• In a decision likely to stir scientific debate across the world, China’s health regulator conditionally approved a new Alzheimer’s drug for patients with mild-to-moderate forms of the neurodegenerative disease.
• The drug, which was developed by the little-known Shanghai Green Valley Pharmaceuticals, will be available throughout China by the end of the year, according to the company and an English statement posted on the website of China’s National Medical Products Administration.
• No new Alzheimer’s drug has won approval since 2003 and drugmaker efforts to change that have consistently come up short, making the NMPA’s decision notable. But it’s not clear how effective Green Valley’s drug is, with limited information about the positive trial results reported by the company last year.

News of Green Valley’s approval comes just weeks after Biogen controversially revived its once-failed Alzheimer’s drug aducanumab, and could further roil a field accustomed to clinical setbacks.

Patients suffering from Alzheimer’s have few treatment options, and those drugs available can only temporarily ease symptoms. With tens of millions of people affected, the disease has for years been a top target for drugmakers despite a lengthening track record of failure.

Green Valley last year claimed a rare Phase 3 success for its drug, called oligomannate and derived from seaweed. The Shanghai-based drugmaker followed up an October 2018 submission to the NMPA with a presentation at the Clinical Trials on Alzheimer’s Disease Conference.

Yet data from that study, which enrolled 818 patients with mild-to-moderate Alzheimer’s disease across 34 trial sites in China, are scarce. Green Valley recently submitted the Phase 3 results to the New England Journal of Medicine, which is reviewing the manuscript, a spokesperson for the company confirmed to BioPharma Dive.

According to Green Valley, patients given oligomannate experienced a roughly 2.7-point decline from baseline on a commonly used rating scale for cognitive function in Alzheimer’s patients. That was statistically better than the 0.16 change from baseline reported among patients given placebo.

Changes in favor of Green Valley’s drug were observed as soon as four weeks, and continued throughout the nine-month study — a duration that’s markedly shorter than the 20- to 30-month timelines of recent Phase 3 trials from Biogen, Eli Lilly and Roche.

“[T]he improvements noted in this trial seem to come on very quickly, which makes me wonder, frankly, if they’re real and reproducible,” wrote Derek Lowe, a drug discovery researcher and author of a well-read industry blog, in a Nov. 4 post.

“Alzheimer’s is not a disease where one expects such results, and we have to remember that modulating neuroinflammation has been tried before as an AD therapy, without seeing anything like this.”

Reducing neuroinflammation is one of the proposed mechanisms of action for oligomannate, which Green Valley says reconditions dysbiosis of gut microbiota as well as reduces amyloid protein deposition.

Links between bacteria in the gut and Alzheimer’s have been proposed before, and researchers from Green Valley made the case for oligomannate’s beneficial role via this pathway in a September 2019 paper published in Cell Research.

“There is no question that this 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 AD,” wrote researchers from Washington University School of Medicine in St. Louis, in an accompanying piece. GV-971 is another name used by Green Valley for oligomannate.

Nearly all late-stage drug candidates that have advanced through late-stage testing in recent years target amyloid beta in some way. But high-profile failures in the clinic for drugs like Eli Lilly’s solanezumab and Roche’s crenezumab have dimmed enthusiasm for the hypothesis that reducing amyloid plaque build-up could lessen the cognitive and functional decline characteristic of Alzheimer’s, if patients are treated early enough.

Even with Biogen’s surprising aducanumab news, the Alzheimer’s field may now turn more fully to exploring alternate disease pathways like the microbiome.

“The basic science studies of oligomannate are intriguing,” said Eric Reiman, executive director of the Banner Alzheimer’s Institute and a scientific advisor to Green Valley, in comments emailed to BioPharma Dive.

“If it exerts therapeutic effects for regulation of the microbiome and related inflammatory effects, it would have an important impact on the field.”

The benefit reported by Green Valley for oligomannate could prompt questions of the drug’s clinical meaningfulness, though.

For example, data supporting the approval of the commonly used Aricept (donepezil) showed patients taking the drug experienced score declines of a relatively similar magnitude on a similar, but slightly narrower cognitive test. Average differences in score changes between two Aricept doses and placebo were 2.8 and 3.1 points, respectively.

Green Valley plans to start another Phase 3 study of oligomannate early next year, this time with trial sites in the U.S., Europe and Asia. If successful, Green Valley plans to use that study to support regulatory filings globally.

That trial, however, won’t be completed for another five years, the company spokesperson said.