Alzheimer’s Pipeline Edges Away From Amyloid

Alzheimer’s disease drug research is moving away from substances that target amyloid and toward disease-modifying agents that target other elements of the underlying disease process, an analysis in Alzheimer’s & Dementia: Translational Research & Clinical Interventions has found. Amyloid has long been associated with Alzheimer’s because of the way it clumps together into plaques between nerve cells, but thus far most drugs that target amyloid have not been effective in clinical trials.

“People are frustrated that [amyloid research] has not led to approved therapies, so the field, while not abandoning amyloid, is diversifying to include tau, metabolism, inflammation, and the protection of synapses and circuits,” lead author Jeffrey L. Cummings, M.D., Sc.D., told Psychiatric News. Cummings is a research professor in the Department of Brain Health at the School of Integrated Health Sciences at the University of Nevada, Las Vegas, and director emeritus of Cleveland Clinic Lou Ruvo Center for Brain Health. Tangled tau proteins are associated with Alzheimer’s disease because they interfere with the transportation of nutrients through cells, which can cause the cells to die.

Cummings and colleagues reviewed clinical trials for Alzheimer’s drug candidates that were listed on the ClinicalTrials.gov website as of February 27, 2020. They found 121 ongoing trials for the treatment of Alzheimer’s, of which 97 are trials for disease-modifying agents. Of those, only 16 target amyloid and 11 target tau. Twelve other agents are intended to enhance cognition and 12 more are intended to treat neuropsychiatric symptoms.

Fifty-seven of the trials are for 52 repurposed drugs that were previously approved for other indications. The researchers noted that repurposed agents may speed drug development because their dosing, safety, tolerability, formulation, manufacturing, and distribution are already known. Nine trials of repurposed drugs are being hosted by the biopharmaceutical industry, while 42 are hosted by academic medical centers with funding from the National Institutes of Health, industry, and/or other entities. Six additional trials are hosted solely by other entities.

“An academic lab can show that a drug is effective … but a phase 3 clinical trial that would lead to FDA approval and to marketing would cost a minimum of $50 million, and that is beyond the budget of federal granting agencies or academic medical centers,” Cummings explained. “It takes an ecosystem to generate a drug. Academic centers do the early work, then biotech companies work on the middle stage, then pharmaceutical companies advance the drug in the late stages.”

Another trend the researchers found is an increasing focus on biomarkers both to define trial populations and to use as an outcome measure. These biomarkers, such as amyloid or tau in cerebrospinal fluid, indicate when the processes driving Alzheimer’s disease are under way, making them helpful for diagnostics and tracking the stages of the disease in patients, Cummings said. One example of this is flortaucipir F18 injection (Tauvid), which is approved for helping to evaluate patients with cognitive impairment who may have Alzheimer’s. Flortaucipir F18 is used with positron emission tomography (PET) imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles.

“[The] choice of drug may [depend on] where the biomarkers indicate Alzheimer’s disease is in the continuum. The use of biomarkers is improving the efficiency of developing drugs because we can see what we are doing much more quickly and accurately,” said Cummings.

“What has advanced is our ability to measure biomarkers in cerebrospinal fluid or the brain through PET or structural or functional MRI, and substances in the blood that are related to neurodegeneration,” said Lon S. Schneider M.D., Della Martin Chair of Psychiatry and Neuroscience at Keck School of Medicine at the University of Southern California, Los Angeles, who was not involved in the research. Schneider is also a professor of psychiatry, neurology, and gerontology at Keck. “We can now focus on whether these biomarkers are helpful in determining who may be responsive to different drugs or predicting the course of illness.”

For Cummings, three agents stand out among those being investigated: aducanumab, which is currently being reviewed by the FDA, BAN2401, and gantenerumab. All three are monoclonal antibodies, and if they make it through the pipeline to FDA approval, they would be the first amyloid-targeting biologics to do so.

“All three have been shown to remove amyloid from the brain, and aducanumab and BAN2401 were shown to slow disease processes by 30% to 50%,” Cummings said.

In addition to developing drugs that slow the progression of Alzheimer’s, researchers continue to look for medications that treat psychiatric symptoms associated with the disease.

Cummings added that pimavanserin (Nuplazid), an atypical antipsychotic that is already approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, looks promising. The FDA is currently reviewing pimavanserin for treating hallucinations and delusions associated with dementia-related psychosis.

Schneider said that the history of unsuccessful drugs in Alzheimer’s research has a silver lining.

“When you look back on trials over the last 20 years, hundreds of drug candidates were put into clinical trials, and nearly all failed, but we can now look forward with a better understanding of the complex pathophysiology of dementia in Alzheimer’s and a better understanding of what therapeutic targets there are,” he said. “Science advances in incremental steps.”

This study was supported by funding from the National Institute of General Medical Sciences and Keep Memory Alive. Cummings has worked as a paid consultant for companies developing drugs to treat Alzheimer’s (a list of the companies with which Cummings has worked appears in the study). Keck School of Medicine, Schneider’s employer, began a large trial of BAN2401 in February. ■