It also marked the beginning of the search for new Alzheimer’s treatments.
In the intervening years, this search has hit a number of snags and hurdles, beginning with the target itself. BACE sits behind the blood-brain barrier, and in general, you need a small molecule drug to penetrate this barrier. To inhibit the enzyme’s activity, a drug needs to fit into BACE the way a key fits into a lock. When the crystal structure of BACE was solved, chemists realized that making the right kind of key would be no small challenge.
“It turned out that the active site was quite large,” said Steve Wood, principal scientist, Neuroscience Discovery Research at Amgen. “A drug molecule has to be small to get into the brain, and it also needs a host of other properties that are largely incompatible with the BACE active site. BACE is one of the more challenging medicinal chemistry targets in Alzheimer’s disease. It’s taken the better part of ten years to solve some of the chemistry challenges.”
Arduous chemistry wasn’t the only hurdle involved in exploring BACE’s potential. Several investigational treatments succumbed to safety issues, either in preclinical studies or early-stage human trials. “That’s the nature of the game with small molecules, and we’ve seen a lot of that in the BACE field,” Wood observed. “Amgen and a number of other companies have had impediments with what seems to be off-target or idiosyncratic safety liabilities. For example, Amgen’s original BACE program was terminated in 2011 due to the potential for retinal toxicity3, a problem similar to the one Eli Lilly & Co. encountered4 with one of their clinical candidates.”
On the clinical side, another challenge was making sure that patients enrolled in Alzheimer’s trials actually had the disease. Historically, a definitive diagnosis could only be confirmed by autopsy, and clinical diagnostic tests weren’t definitive. “In some of the earlier clinical studies, it’s likely that a significant number of the patients had some form of dementia other than Alzheimer’s,” said Lenz.
But perhaps the biggest barrier to success in earlier studies may be that patients enrolled were past the stage of disease where amyloid-lowering therapies might have helped them. “One of the leading hypotheses today is that elevation of amyloid beta is necessary but not sufficient for Alzheimer’s disease,” said Lenz. “We now know that people can have evidence of amyloid accumulation in their brains for up to a decade and a half before they develop overt symptoms of cognitive impairment.”
“The thinking now is that elevated amyloid beta may trigger some downstream cascade, perhaps increasing tau hyperphosphorylation, which is more closely correlated with cognitive impairment. If you’re intervening after a patient already has a brain that’s full of amyloid, which has already triggered these damaging downstream events, even clearing the brain of amyloid may not have any positive effects. This hypothesis hasn’t been proven yet, but in general, the field is pushing toward intervening as early as possible.”
The search for amyloid-lowering treatments has also been aided by the arrival of better diagnostic tools. They include PET scans done with new tracing agents that can detect amyloid beta plaques in the brain. This test and others are helpful in identifying patients with very early-stage disease and ensuring that patients enrolled in clinical studies are very likely to have Alzheimer’s.
As part of the agreement with Novartis, Amgen is joining an effort to take Alzheimer’s prevention in a new direction. The collaboration’s lead BACE inhibitor will be included in a pioneering prevention study in adults, age 60 to 75 years, who have no cognitive symptoms but face a very high risk of Alzheimer’s. The trial is enrolling patients who have two copies of the gene APOE4 (apolipoprotein E4), one from each parent. Roughly two to three percent of people worldwide have this genetic profile, which carries a 12-fold increased risk of developing Alzheimer’s.6 The five-year APOE4 study is being conducted in collaboration with the Banner Alzheimer’s Institute and is part of the institute’s broader Alzheimer’s Prevention Initiative.
Human Genetics Yields Additional Targets
Even assuming the APOE4 study succeeds, there will still be an urgent need for additional therapies. “I think there’s a strong consensus in the field and from the FDA that we are going to need a cocktail of drugs,” said Wood. “We’re not going to catch everybody in the pre-symptomatic phase. So we need to address more aspects of the underlying pathology of Alzheimer’s, including the neuro-inflammatory component and abnormal tau.”
The search for new and relevant drug targets is being advanced by genetic insights, including additional findings from deCODE Genetics, a subsidiary of Amgen. In 2013, a deCODE-led study, published in the New England Journal of Medicine, showed that a rare mutation in a gene called TREM2 (triggering receptor expressed on myeloid cells 2) is associated with an approximately three-fold increase in the risk for developing Alzheimer’s.7 The TREM2 protein is expressed on a range of immature immune cells, including microglial cells, the brain’s scavenger cells. One theory is that reduced TREM2 function may contribute to Alzheimer’s by impairing the brain’s ability to respond appropriately to damaged neurons.
In a recent brief communication to Nature, deCODE reported that a loss-of-function variant in the gene for ABCA7 (ATP-binding cassette transporter A7) roughly doubles the risk of Alzheimer’s disease in Icelanders and several other populations that were studied.8 ABCA7 is also strongly expressed in the brain’s microglial cells.
“The neuroinflammatory component of Alzheimer’s has been recognized for some time, but it’s only recently that we’ve identified genetically validated targets that are linked to this aspect of the disease,” said Lenz. “It’s something we’re looking at closely inside Amgen because the human genetic evidence suggests it’s a very important part of the disease.”
As an 18-year veteran of Amgen’s Alzheimer’s program, Wood has seen the company’s resolve to unlock the biology of the disease. He serves as a project leader for Amgen’s preclinical BACE inhibitors, which are now included as potential follow-on programs in the collaboration with Novartis.
Wood remembers times when Amgen’s program was making headlines with its ground-breaking research, and he also recalls being asked by industry peers if Amgen was still pursuing Alzheimer’s. “We’ve been in and out of the spotlight, but our commitment hasn’t waned in all the time that I’ve been here,” he said. “This new collaboration with Novartis is one of the most exciting things that has happened since the cloning of BACE.”
That sentiment was echoed by Lenz, who noted the keen response from Amgen staff when the new collaboration was highlighted at a recent Global Development all-staff meeting. “There was so much enthusiasm in the room because people at Amgen have been working on BACE for so many years now. People are very excited about this new collaborative opportunity that accelerates the BACE research program and what it might mean for patients.”
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