Scientists Criticize Mouse Study of New Alzheimer’s Drug
Scientists Criticize Mouse Study of New Alzheimer’s Drug

Scientists Criticize Mouse Study of New Alzheimer’s Drug

Oligomannate, recently approved in China, is being met with some skepticism from researchers.

Nov 13, 2019
Emily Makowski

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China’s approval of the drug oligomannate earlier this month for treating mild to moderate Alzheimer’s disease has been met with surprise and skepticism from some members of the scientific community, who claim that the preclinical data raise questions about the underlying mechanism of the drug. One microbiome researcher has pointed out inconsistencies between the researchers’ data and their proposed mechanism for how oligomannate could treat Alzheimer’s. 

“The field is seeing this [research] with a large dose of skepticism,” Malú Tansey, a neuroimmunologist at the University of Florida College of Medicine, tells The Scientist.

On November 2, Shanghai Green Valley Pharmaceuticals announced that oligomannate, an oligosaccharide mixture derived from brown algae, had been approved by the National Medical Product Administration (NMPA), China’s equivalent of the US Food and Drug Administration. The announcement followed the completion of a Phase 3 clinical trial in China that found the drug appeared to slow cognitive decline in Alzheimer’s patients. In addition, researchers led by Meiyu Geng at the Shanghai Institute of Materia Medica published a paper in Cell Research in September on oligomannate’s ability to remodel the gut microbiome in mice and reduce neuroinflammation. There is an emerging link between the gut microbiome and Alzheimer’s disease in humans.

In the study, the researchers gave oligomannate to mice that are genetically engineered to show physical and behavioral symptoms similar to Alzheimer’s disease. The team collected mouse feces to study the microorganisms present in gut microbiota, drew blood to analyze the presence of immune cells, and also examined the levels of cytokines, which are inflammatory compounds, in the brain. They found that oligomannate treatment altered the mouse gut microbiome, increased levels of some cytokines in the brain while decreasing others, tamped down the activity of microglia, and reduced the number of pro-inflammatory helper T cells in the brain and the blood, suggesting that oligomannate decreases neuroinflammation in mice by reshaping the microbial community in the intestines.

See “China Approves Alzheimer’s Treatment that Targets the Microbiome

Not everyone is convinced by that conclusion. Liping Zhao, a microbiome researcher at Shanghai Jiao Tong University and Rutgers University, says that not all of the paper’s data support the hypothesis that oligomannate reduces neuroinflammation by changing the gut microbiome. For example, bacteria called Desulfovibrionaceae, which produce an endotoxin that can increase inflammation, became more abundant in mice treated with oligomannate than in untreated mice. “There are many, many publications showing that members of this family of bacteria are pro-inflammatory,” Zhao tells The Scientist.

He also notes that bacteria in the genus Rosburia, a “well-known, beneficial group of bacteria” associated with reduced inflammation, decreased in the experimental mice. “When I first saw this data, I really couldn’t believe my eyes,” he says. “I was really surprised because such a change is actually opposite to what you would expect.”

Jeffrey Cummings, a neuroscientist at the University of Nevada, Las Vegas, and the Cleveland Clinic Lerner College of Medicine who consults for Green Valley, tells The Scientist that Zhao is making “a prediction based on his understanding of the microbiome, which I assume he is an expert and I respect. On the other hand, [the researchers] actually measured the inflammatory cells in the blood . . . and showed them to go down. So the data contradict his opinion. I would say that the important observation here, from my point of view, is that the decrease in the peripheral inflammatory cells adhere to what they say the mechanism is.” 

Tansey, who is not affiliated with Green Valley, says that Zhao makes “a very relevant point. When people say inflammation, it’s a catch-all term.” She adds that it can be difficult to interpret whether inflammation is increasing based on the levels of cytokines. “Some of these cytokines . . . have an anti-inflammatory role, but they are produced during inflammation. You could interpret it either way. If it’s inflammation, the pro-inflammatory cytokines are going to be up, but so are the anti-inflammatory cytokines because the body is trying to resolve that inflammation,” she tells The Scientist.

A global phase 3 trial is in the works to further analyze oligomannate before it is approved in other countries. “We’re planning on [measuring] quite a few different biomarkers of blood . . . that cumulatively should help us understand the mechanism of [oligomannate],” says Cummings, who is assisting Green Valley with the design of the trial.

Oligomannate is the first Alzheimer’s drug to be approved since 2003, and hundreds of potential treatments have failed to meet FDA approval in the past couple decades, according to Healthline. “The field needs a lot of hope, but we have to be careful about the hype,” says Tansey. “We need to be able to show that a drug really hits the target.” 

Meiyu Geng and Green Valley did not immediately respond to requests for comment. 

Emily Makowski is an intern at The Scientist. Email her at emakowski@the-scientist.com.