Therapeutics

GV-971

Overview

Name: GV-971
Synonyms: sodium oligomannate, sodium oligo-mannurarate
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Status in Select Countries: Approved in China
Company: Shanghai Green Valley Pharmaceuticals

Background

This mixture of acidic linear oligosaccharides is derived from brown algae. The mechanism of action of the preparation remains unclear, although several different mechanims have been proposed by the same research group between 2003 and 2013. Among those are a report that algae-derived acidic oligosaccharides de-aggregate Aβ (Hu et al,., 2004), one that they prevent astrocyte-mediated inflammatory responses to amyloid plaques (Wang et al., 2007), and one that they bind to many proteins inside neurons (Liu et al., 2009).

The most recent preclinical study concerns an effect via alteration of intestinal bacteria (Wang et al., 2019). In this study, the gut microflora in 5XFAD and APP/PS1 AD mice facilitated peripheral immune cell entry into the brain, microglia activation, and disease progression, and treatment with GV-971 was reported to restore the gut microbial profile to normal and to lessen brain immune cell infiltration and inflammation. GV-971 reportedly also reduced brain Aβ burden, tau hyperphosphorylation, and cognitive deficits in these mice.

This paper was subsequently challenged as a matter arising in the same journal (Rao, 2020) and on the online journal club website PubPeer.

Findings

According to the company, Green Valley completed a Phase 1 study in 112 normal people in 2008, though no information on this trial appears in ClinicalTrials.gov.  

In October 2011, the company launched a Phase 2 trial at multiple sites in China, enrolling 255 people with mild to moderate AD who were not receiving treatment with any other AD drugs. They received 600 or 900 mg of GV-971 per day or placebo for six months. The primary endpoint was the change in ADAS-Cog12; secondary endpoints include changes on the Clinician’s Impression of Change-plus (CIBIC-plus), activities of daily living (ADL), and neuropsychiatric inventory (NPI). According to results presented at the 2014 CTAD conference, the trial failed to meet its primary endpoint, with no slowing of decline on the ADAS-cog in the treated group. The 900 mg dose did slow decline on the CIBIC-plus compared with placebo (Medscape news; see also Derek Lowe commentary). In September 2020, results of this trial were published, including an FDG-Pet substudy with 25 patients (Wang et al., 2020). Glucose metabolism declined less in some brain regions in the 900 mg treatment than placebo group, but the differences fell short of statistical significance.

In April 2014, Green Valley started a Phase 3 trial at 34 sites in China. In the study, 818 people with clinically diagnosed mild to moderate AD were randomized to 900 mg drug per day or placebo for nine months. Participants were not allowed to take acetyl cholinesterase inhibitors or namenda during the study. No amyloid or tau biomarkers were used. Again, the primary outcome was change on ADAS-Cog; secondary outcomes were the same as in Phase 2, with the addition of FDG-PET. As reported at CTAD 2018, this trial reached its primary endpoint, with the treatment group posting higher ADAS-Cog scores than placebo at four, 12, 24 and 36 weeks. There was a trend toward improvement on the CIBIC, but no change in any other secondary outcomes (Nov 2018 conference news). A subgroup analysis suggested drug effects were larger in people with lower MMSE scores at the start of the trial. GV-971 was well-tolerated. Eighty percent of participants completed the trial, and rates of adverse events were similar between treatment and placebo groups.

On November 2, 2019, Green Valley announced that the drug had received conditional marketing approval in China to improve cognitive function in mild to moderate AD (see press release). The drug began selling in China in December 2019. The company expects full approval in early 2020, pending the submission of animal safety data (Nov 2019 news and commentary).

In August 2020, Green Valley registered a Phase 3 trial called Green Memory. It will enroll 2,046 people with mild to moderate AD and randomize them to GV-971 or placebo for one year, followed by six months of open-label GV-971 for all participants. Primary endpoints are ADAS-Cog11 and the ADCS-Clinical Global Impression of Change; secondary endpoints include other climnical and psychiatric measures. The registration lists blood pk and MRI as additional outcomes, but no AD-specific biomarkers. Like prior trials of this oligomannate preparation, this study also does not allow concomitant use of the standard FDA-approved AD medications. As of September 23, study sites were not yet listed, but the company had previously announced they would conduct the trial at 200 sites in North America, Europe, and Asia-Pacific regions (Apr 2020 press release). The study is expected to run through 2025.

According to ClinicalTrials.gov, the investigators completed a second Phase 1 study in China, testing bioavailability of different capsule formulations in healthy adults, and are recruiting for an additional Phase 1 study, also in China, to assess safety and pharmacokinetics of higher doses up to 1,500 mg.

For details, see clinicaltrials.gov.

Last Updated: 24 Sep 2020

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References

News Citations

  1. Fits and Starts: Trial Results from the CTAD Conference
  2. China Approves Seaweed Sugar as First New Alzheimer’s Drug in 17 Years

Paper Citations

  1. . A phase II randomized trial of sodium oligomannate in Alzheimer's dementia. Alzheimers Res Ther. 2020 Sep 14;12(1):110. PubMed.
  2. . Acidic oligosaccharide sugar chain, a marine-derived acidic oligosaccharide, inhibits the cytotoxicity and aggregation of amyloid beta protein. J Pharmacol Sci. 2004 Jun;95(2):248-55. PubMed.
  3. . A marine-derived acidic oligosaccharide sugar chain specifically inhibits neuronal cell injury mediated by beta-amyloid-induced astrocyte activation in vitro. Neurol Res. 2007 Jan;29(1):96-102. PubMed.
  4. . Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression. Cell Res. 2019 Oct;29(10):787-803. Epub 2019 Sep 6 PubMed.
  5. . Omission of previous publications by an author should be corrected. Cell Res. 2020 Sep;30(9):819. PubMed.

External Citations

  1. Medscape news
  2. Derek Lowe commentary
  3. press release
  4. Apr 2020 press release
  5. clinicaltrials.gov
  6. Liu et al., 2009
  7. PubPeer

Further Reading

External Resources

  1. Alzheimer’s experts greet China’s surprise approval of a drug for brain disease with hope and caution
  2. Identification of AOSC-binding proteins in neurons