US experts are curious and skeptical about a new Alzheimer's disease (AD) drug (GV-971; oligomannate; Shanghai Green Valley Pharmaceuticals, China) that was conditionally approved earlier this month by China's National Medical Products Administration for mild-to-moderate AD.
Oligomannate is a drug manufactured from an oligosaccharide extracted from marine algae and is the first novel drug approved for AD globally since 2003, the company said in a press release. It's expected to be available in China by the end of the year.
The drug works on the gut microbiome. It reportedly reconditions dysbiosis of gut microbiota, inhibits the abnormal increase of intestinal flora metabolites, and modulates peripheral and central inflammation, thereby reducing amyloid protein deposition and tau hyperphosphorylation to improve cognitive function.
Most AD trials have used monoclonal antibodies (MAbs) to target beta amyloid (Aβ) but these agents have failed to modify the disease course. MAbs typically bind to Aβ at limited sites in the brain, but the drug company claims this new agent affects multiple brain regions.
The conditional approval of oligomannate was based on results from a phase 3 multicenter, randomized, double-blind, placebo-controlled, 36-week study that was conducted in hospitals across China, as previously reported by Medscape Medical News. A total of 818 patients with mild to moderate AD completed the study.
Shanghai Green Valley Pharmaceuticals reported that the mean difference between the active drug and placebo groups on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/12) score was 2.54 (P < .0001).
The company also reported sustained efficacy from the first month of treatment to the end of 9 months of treatment. Investigators found oligomannate was safe and well tolerated with side effects comparable to the placebo group.
Call for More Data, Information
Weighing in on the drug's conditional approval by Chinese regulatory authorities, Alzheimer's expert Ronald Petersen, MD, PhD, who directs the Mayo Clinic Alzheimer's Disease Research Center and the Mayo Clinic Study of Aging in Rochester, Minnesota, told Medscape Medical News that the gut microbiome and its relationship with inflammation and immune response "is an interesting area of research in Alzheimer's disease."
However, he urged caution about the new drug and the related study.
"It's interesting and worthy of further study, but clearly, there needs to be an international study, not just a Chinese study," he said.
Justin M. Long, MD, PhD, postdoctoral clinical fellow, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, has examined some of the animal studies showing that changes in the composition of the microbiome alter pathology.
"It's plausible that changing the microbiome of a patient could also change pathology, so it doesn't seem like science fiction to me at this point," he said.
However, he emphasized that he needs to learn more about the drug and the studies surrounding it, as he now has only "peripheral" knowledge.
"If it's effective at slowing cognitive decline in patients, that's exciting," Long told Medscape Medical News. "But I would want to see more data related to the phase 3 trial to understand how significant the benefit is, and I need to understand more about the mechanism of action."
In a recent article published in the journal Cell Research, David M. Holtzman, MD, chair of the Department of Neurology and scientific director of the Hope Center for Neurological Diseases at Washington University, and colleagues note there is an increasing focus on potential links between gut microbial dysbiosis, colonization with maladaptive or pathogenic microbiota, and AD pathogenesis.
In an article written by Xinyi Wang and colleagues, also published in Cell Research, the researchers write that given "carbohydrates, in the forms of monosaccharide or oligosaccharide, are the primary nutrient source for bacteria and have shown diverse modulatory effects on bacteria, we were interested to explore whether GV-971 could affect the gut microbiota."
They also point out that a mouse model showed that after 1 month of oral administration of GV-971, the composition of gut microbiota was "markedly altered."
In line with the gut microbiota alteration, GV-971 treatment disrupted the correlation previously seen between brain lymphocytes and gut bacterial change, decreased brain Th1 cells, significantly reduced microglial activation, and decreased levels of multiple brain cytokines.
"In parallel, GV-971 treatment significantly reduced the Aβ plaque deposition, tau phosphorylation, and ameliorated the decline in discrimination learning," in the mice, Wang and colleagues note.
For its part, the Alzheimer's Association welcomes the announcement of the drug's conditional approval, Maria C. Carrillo, PhD, chief science officer, Alzheimer's Association, said in a statement.
"We are intrigued by the possibility that this drug may work through the gut-brain axis and immune system to benefit cognitive function, reduce amyloid build-up in the brain, and protect tau proteins, as is suggested by the company.
"That said, little is known at this point about exactly how the drug works. We look forward to seeing the results of international phase 3 studies in larger and more diverse populations."
At this point, the Alzheimer's Association can't recommend that people in the US take this drug until it has met the safety and efficacy standards of the US Food and Drug Administration (FDA), added Carrillo.
Shanghai Green Valley Pharmaceuticals has announced it will launch a multicenter global phase 3 clinical trial with sites in the US, Europe, and Asia in early 2020.
Petersen, Long and Holtzman have disclosed no relevant financial relationships.
Medscape Medical News © 2019
Cite this: Curiosity, Skepticism Over New Algae-Derived Chinese Alzheimer's Drug - Medscape - Nov 14, 2019.