Alzheimer’s Research Shifting to Tau as a Target

About six million Americans are currently living with Alzheimer’s disease, and it is now the sixth leading cause of death in the U.S. According to several estimates, the number of Americans living with the condition will almost double by 2050, partly because of the demographic bulge of baby boomers entering their oldest years.

Andrea Pfeifer, Ph.D., CEO and co-founder of AC Immune, a Swiss biotech company that has several Alzheimer’s treatments in development, says dementia is one of the greatest challenges in healthcare.

“Globally, there is a new case of dementia every three seconds, adding up to around 50 million people worldwide, and the global cost of dementia stands at about $1 trillion — and we still don’t have an effective treatment or cure.”

By some accounts, the cupboard is bare because Alzheimer’s researchers have been going after the wrong target. For years, the prevailing theory about the disease has implicated accumulation of beta amyloid plaques in the brain as a primary cause. But agents targeting beta amyloid have fizzled in clinical trials. Researchers — and drug developers — have been forced to reconsider the hypothesis.

Biogen persists

Mesfin Tegenu, M.S., R.Ph., president of PerformRx, a PBM in Philadelphia owned by AmeriHealth Caritas, says researchers are now eyeing other targets for treatment. “One such target is the tau protein, which is believed to be integral in the formation of (neurofibrillary) tangles seen in the brains of individuals with Alzheimer’s disease,” he says. The “tauists” have been debating “beta amyloidians” for decades, and beta amyloidians have had the upper hand until recently, particularly with respect to treatments that made it into clinical trials. But there is new interest in tau as a target and in February of this year, 650 people attended Tau2020 in Washington, D.C., a global conference devoted to “taupathies.”

But the turn to tau hasn’t meant a complete about-face on beta amyloid. In fact, the most-watched Alzheimer’s agent right now is Biogen’s aducanumab, a monoclonal antibody that targets beta amyloid. Despite some negative trial results, which Biogen interprets differently, the Boston-based company has forged ahead with seeking FDA approval for aducanumab. And the agency has put aducanumab in its “priority review” approval category, so there should be a decision on whether it is approved or not in March 2021.

Biogen’s aducanumab push is occurring against a backdrop of disappointing news this year about monoclonal antibodies that target beta amyloid. Most conspicuously, investigators announced that solanezumab, a monoclonal antibody, had faltered in a late-phase trial. Results showed no improvement in patients in a composite score of four different cognitive tests.

Gantenerumab, an antibody designed to degrade beta amyloid plaques, was tested in the same trial as solanezumab and, like solanezumab, it also didn’t pass muster with respect to the primary outcome of improved results on cognitive tests. However, other results suggested it still has some promise, and patients in the original trial were invited to participate in an continuing open-label extension.

Jeffrey L. Cummings, M.D., Sc.D., a research professor at the University of Nevada School of Integrated Health Sciences, Las Vegas, and director of the Chambers-Grundy Center for Transformative Neuroscience, says that Alzheimer’s clinical trials over the past five years have shown a “progressive emphasis” on targets other than beta amyloid, including inflammation, synapse and neuronal protection, and vascular factors. Cummings also notes a marked growth in repurposed agents.

Negative results for semorinemab

Pfeifer, at AC Immune, highlighted semorinemab, an anti-tau antibody that her company is developing in partnership with Genentech, when discussing the products her company has in its pipeline.

“Tau protein is mostly present in neurons and functions as a component of the cytoskeleton inside the cells and is involved in axonal transport,” Pfeifer explains. “Misfolded tau protein aggregates in AD and other tau-related neurodegenerative diseases (for example, progressive supranuclear palsy, frontotemporal dementia and others). The progression of tau pathology throughout the brain is closely associated with the onset and progression of cognitive decline, underscoring the importance of tau-targeted therapies.”

After the interview with Managed Healthcare Executive® and after earlier version of this story appeared in the September print issue of the publication, AC Immune and Genentech announced negative results from a high-profile phase 2 trial of semorinemab called the Tauriel Phase 2 trial. The drug failed to meet its primary endpoint and two secondary endpoints, according to an announcement dated September 23. The headlines about the drug described it as a flop and cast tau as another off-base target. "Blocking tau appears to be just as fruitless as clearing amyloid buildup when it comes to helping Alzheimer's disease patients," was the first line of the Fierce Biotech story about the semorinemab results. Pfeifer was quoted in the prepared statements as saying the news was "surprising and disappointing," but she also spoke of the company's diversified approach to Alzheimer's.

Multiple targets

The beta amyloid versus tau divisions may be fading. Pfeifer says opinion leaders in Alzheimer’s have started to float the idea that combination therapies are going to be needed in much the same way they are used to treat HIV, cancer and other diseases.

“We think this will be the case in Alzheimer’s as well because it is a complex disease with many contributing and potentially causal factors,” said Pfeifer in the interview with MHE before the semorinemab phase 2 results came out. “As such, it may be difficult for a drug with a mechanism of action focused on a single part of the disease process, such as beta-amyloid plaques, to make a meaningful impact, especially in symptomatic patients.”

“This is excellent news for everyone involved in Alzheimer’s research, and hence for AC Immune—every new piece of data we build up as an industry is important for informing the search for a successful treatment,” she continued.

Pfeifer sees another development on the horizon: Precision medicine to properly diagnose and treat neurodegenerative diseases, including Alzheimer’s disease. Her company is actively pursuing positron-emission tomography (PET) tracers against multiple relevant targets, including alpha-synuclein and TDP-43, as well as tau.

Tau may be enjoying a star turn, but Pfeifer says the concept that anti-beta amyloid therapies are most effective in the early stage of the disease, and, in particular, in preclinical AD, is still a valid one.

Her company has several active anti-beta amyloid projects, including an anti-beta amyloid antibody, called crenezumab, and an anti-beta amyloid vaccine, called ACI-24. The re-analyses and potential approval of aducanumab could potentially be highly relevant for those products and the beta amyloid approach in general, notes Pfeifer.

“We will have to wait and see how the FDA responds to Biogen’s filing,” she says.

Editor's note: The negative results from the phase 2 trial of semorinemab were reported after this story was published in our September print issue. This version was edited afterward to include information about that trial.

Keith Loria, a regular contributor to Managed Healthcare Executive®, lives in the Washington, D.C., area.