Microbiome-altering Alzheimer’s drug unexpectedly approved in China
In a surprise to many researchers around the world, Chinese authorities recently approved a novel drug claimed to improve cognitive function in patients with Alzheimer’s disease. The drug, derived from a marine algae, is the first new Alzheimer’s drug to reach the market anywhere in the world in almost 20 years, and is suggested to reduce neuroinflammation by modulating a person’s gut microbiome.
GV-971, or sodium oligomannate, is derived from a common form of seaweed called brown algae. For several years the compound has been under investigation in China as a treatment to slow, or even reverse, cognitive decline associated with mild to moderate cases of Alzheimer’s disease.
The latest announcement from China’s National Medical Products Administration (NMPA) has granted the drug “conditional approval”, meaning it is to be fast-tracked to market based on positive early Phase 3 trial results. The “conditional approval” requires ongoing studies to verify efficacy and safety, however, it can now move to open market sales in China within the next month or two.
"I have been doing research on Alzheimer's disease for 50 years, participated in multiple global multi-center studies of multiple drugs, and have never found a satisfactory treatment for Alzheimer's disease," says Zhang Zhenxin, MD, a principal investigator on the latest trial. "The result of the 9-month trial of Oligomannate is exciting. We finally see hope and dawn. I am sincerely happy for the patients and their families."
The particular Phase 3 clinical trial covered 818 patients across 34 hospitals in China. The trial was double-blind and placebo-controlled, running for 36 weeks. The results are yet to be published in a scientific journal but it is claimed cognitive improvements were seen in patients as soon as four weeks after treatment commenced.
“The mean difference between Oligomannate and placebo groups in ADAS-Cog12 Score (a standard cognitive measure commonly used in AD studies) was 2.54 (p< 0.0001), with sustained efficacy from first month of treatment to the end of 9 months of treatment,” says Shanghai Green Valley Pharmaceuticals, the company developing the drug. “Oligomannate was safe and well tolerated with side effects comparable to the placebo arm.”
It is unclear exactly how clinically meaningful those improvements actually are. While they are undeniably statistically significant, experts such as Mark Oremus from the University of Waterloo in Canada, are skeptical.
“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,” Oremus recently said to Science magazine.
Perhaps the most compelling mystery surrounding the new drug is its mechanism of action. An article published in September in the highly credible journal Cell Research presented the first clear hypothesis explaining how it may be working, suggesting the drug reduces neuroinflammation by remodeling the gut microbiome. Unlike the majority of recent Alzheimer’s research, which focuses directly on clearing out the toxic protein accumulations thought to be the primary cause of neurodegeneration in Alzheimer’s, the new drug seems to modulate bacteria activity in the gut.
A commentary on the research published in September suggests the description of Oligomannate’s mode of action elegantly demonstrates how, “a gut microbiota imbalance facilitates peripheral immune cells to infiltrate the brain, resulting in enhanced microglial activation that contributes to cognitive impairment and Aβ burden in mouse models of Aβ amyloidosis.”
The research is certainly an intriguing insight into the gut-brain connection, with profound implications for future Alzheimer’s research, suggesting microbiome modulation may be a highly effective way to counter the neurodegeneration associated with the disease.
Many questions remain unanswered though, and while Chinese authorities have approved the drug for its local market, the current volume of research is not enough to pass muster for US or European approval agencies. Shanghai Green Valley Pharmaceuticals, well aware of global regulatory hurdles, is planning a larger Phase 3 trial spanning Europe, the US and Asia. Called GREEN MEMORY, this broader trial hopes to cover off on regulatory hurdles required by agencies such as the FDA and will commence sometime in 2020.
How safe is the compound for long-term use? Can it reverse cognitive decline in severe cases of Alzheimer’s? And how does it exactly work? These are all questions that will need to be answered before the drug is available outside of China, but at its core the research at the very least validates the microbiome as a promising target of study for treating dementia and Alzheimer’s disease.
"These results advance our understanding of the mechanisms that play a role in Alzheimer's disease and implies that the gut microbiome is a valid target for development of AD therapies,” says Philip Scheltens, scientific advisor to Shanghai Green Valley, and CEO of Alzheimer Center Amsterdam.