Oligomannate (GV-971), a compound derived from marine brown algae that promotes a healthy gut microbiome, is now conditionally approved in China to treat mild to moderate Alzheimer’s disease (AD), making it the first new disease therapy approved anywhere since Allergan’s Namenda (memantine) in late 2003.
The decision was based on results from a 36-week Phase 3 trial, where treatment with oral Oligomannate was found to improve cognitive function in mild to moderate AD patients compared to placebo, and with sustained benefits. A similar pivotal trial is planned for next year in the U.S., Europe and elsewhere.
Conditional approval means that the therapy’s marketing will be strictly monitored, and could be withdrawn if safety issues arise. Chinese regulators also requested further research to validate the therapy’s mechanism and long-term safety and effectiveness.
“There are only few drugs available to treat Alzheimer’s disease, and none can delay or prevent progression of the disease,” Xiao Shifu, a principal investigator for the clinical trial, said in a press release.
“The results of the Phase 3 clinical study showed rapid onset of efficacy of oligomannate within 4 weeks, and that patients’ cognitive function continued to improve,” said Shifu, adding that safety was also evident throughout the study.
Oligomannate, developed by Shangai-based Green Valley Pharmaceuticals, is expected to be available in China by the end of 2019.
Another Phase 3 trial, called GREEN MEMORY, is planned to open in the U.S., Europe and other parts of Asia in early 2020. Positive results here will be used to support requests for Oligomannate’s approval beyond China, Green Valley said in the release.
“We are very excited that Oligomannate is the first new drug approved for treating Alzheimer’s patients in the past 17 years, we are grateful to our patients and families who are the real heroes in the fight against this debilitating disease,” said Lv Songtao, chairman of Green Valley. “We look forward to continuing this journey to bring new treatment to all patients around the world.”
The most recent approval for any Alzheimer’s treatment was in 2007, when the U.S. Food and Drug Administration favored marketing of the Exelon Patch (rivastigmine transdermal) by Novartis. But this was simply a change in delivery for Exelon (rivastigmine), also by Novartis and approved as an oral capsule in 2000. Like many Alzheimer’s therapies, Exelon treats disease symptoms but cannot slow progression.
Alzheimer’s is characterized by the accumulation of plaques, or clumps, made up of toxic amyloid-beta aggregates within nerve cells, as well as by chemical alterations in the tau protein (called hyperphosphorylation) which are toxic to brain cells.
But evidence also supports that the gut microbiota — the “collection” of microorganisms that live inside the human gut — is altered in Alzheimer’s. In mouse models, this imbalance (called dysbiosis) has been shown to promote inflammation associated with neurodegeneration.
Abnormally high levels of intestinal metabolites (known as phenylalanine and isoleucine) that drive inflammation have also been found in the blood of people with Alzheimer’s and mouse disease models.
Preclinical data found that oligomannate reconditioned the gut microbiota in a mouse model of Alzheimer’s and prevented the abnormal release of intestinal metabolites. Treatment also lowered inflammation in the peripheral and central nervous system, lessened amyloid beta plaques and tau hyperphosphorylation, and improved cognitive function in these mice.
Such animal data support “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 AD,” David M. Holtzman, director of Hope Center for Neurological Diseases at Washington University in St. Louis and colleagues wrote in a research highlight article that accompanied the above study.
Oligomannate’s approval was based on results from a randomized, placebo-controlled Phase 3 clinical trial (NCT02293915) conducted across 34 clinical sites in China.
It assessed the treatment’s efficacy and safety in 818 people with mild to moderate Alzheimer’s, given either 900 mg of Oligomannate or a placebo twice a day for 24 weeks. All were followed up for 36 weeks.
Treatment with Oligomannate significantly improved cognitive function in patients as early as four weeks, the company reported. The mean difference in ADAS-Cog12 Score (an 80-point scale that is a standard measure of cognition and often used in Alzheimer’s studies) between patients given Oligomannate and those on placebo was 2.54. This response was sustained from the first month of treatment to the end of the 9-month observation period. Oligomannate was also found safe and well-tolerated.
“I have been doing research on Alzheimer’s disease for 50 years, participated in multiple global multi-center studies … and have never found a satisfactory treatment for Alzheimer’s disease,” said Zhang Zhenxin, a lead trial investigator and neurology professor at Peking Union Medical College Hospital. “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 is the first new therapy for Alzheimer’s disease approved in many years and we applaud this innovation,” said Jeffrey Cummings, a professor and director of Center for Neurodegeneration and Translational Neuroscience, a collaboration between the Cleveland Clinic and the University of Nevada Las Vegas, and a scientific advisor to Green Valley.
“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,” he added.
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