Dr. Jeffrey CummingsJeffrey Cummings, MD
For the first time worldwide since 2003, a therapy aimed at the treatment of Alzheimer disease has been approved by a regulatory agency, with China’s National Medical Products Administration (NMPA) giving the green light to oligomannate (GC-971; Shanghai Green Valley Pharmaceuticals) for the treatment of mild to moderate Alzheimer disease and to improve cognitive function.1

The treatment, which is derived from seaweed, was granted a fast-track review designation by the NMPA in November 2018. It is anticipated to make its debut on the market in China in late 2019. It operates on the emerging idea that reconditioning the gut microbiome may be able to impact or slow the progression of Alzheimer.2

"The phase 3 clinical trial of oligomannate conducted in China showed a sustainable cognitive benefit. It was well tolerated. This is the first new therapy for Alzheimer's disease approved in many years and we applaud this innovation," said Jeffrey Cummings, MD, vice chair for research and research professor, UNLV Department of Brain Health, and director, Center for Neurodegeneration and Translational Neuroscience, Lou Ruvo Center for Brain Health, Cleveland Clinic, and scientific advisor to Green Valley, in a statement. "We look forward to the global phase 3 trial of oligomannate to investigate its clinical effects in larger and more diverse populations and to collect samples that will provide evidence of the agent's biological effects.”

Despite a number of failures in Alzheimer over the last few decades, this news comes on the heels of another encouraging decision in the space. Last week, Biogen made a surprising about-face and announced that it would bring aducanumab before the FDA for approval after reporting failure in a futility analysis earlier in the year.3

That decision was made after Biogen analyzed an expanded dataset from the phase 3 EMERGE trial, including an additional 3 months of data on patients receiving high-dose aducanumab. Biogen reported observing statistically significant changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores, with P values of .010 or .031 based on cutoff dates. The high-dose group also hit several secondary end points, leading Biogen to claim that “the result of the futility analysis was incorrect.”

In a phase 3 clinical trial, oligomannate showed significant improvements in adults with mild to moderate Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores compared to a placebo group. The study included 818 patients, conducted in collaboration with a number of partners.

All told, after 36 weeks of parallel-group, double-blind study, ADAS-Cog scores were 2.54 points higher in the oligomannate group compared to the placebo group (P <.0001). The efficacy was shown to be sustained from the first month to the ninth month of treatment. Safety was deemed good and the treatment was well-tolerated.

"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," said Professor Zhang Zhenxin, MD, leading principal investigator, and professor of neurology, Peking Union Medical College Hospital, in a statement. "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."

This news has been brought to light with some skepticism, with some outlets pointing to the significant improvements only being shown on ADAS-Cog, with no significant changes in Clinician Interview-Based Impression of Change plus caregiver input (CIBIC plus) scores, nor in secondary end points, observed in the phase 3 trial. It has also been reported that Chinese local media noted that Green Valley was involved in a 2008 marketing scam exposed by China Central Television, in which it was promoting a Ganoderma-based treatment it claimed could stop cancer growth, progression, and resurgence after surgery.4

Additionally, a 2018 FDA draft guidance5 for the development of Alzheimer treatments states that, “Given the panoply of available neuropsychological tests, a pattern of putatively beneficial effects demonstrated across multiple individual tests would increase the persuasiveness of the finding; conversely, a finding on a single test unsupported by consistent findings on other tests would be less persuasive.”

Oligomannate, despite this skepticism, has displayed a unique mechanism of action from other investigative therapies in Alzheimer, with preclinical data suggesting it alters the dysbiosis of gut microbiota, inhibits intestinal flora metabolite increases, modulates peripheral and central inflammation, reduces amyloid protein deposition and tau hyperphosphorylation, and improves cognitive function.6

Green Valley has also announced that it plans to submit the marketing authorization applications for oligomannate in selected countries and is planning GREEN MEMORY, a phase 3 multicenter global clinical trial with sites in the US, Europe, and Asia, for early 2020 to support those filings.
REFERENCES
1. Green Valley Announces NMPA Approval Of Oligomannate For Mild To Moderate Alzheimer's Disease [press release]. Shanghai, China: Green Valley; Published November 2, 2019. prnewswire.com/news-releases/green-valley-announces-nmpa-approval-of-oligomannate-for-mild-to-moderate-alzheimers-disease-300950349.html. Accessed November 4, 2019.
2. Seo DO, Boros BD, and Holtzman DM. The microbiome: A target for Alzheimer disease? Cell Res. 2019;29(10):779-780.
3. Biogen Plans Regulatory Filing for Aducanumab in Alzheimer’s Disease Based on New Analysis of Larger Dataset from Phase 3 Studies [news release]. Cambridge, MA and Tokyo: Biogen and Eisai. October 22, 2019. biospace.com/article/releases/biogen-plans-regulatory-filing-for-aducanumab-in-alzheimer-s-disease-based-on-new-analysis-of-larger-dataset-from-phase-3-studies/. Accessed October 22, 2019.
4. Liu A. China approves a new, home-grown Alzheimer's drug—and questions immediately follow. Fierce Pharma website. Published November 4, 2019. fiercepharma.com/pharma-asia/china-approves-a-new-alzheimer-s-drug-and-questions-immediately-follow. Accessed November 4, 2019.
5. FDA. Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry. FDA website. Published January 29, 2018. Revised February 2018. fda.gov/media/110903/download. Accessed November 4, 2019.
6. Wang X and Sun G et. al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression. Cell Res. 2019;29(10):787-803. doi: 10.1038/s41422-019-0216-x.