This feature is part of a series focused on Alzheimer's disease. To view other posts in the series, check out the spotlight page.
Making it into the lineup of late-stage Alzheimer’s disease (AD) drug candidates can seem more like facing a firing squad than finally having a chance at bat. And yet, despite the field’s dismal record there is still a lot of optimism and fight left among remaining contenders.
At least ten compounds are in Phase 3 trials for AD (see table), and plenty more are lined up behind them. "There was a time when companies were divesting from Alzheimer’s," said Mike Irizarry, VP of Early Phase Neurosciences at Eli Lilly, "But that’s not the case anymore."
Select Drug Candidates in Phase 3
|Amgen/Novartis||AMG 520||BACE inhibitor|
|Archer Pharmaceuticals/NILVAD Consortium||ARC-029 (nilvadipine)||Amyloid beta inhibitor|
|AZ Therapies||ALZT OP1||Amyloid beta inhibitor|
|Biogen||Aducanumab||Amyloid beta inhibitor|
|Eli Lilly/Astra Zeneca||Lanabecestat||BACE inhibitor|
|Roche||Crenezumab||Amyloid beta inhibitor|
|Roche||Gantenerumab||Amyloid beta inhibitor|
|Novartis||CAD106||Amyloid beta-targeting immunotherapy (vaccine)|
|vTv Therapeutics||Azeliragon (TTP488)||RAGE inhibitor|
SOURCE: Company Reports
Two key factors are fueling this renewed enthusiasm: the unmet need presented by an ever-growing patient population and increasing faith that researchers are getting a better understanding of the scientific nuances of this disease.
An estimated 30 million people are living with AD all around the world, according to the World Health Organization. While there is an early-onset form of the disease, it starts becoming most prevalent by about age 60 and the risk steadily increases after that. In the U.S., deaths from Alzheimer’s rose by 55% between 1999 and 2014, says the Centers for Disease Control and Prevention.
The market is currently estimated at about $5 billion, but increasing awareness of AD, as well as new diagnostic protocols and technologies are expected to lift prescribing. Most importantly, current drugs only treat symptoms. If any company can launch an actual disease-modifying drug, the market will expand substantially, particularly if the product is useful in both advanced and early-stage disease.
Developers of this latest round of AD drugs argue their products are still relevant, even though they are all based at least in part on the same main hypothesis that led so many off a cliff (i.e. the theory that beta amyloid plaques cause AD). "I think the programs in Phase 3 now are the first well-designed drugs that really engage their targets," said Samantha Budd Haeberline, VP of Alzheimer’s Discovery and Development at Biogen.
Still targeting plaque
Beta amyloid became a favorite drug target because plaques made of this protein are such a conspicuous finding in AD patients’ brains. Further, inherited and early-onset forms of AD are associated with mutations in the beta amyloid precursor protein (APP), reinforcing the hypothesis. However, several drugs that reduced the level of amyloid plaque in patients’ brains did little or nothing to slow the progress of the disease.
Some experts think the solution is to target the disease earlier. As a result, companies including Roche's Genentech, Biogen and Lilly, are focusing on studies in "mild-to-moderate" AD patients or even earlier. Others, such as Novartis, are looking at some patients who have no symptoms at all, but are at high risk of the disease.
Archer Therapeutics’ ARC029, meanwhile, specifically targets soluble forms of beta amyloid. Clearing these precursors from the brain, they hope, will prevent the plaques from forming at all.
Although still in early-stage development, ProMis Neurosciences has another intriguing approach to battling amyloid. "The plaques may actually be beneficial because they act a bit like a garbage dump," said Elliot Goldstein, the company’s President and CEO. As a result, he argues, plaques are not the right target. "But some of the things they trap include misfolded forms of the protein, and those are directly neurotoxic." His company identifies epitopes on these misfolded beta amyloid proteins, and is now developing monoclonal antibodies targeting them.
The drugs now at the lead in this contest are all based on older ideas. Biogen’s aducanumab is the furthest along of the surviving plaque-busters. A monoclonal antibody that targets beta amyloid plaques directly, it is currently being studied in two Phase 3 trials at 300 clinical trial sites around the globe. The studies are targeting early-stage AD. Results should be available in about two years.
The BACE race
Others think it’s not the plaques themselves that should be targeted. Beta-secretase (BACE) inhibitors attack an enzyme critical to plaque formation, and several of the late-stage AD drugs in development work through this mechanism of action. Amgen, Janssen, Lilly, Biogen and others are developing such drugs.
But this class took a hard hit early this year when Merck & Co. halted a pivotal trial of verubecestat in mild-to-moderate AD due to futility. Verubecestat was the front runner in this field at the time. Merck will continue to study the drug in prodromal patients (those with early signs of the disease), and results are expected in 2019. Eli Lilly is also expecting results from their BACE inhibitor that year.
All the RAGE
"We are next in line," says Stephen Holcombe, president and CEO of vTv Therapeutics whose azeliragon (TTP488) inhibits the receptor for advanced glycation endproducts (RAGE) — an immunoglobulin supergene family member expressed on multiple cell types in the brain. RAGE-ligand interactions are believed to contribute to AD pathology by promoting vascular leakage and influx of peripheral beta amyloid into the brain, as well as mediating beta amyloid induced oxidative stress, hyperphosphorylation of tau, and beta amyloid-caused neuronal death.
The drug, said Holcombe, "sits at the nexus" of three key processes thought to be drivers of AD: inflammation, beta amyloid formation that leads to plaques and tau phosphorylation that leads to tangles. All three of these are "products of the normal wear and tear of aging," he explained.
Azeliragon is in Phase 3 with two independently powered studies under the same protocol. The company expects data from the first study at the end of March 2018, while data from the second study will come in September of that year. "If we are successful, we will be the first drug able to slow progression of Alzheimer’s," Holcombe said.
"One thing that is unique about our program is that we ran Phase 2 studies," said Larry Altstiel, EVP and chief medical officer at vTv. Many other companies have skipped from Phase 1 results straight to Phase 3 in AD based on "exuberant enthusiasm," he explained, but vTv did the work to establish safe dosing in Phase 2, concentrated on people with early, mild AD, and is also collecting data on trial participants’ genetic test results for APOE — a key generic risk for developing AD.
In the wake of all the clinical implosions, drug developers and other AD advocates have taken a hard look at how these trials are carried out. Companies are trying to make sure patients actually have AD, and not some other form of dementia.
"You need definitive proof the patient has amyloid plaques before you put them in a trial targeting amyloid," said Phyllis Ferrell, VP of Global Alzheimer’s Disease Platform Team at Lilly. "In some studies as many as 24% of the people enrolled turned out to be amyloid negative."
They are also looking for new diagnostic tools and better ways to use them.
"Once we learned that amyloid plaques and tau tangles show up 10 to 20 years before symptoms, we started working to fund diagnostics as well as cures," said James Hendrix, director of the Global Science Initiatives at the Alzheimer’s Association. The Association has since funded multiple studies of diagnostics.
"There are now three FDA-approved imaging agents for Alzheimer’s," Hendrix said, adding that he believes utilization of positron emission tomography (PET), in particular, can "revolutionize the way we are doing trials."
Irizarry concured, saying he thinks these tools will help further uncover the mysteries of AD pathology. "It is already amazing that we can measure plaques and tangles in people," he said. "Since these arise at different times and in different parts of the brain, we need to understand that to better design drugs and trials."
However well these latest contenders do, some experts are still skeptical that any one of them can be the answer to AD.
"I believe beta amyloid is disease causative, " said Biogen’s Haeberlein, "but I do not believe any one treatment will cure Alzheimer’s."
That means the next step will be combining drugs, initially any disease-modifying treatment with one of the few approved treatments that just affect symptoms. But if more than one of these companies hits an AD homer, a combination treatment could be possible.
CORRECTION: A previous version of this article had the wrong first name and spelling for Stephen Holcombe.