Buoyed by strong scientific evidence and subtle hints of success in clinical trials, the search continues for disease-modifying therapies for Alzheimer's disease (AD) that target amyloid-beta.
The subtle hints of success, though, occur within an overall landscape of anything-but-subtle late-stage trial failures.
As a result, and because even a successful amyloid-targeting drug will be useful only in the early stages of AD, even those who believe that it is possible to develop approvable amyloid-targeting drugs recognize the necessity of adding other approaches.
"Amyloid can be part of the answer, but what we know now is that we are going to need multiple therapies," Laurie Ryan, chief of the Dementias of Aging Branch in the National Institute of Aging's Division of Neuroscience, told BioWorld.
"We have a very rich pipeline beyond amyloid and tau," she said.
Programs such as the NIA's Alzheimer's Disease Drug Development Program and the NIH-wide Blueprint Neurotherapeutics Network are funding both amyloid-based and alternative approaches to AD. Among the companies receiving funding for alternative approaches is Pharmatrophix Inc., which is testing the nerve growth factor receptor agonist LM11A-31 in a phase II trial. Agenebio Inc. has two GABA-receptor targeting compounds in phase I and II trials, and Tetra Discovery Partners is in phase I with phosphodiesterase inhibitors.
Other funders, too, are looking beyond amyloid and tau.
The largest such effort is the Britain-based Dementia Discovery Fund (DDF), a joint venture between the U.K. government, biopharmaceutical companies, Biogen Inc., Glaxosmithkline (GSK) plc, Johnson and Johnson Inc., Eli Lilly and Co., Otsuka Pharmaceutical Co. Ltd., Pfizer Inc. and Takeda Pharmaceutical Co. Ltd., and private investors. In November, Bill Gates made a private investment of $50 million into the DDF, and the National Football League Players Association (NFLPA) invested an undisclosed amount.
Keytruda rides again?
Targeting the immune system, and specifically microglia, which are brain-specific innate immune cells, is one anti-AD approach getting attention from a number of companies. Ironically, the link between the brain and the immune system was thought to be nonexistent when amyloid targeting was getting its start.
It has become clear over time that the immune system and the brain are very much in communication with each other. The single largest fraction of AD risk variants uncovered by genomewide association studies (GWAS) is important specifically in microglia.
"This is not a field that is extremely mature" yet, Morgan Sheng, vice president of neuroscience at Roche AG subsidiary Genentech Inc., told BioWorld.
But an emerging theme is that overall, people who are predisposed to AD have microglia that are less capable of dealing with amyloid, whether through getting rid of plaques or preventing the toxic amyloid species from diffusion.
Genentech has early stage programs that are looking at microglia. Other companies in the space are Alector LLC, which has funding from Polaris and Orbimed Ventures as well as the DDF, and is targeting microglia in collaboration with Abbvie Inc. (See BioWorld, Nov. 25, 2017.)
Annexon Biosciences Inc. is targeting the C1q, an activator of the complement cascade whose levels are increased in the synapses of aging brains, leaving them vulnerable to microglial destruction.
Denali Therapeutics, which went public earlier this month, has a preclinical program targeting TREM2, a surface receptor that is required for microglial responses to neurodegeneration. Genentech is also looking at TREM2. In 2016, Sheng and his colleagues published data showing that TREM2's binding partners included ApoE, that ApoE/ amyloid beta complexes were taken up by microglia, and that microglial ability to take up those complexes were reduced in microglia with an AD risk variant, tying together three risk factors for AD.
Microglia also express a surface receptor that is well known in the oncology community, the checkpoint blocker PD-1. In 2016, scientists from the Weizmann Institute reported that treating mouse models of AD with Merck & Co Inc.'s PD-1 blocker Keytruda (pembrolizumab) increased plaque clearance and improved cognitive function.
Whether Keytruda's acting on microglia played a role in those results is not clear. Michal Schwartz, Maurice and Ilse Katz Professorial Chair in Neuroimmunology at the Weizmann Institute and the senior author of the paper reporting Keytruda's effects in mouse models of AD, attributed the findings to Keytruda's acting on T cells. (See BioWorld, Jan. 22, 2016.)
But Sheng said that the results also "fit with idea of exhausted microglia" as a contributor to neurodegeneration.
At Genentech, which has its own PD-L1 blocker in Tecentriq (atezolizumab,) "that was a paper that definitely caught our attention," Sheng said.
Genentech scientists are following up on the findings, he added, though at this point, "I don't have any data to share with you."
Amyloid, other proteins 'stick around longer'
Another emerging idea about AD is that proteostasis the normal turnover of proteins in the cell, which gets rid of damaged proteins and is a key part of cellular housekeeping is disturbed in AD.
Companies such as Mitobridge Inc. and Mitoconix Bio Ltd. are looking specifically at proteostasis in mitochondria, while Proteostasis Therapeutics Inc., which has an AD collaboration with Biogen Inc., targets ubiquitin-specific protease 14 (USP14), an enzyme involved in the tagging of proteins for destruction.
A paper in Cell Reports showed that "amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer's Disease-like pathology," as its title stated.
First author Jeffrey Savas, an assistant professor at Northwestern University who undertook the work as a postdoctoral fellow at Scripps Florida, told BioWorld that the work showed that "in the context of increased amyloid, there's massive proteome remodeling," including in the level of many proteins that have been linked to AD via GWAS.
While the team found both increases and decreases in the levels of specific proteins, overall, "more proteins are accumulating. . . . "Things are sticking around longer."
And of the 10,000 proteins the team measured, the most significant increases were seen in ApoE, whose levels were increased in every brain region where amyloid beta was increased.
Savas said that "ApoE levels seem to increase as a consequence of low levels of Abeta clearance rather than production," which means that therapeutically speaking, there is "likely a strategic advantage in boosting protein clearance mechanisms."
The researchers did not have a specific hypothesis about whether they would see increases or decreases. But they did expect that the proteins that would be most dysregulated would be the proteins bound to amyloid beta.
However, "that is not what happened," he said. "These proteins do all different things. . . . It really speaks to the complexity of the problem and the challenge that AD presents."