BEIJING Chinese drug regulators granted conditional approval to Shanghai Green Valley (Group) Co. Ltd.'s marine-derived oligosaccharide, GV-971, to treat Alzheimer's disease (AD), but required further trials to prove the drug's efficacy after marketing.
The drug is expected to be available in China by the end of this year, according to Green Valley. The drugmaker also plans to submit an NDA in selected countries following the China launch, supported by data from a multicenter global phase III trial with sites in the U.S., Europe and Asia that is to begin in early 2020.
GV-971 is said to be the world's first multitargeting carbohydrate-based drug for treating AD. It is an anti-amyloid oligosaccharide drug extracted from brown algae and is considered innovative given its mechanism of action.
Unlike other monoclonal antibodies that typically target limited sites of the amyloid beta species, GV-971 can bind to multiple amyloid beta regions and in its different states and thus inhibit amyloid beta aggregation and destabilize aggregated fibrils into monomeric nontoxic forms. It inhibits neuroinflammation by harnessing the amino acid metabolism.
"Our study found that AD is triggered by the imbalance of gut microbiota, which leads to the inflammation of peripheral immune cells that are concentrated in the brain," said Geng Meiyu, lead researcher of GV-971, during a biotech conference in Suzhou in September. "Neuroinflammation then results in the development of AD."
For now, GV-971 is approved, with conditions, in China for the treatment of mild to moderate Alzheimer's disease and for improving cognitive function, after Green Valley said it had hit phase III endpoints. That multicenter, randomized, double-blind, placebo-controlled, parallel-group study randomized 818 patients to receive either GV-971 450 mg twice per day by oral administration or a placebo for a treatment period of 36 weeks.
The subjects were between the ages of 50 and 85. They met clinical criteria for mild to moderate AD, had MMSE scores of 11-26, and MRI evidence included medial temporal lobe atrophy visual rating scale (MTA) grade ≥2, Fazekas scale for white matter lesions grade <3, no more than two lacunar infarction lesions and no lacunar infarction lesions in the key brain regions.
The primary efficacy endpoint was the change from baseline to week 36 on the ADAS-Cog 12, which is a standard cognitive measure commonly used in AD studies. The secondary efficacy endpoints included the change from baseline to week 36 on CIBIC plus, ADCS-ADL and NPI. The safety evaluation includes AE, laboratory assessment, vital signs, ECGs and physical examinations.
Green Valley said trial results demonstrated that GV-971 statistically improved cognitive function in mild to moderate AD patients as early as week four, and the benefit was sustained at each follow-up assessment visit.
"The mean difference between GV-971 and placebo groups in ADAS-Cog12 Score was 2.54 (p< 0.0001), with sustained efficacy from the first month of treatment to the end of nine months of treatment," Green Valley said.
"The drug placebo difference was also statistically significant in all three subgroups of patients with MMSE scores ranging from 11-14, 15-19 and 20-26. There was a non-significant trend for greater improvement on the CIBIC-plus (p=0.059). No statistically significant differences were observed in ADCS-ADL or NPI," it added.
The drugmaker also noted that the twice-per-day oral treatment was found to be safe and well-tolerated. There were no statistically significant group differences in the percentage of participants with adverse or severe adverse effects.
A novel strategy
GV-971 stands out due to its ability to inhibit Alzheimer's disease progression, Green Valley claimed. It can remodel gut microbiota and it suppresses gut bacterial amino acids-shaped neuroinflammation to do so.
"Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation," GV-971 researchers wrote in Cell Research.
They also suggested that GV-971 could suppress gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harness neuroinflammation and reverse the cognition impairment.
"Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodeling the gut microbiota," they concluded.
Currently, there are only five FDA-approved drugs for AD, including acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), an NMDA receptor modulator (memantine) and a donepezil/memantine extended release drug.
"However, they do not slow or stop the progression of AD but only offer temporary relief of the disease symptoms," Nancy Ip, a neuroscientist from The Hong Kong University of Science and Technology, told BioWorld.
"To develop better clinical interventions, it is important to understand the pathophysiology of AD, identify and decipher the diseased pathways and mechanisms, and uncover new disease targets," she added.
It has been some time since an AD drug last entered the market. 2014 was when the FDA granted clearance to Namzaric (memantine/donepezil, Actavis plc and Adamas Pharmaceuticals Inc.). The approval by China demonstrates the country's determination to clear regulatory hurdles to let innovative drugs reach patients as soon as possible, if clinical trials have shown somewhat promising data.
But since GV-971 works very differently from other AD drugs, the NMPA requires the drugmaker to continue studies to prove the drug's mechanism of action and long-term efficacy and safety. Green Valley will have to submit more clinical data, or otherwise the marketing approval could be revoked.
Meanwhile, Biogen Inc. and Eisai Co. Ltd. plan to submit a BLA for aducanumab, an investigational treatment for early AD, with the FDA in early 2020. They said a new analysis of a larger dataset showed that aducanumab reduced clinical decline in patients with early AD as measured by the prespecified primary and secondary endpoints. (See BioWorld, Oct. 23, 2019.)