As Drugs Fail, Some Researchers Urge a Return to Alzheimer’s Roots

Alex Lash October 25th, 2017

As the quest to find treatments for Alzheimer’s disease keeps crashing against rocks, a group of researchers in the field want their peers to pay more attention to the part of the brain where Alzheimer’s disease first wreaks havoc.

A new paper from the researchers, published this month in the journal Alzheimer’s & Dementia, is on one level a reminder of decades of research on the cholinergic system—neurons that produce a signaling chemical called acetylcholine. The authors also say that technical advances in imaging, diagnostics, and more could be a doorway to treatments that don’t just alleviate Alzheimer’s symptoms for a while, as current cholinergic drugs do, but also could have longer-term meaningful effects on patients’ lives.

“This paper builds upon what some people have been saying for a long time,” says Rachelle Doody, the global head of neurodegeneration at Roche and its Genentech division. She was not involved in the publication.

“The evidence keeps mounting,” says Doody, who agrees with the authors that cholinergic research should play a larger role in putting a brake on Alzheimer’s. The disease affects more than 5 million Americans and could reach 16 million by mid-century, according to the Alzheimer’s Association.

Proponents of more cholinergic action face continued skepticism, however. Cholinergic drugs, which represent the only ones approved for Alzheimer’s, only blunt the disease’s symptoms for a relatively short period for many patients.

But nothing else has worked at all. The attrition rate in clinical studies was nearly 100 percent three years ago, and it’s only gotten worse. Many of the recent failed Alzheimer’s drugs have aimed to clear out or prevent the build-up of beta-amyloid plaques in the brain during later stages of the disease. Attacking amyloid still has many champions, and the sticky clumps formed by the misfolded protein are a hallmark of the disease. But the conviction about amyloid’s primacy in Alzheimer’s has elbowed aside work elsewhere, according to the paper’s authors.

“The cholinergic hypothesis fell out of favor simply because it was overtaken by the more ‘sexy’ amyloid hypothesis,” says Peter Snyder, a neurologist and chief research officer of Rhode Island’s Lifespan health system. Snyder is one of several contributors to the new article, which is titled “Revisiting the Cholinergic Hypothesis.” The researchers involved call themselves the Cholinergic System Workgroup, which is led by Harald Hampel, scientific director of the Institut de la Mémoire et de la Maladie d’Alzheimer in Paris.

Companies have bet and lost billions of dollars on failed anti-amyloid treatments. Because they were trying to treat patients whose disease was too advanced—the pharmaceutical version of applying a Band-Aid to someone bleeding to death—some have shifted to earlier-stage patients, where Biogen, Roche, and others press on.

At an upcoming Alzheimer’s conference, updates from several studies are expected, but definitive data won’t likely arrive for two or three more years.

The tide might be turning against the amyloid predilection. As a recent analysis showed, other mechanisms of action now make up a higher percentage of drugs being evaluated in Phase 1 and Phase 2. The next wave of therapies is not as amyloid-heavy, so to speak. Reducing brain inflammation is one emerging mechanism; addressing the malformation of a protein called tau is another.

WHERE ALZHEIMER’S STRIKES FIRST

Alzheimer’s first damages neurons in the basal forebrain, a small nugget near the bottom of the brain where the spinal column and brain attach. As in many parts of the nervous system, the neurons here—cholinergic neurons—produce acetylcholine, which transmits signals that are crucial for memory, cognition, and more.

Of the few Alzheimer’s drugs on the market, all approved at least 15 years ago, two boost acetylcholine by blocking enzymes that break it down. But these treatments—donezepil (Aricept) is the most common—are generally regarded as short-term fixes, staving off the disease’s inevitable cognitive decline for a while. (Another approved drug, memantine (Namenda), also works in the cholinergic system but with a different mechanism of action.)

Cholinergic drugs fail, too. One example is the drug intepirdine, which in highly anticipated results released in September did not improve patients’ cognition or their daily activities when combined with donezepil, compared to patients taking donezepil alone.

But intepirdine was not a strong candidate. Its owner Axovant Sciences (NASDAQ: AXON) bought it in 2014 for $5 million—mere peanuts in pharma money—from drug giant GlaxoSmithKline (NYSE: GSK), which had shelved it due to poor clinical results. Axovant convinced investors to get on board; its $315 million IPO in 2015 was one of the largest biotech debuts on record.

Intepirdine targeted a receptor called 5-HT6, which other drugs have tried and failed to exploit.

In other words, intepirdine was a longshot, and the number of advanced experimental Alzheimer’s drugs that focus on the cholinergic system remains tiny.

Indeed, the latest failure only reinforces prevailing views of cholinergic drugs as only temporary, or “symptomatic,” fixes, rather than significant ways to change the course of the disease. “There’s only so much you can do with neurons that are gone. You can push higher but you’re not going to change the disease,” says Martin Tolar, CEO of Alzheon, which is trying to revive a once-failed anti-amyloid treatment, tramiprosate, by tweaking its chemistry and targeting Alzheimer’s patients with the highest-risk genetic profile. (Tolar told Xconomy in early 2016 he needed to raise $100 million to start a pivotal study. He has since raised about half that.)

That narrow view of potential disease-modifying effect has steered money away from cholinergic research. Case in point is the small but influential Alzheimer’s Drug Discovery Foundation. Faced with limits, the foundation has opted to fund what it sees as more cutting-edge investigations into the role of inflammation.

“We’ve heard many approaches to engaging the cholinergic system and other neurotransmitter systems,” says Lauren Friedman, the foundation’s acting scientific director. “The question is, will it really affect disease progression? … NEXT PAGE »

If you dose high enough it might work, but are you stopping neurodegeneration? That’s why the real focus has been on other systems.”

To date, higher doses of cholinergic drugs, as Friedman alludes to, haven’t been possible because of their side effects such as debilitating nausea and vomiting.

“We simply cannot dose high enough on donepezil,” says Snyder, using the generic name for Aricept. “The top dose is typically 10 mg per day, which is likely at the low end of the therapeutic range, but if we go much higher in dose this leads to reduced tolerability.”

ALLEVIATING BRAIN ATROPHY?

One example of more sophisticated technology opening new windows came recently from Hampel. He and colleagues recently published a randomized, double-blinded study of prodromal patients—those who show cognitive symptoms but not dementia—who took 10mg a day of donepezil for 12 months. They had more reduction in the brain atrophy that is common to Alzheimer’s disease. They were compared to patients who took a placebo. Lessatrophy seems like cold comfort, and it is far from proof that this type of drug can change the course of the disease. But Hampel calls it a “significant effect” and one of a few “robust and valid biomarkers,” or biological signals, that cholinergic intervention could have a disease-modifying effect.

The workgroup’s call to action also emphasizes the need for a more holistic approach. They say the pendulum should not swing fully toward the cholinergic system, or any one part of the brain. As with cancer, combinations of therapies will likely be necessary. “The continuation of the traditional search for magic bullets or ‘one-size-fits-all’ drugs will not likely succeed” in treating the most common form of Alzheimer’s, the authors write.

Their paper was in fact funded by Axovant, which the authors say had no influence on the content. But other high-profile figures in the field are advocates for more aggressive exploration of the cholinergic system as a bad actor in Alzheimer’s.

Now with Roche, Doody has pushed back against the amyloid-or-bust mentality for years. Until recently she was a top neurologist at Baylor College of Medicine in Houston and director of its Alzheimer’s Disease and Memory Disorders Center. In a 2016 interview with Xconomy, Doody criticized academics and the press for a dismissive attitude toward cholinergic drugs: “There’s a tremendous amount of nihilism.”

“It’s clear that disruption of the cholinergic system is tied to the symptoms and to the areas of brain where Alzheimer’s starts,” she says now. “Don’t ignore the cholinergic system. It’s a target.”

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