Alzheimer’s experts greet China’s surprise approval of a drug for brain disease with hope and caution

A Chinese biotech startup has startled neuroscientists and drug developers with a new plant-based compound it claims improves cognitive function in Alzheimer’s patients by altering their gut microbiomes. In mouse studies published earlier this year, this approach reduced inflammation in the brains of rodents engineered to develop Alzheimer’s-like pathology. The drug’s backers also claim a phase III clinical trial of about 800 people “demonstrated solid and consistent cognition improvement” among those treated versus a control group. Though not yet published, the results convinced China’s drug regulator last week to approve the marketing of the drug, known as GV-971, with the condition that additional data be gathered to demonstrate safety and efficacy.

“This is very exciting and important; GV-971 is the first drug approved anywhere in the world for Alzheimer’s disease since 2003,” says Jeffrey Cummings, an Alzheimer’s researcher at the University of Nevada in Las Vegas, who is advising the drug’s developer, Shanghai, China–based Green Valley Pharmaceutical Co.

The news has elicited both hope and skepticism from researchers not connected to the company. “I think it’s fascinating, and if it’s true that [the effects are happening] through the microbiome, that’s fantastic,” says Sangram Sisodia, a neurobiologist at University of Chicago in Illinois who has studied the impact of the microbiome on Alzheimer’s disease in mice but is not associated with the research. But just like China’s regulators, he and others want to see more evidence. Some aren’t yet convinced that the subtle improvement among Alzheimer’s patients measured by a cognitive test is clinically meaningful.

Green Valley has presented its clinical findings at one or more conferences and they’re described in releases from the company and a research institute where work on the compound originated, though not yet in a peer-reviewed paper. “We’re still cautiously optimistic,” regarding the drug’s promise, says Rebecca Edelmayer, director of scientific engagement at the Chicago-based Alzheimer’s Association. But, she adds, “I think we need to really understand for sure what kinds of changes are occurring through a medicine like this and how they actually relate to a disease process.”

The drug grew out of research by Geng Meiyu of the Chinese Academy of Sciences’s Shanghai Institute of Materia Medica, a center focusing on research into traditional Chinese medicine. The active ingredient in GV-971, sodium oligo-mannurarate, is derived from brown algae, a seaweed. Geng and her colleagues published a mouse study in Cell Research in September suggesting that as the disease progresses, an imbalance in the gut’s microbiota produces immune cells that infiltrate the brain and exacerbate the neuroinflammation associated with Alzheimer’s disease progression. Feeding the mice GV-971 remodeled the gut microbiome in a way that reduced the accumulation of neuroinflammatory cells. Geng and Green Valley researchers also briefly described the human clinical trials of the compound in the paper.

Most Alzheimer’s drug development has focused on attacking the beta-amyloid plaques that form in the brains of Alzheimer’s disease patients, which are thought to interfere with neural signaling. But given the numerous failures of antiamyloid drugs in clinical trials, Alzheimer’s scientists are increasingly exploring other strategies. “There is no question that this [mouse] data further supports the emerging idea that modulation of the gut microbiome via treatments such as GV-971 or other strategies should be further explored as novel strategies to slow the progression of Alzheimer’s disease,” Alzheimer’s researcher David Holtzman of Washington University in St. Louis, Missouri, and colleagues wrote in a commentary accompanying the Cell Research paper.

In a statement, Green Valley Pharmaceuticals describes the phase III trial as a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 36-week study involving 818 patients with diagnosed mild to moderate Alzheimer’s disease. “Trial results demonstrated that Oligomannate statistically improved cognitive function in mild-to-moderate Alzheimer’s patients as early as week 4 and the benefit was sustained at each follow-up assessment visit.”

The team evaluated cognitive capabilities using the Alzheimer’s Disease Assessment Scale–Cognitive Subscale 12 (ADAS-Cog-12)—a standard assay in the field that measures immediate and delayed word recall, comprehension of commands and other tasks and incorporates test administrator observations—and found a statistically significant average difference in the score between treatment and control groups was 2.54.

Alzheimer’s researchers split on the clinical significance of the difference, however. “I would say that a 2.54 improvement on the ADAS-Cog is not clinically important, and I would also point out that a 36-week study is far too short to evaluate the medium- to long-term effects of any Alzheimer’s disease medication,” says Mark Oremus, an epidemiologist at the University of Waterloo in Canada. He adds that the study does not address how GV-971 compares to existing Alzheimer’s medications.

“The cognitive improvement was clinically meaningful and in the upper range of what is seen with currently approved drugs,” Cummings says.

He and others involved with the drug, however, agree on the need for more research. Further studies may lead to understanding “other mechanistic links connecting gut microbiota and neuroinflammation,” and “the broader therapeutic potential of GV-971,” Geng and her colleagues write in the Cell Research paper. China’s National Medical Products Administration’s conditional approval calls for additional research on the pharmacological mechanisms and long-term safety and effectiveness of the drug.

Cummings says GV-971 would not yet meet the criteria for approval in the United States, which requires significant results on two measures of cognitive ability and usually requires two positive phase III clinical trials. Green Valley says it plans to initiate a multicenter global phase III clinical trial with sites in the United States, Europe, and Asia in early 2020 to gather data needed to support regulatory approval in other countries.

Probably the most important aspect of the news is that “it validates the increasing intensity of the interest in gut microbes [and] inflammation,” says Zaven Khachaturian, editor-in-chief of Alzheimer’s & Dementia , the journal of the Alzheimer’s Association, who is based in Washington, D.C. “Once we get insight into the mode of action, we’ll be able to use that knowledge to produce, through rational drug design, more potent compounds that attack that target,” he says.

And Khachaturian says that given the lack of any obvious side effects for the compound, he would not be surprised if the Food and Drug Administration made an exception to its normal standards and approved the drug for the U.S. market.