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Sea algae-derived drug floats to the top of Alzheimer's news.

China's National Medical Products Administration has approved a new therapy for patients with mild to moderate Alzheimer's disease--a sea algae extract thought to alter the gut microbiome profile and decrease microbiome-driven neuroinflammation.

Sodium oligomannate--dubbed GV-971--won approval based on a 36-week, placebo-controlled, phase 3 study of 818 patients with mild to moderate Alzheimer's disease (AD). The study hit its primary endpoint of change on the Alzheimer's Disease Assessment Scale cognitive portion (ADAS-cogl2). It did not meet any of the trial's other cognitive or functional secondary endpoints.

A portion of the data was presented last year at the Clinical Trials on Alzheimer's Disease meeting in Barcelona. But the full study has never appeared in a peer-reviewed journal. A truncated version is publicly available on the website of Shanghai Green Valley Pharmaceuticals, the company developing the molecule.

Shanghai Green Valley said it reduces neuroinflammation by improving a proinflammatory microbiome profile that it says is characteristic of AD. However, the mechanism by which GV-971 alters intestinal bacterial composition is unclear--or at least it is not fully described in the public literature.

In the United States, some key researchers appraised the news with a cautiously optimistic eye, while others noted that the AD-microbiome link is an unproven concept, and that it was evaluated in a study of questionable worth.

"The company has presented data that suggest there is a modest cognitive benefit to this treatment," Paul S. Aisen, MD, said in an interview. "The key secondary endpoint was missed, and the other secondary endpoints showed no benefit. It's a single trial and the mechanism is still unclear."

"We do need to pursue all possible leads, and I'm glad the company is pursuing additional studies, but I wouldn't draw a firm conclusion from these data. And they certainly would not be enough to win approval in the U.S.," said Dr. Aisen, founding director Alzheimer's Therapeutic Research Institute at the University of Southern California, Los Angeles.

Preclinical findings on GV-971

In commenting on preclinical findings of GV-971 published in Cell Research in September 2019, David Holtzman, MD, associate director of the Alzheimer's disease research center at Washington University in St. Louis, and coauthors observed that the data support research exploring treatments that modulate the gut microbiome but leave it unclear as to whether GV971 has AD-specific effects.

"[The company shows] that GV-971 decreases amyloid beta-related pathologies by reconditioning the gut microbiota, providing further evidence that gut-targeted interventions may serve as novel strategies to tackle AD," Dr. Holtzman and coauthors wrote. "Whether this potential mechanism represents an AD-specific process is not clear, since there is great overlap in immunological changes and gut dysbiosis with other diseases. ... In addition, although this study reveals that gut reconditioning may be one mechanism of action of the drug GV-971, it does not rule out other possible mechanisms. For example, GV-971 may attenuate AD pathogenesis by directly inhibiting neuroinflammation or amyloid-beta fibril formation. However, there is no question that [these] data further [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."

Sodium oligomannate is a long-chain saccharide extracted from brown sea algae and consists of acidic linear oligosaccharides with structures ranging from dimers to decamers. Related molecules without the sugar backbone were inactive, suggesting that the saccharides are the active portion, Xinyi Wang of Shanghai Green Valley and colleagues wrote iCell Research.

Based on those studies, the company contends that Alzheimer's progression is accompanied by a characteristic microbiome change to a proinflammatory profile. And indeed, two transgenic Alzheimer's mouse models - one with five familial AD mutations (5xFAD) and one with mutations of amyloid precursor protein and presenilin 1 (APP/PSl)--showed similar gradual age- and progression-related decreases of Bacteroides and Verrucomicrobia, two components of a normal microbiome. Bacteroides species perform key functions necessary for survival, including sensing and adapting to nutrient variability. Species of the Verrucomicrobia phylum are important in glucose homeostasis. The decline in Bacteroides and Verrucomicrobia species is accompanied by an increase in concomitant proinflammatory species.

The investigators then explored the relationship between the microbiome composition and cognitive function in transgenic models and a wild-type mouse.

First, they showed that the bacterial populations shifted as the mice aged and their AD pathology developed. This was accompanied by an uptick in activated microglia and, in turn, proinflammatory Tl helper cells that migrated through the intestinal membranes and into the periphery, then cross the blood-brain barrier to enter the brain.

Then the investigators used a cocktail of powerful antibiotics to disturb the intestinal flora in transgenic and wild-type mice. After this, the 5xFAD mice showed fewer activated microglia and fewer infiltrating T cells. Later, they gave wild-type mice a fecal transplant from the 5xFAD mice. The wildtype mice developed more activated and infiltrating cells and their microbiome began to resemble that of the transgenic mice. Conversely, when the transgenic mice received a transplant from the wild-type mice, their microbiome changed to resemble the donors', and their activated and infiltrating cells declined. After this, the team gave GV971 to the mice. The APP/PS1 mice improved cognitively, and the 5xFAD mice had fewer activated and infiltrating cells, fewer amyloid brain plaques, and less tau phosphorylation. These changes were accompanied by higher levels of two amino acids, phenylalanine and isoleucine. These proteins appear to act on T-cell proliferation and differentiation, they said.

The phase 3 study

The approval of GV-971 was based on the subsequent 36-week, phase 3, placebo-controlled study of 818 patients with mild to moderate AD, which was reported last year. Patients were randomized to placebo or to GV-971 450 mg twice daily. Amyloid PET imaging was not required at entrance to the study, so there was no measure of baseline amyloid load. However, all patients showed MRI evidence of cortical atrophy. The Mini Mental State Exam (MMSE) ranged from 11 to 26, indicating mild to moderate AD.

Secondary endpoints included change on the Alzheimer's Disease Cooperative Study Activities of Daily Living, the Clinician's Interview-Based Impression of ChangePlus, and the Neuropsychiatrie Index.

Patients taking GV-971 experienced a statistically significant 2.54-point difference on the ADAS-cogl2, compared with placebo. The difference was apparent by week 4 and was seen at every clinical visit. When patients were grouped according to baseline MMSE (11-14, 15-19, and 20-26), the drug performed similarly.

But none of the secondary endpoints significantly favored GV-971. And the placebo group behaved in an unexpected way, which could throw the data interpretation off-kilter somewhat, David Knopman, MD, said in an interview.

"It was a very weird and unusual-looking trajectory of the placebo and treated groups," said Dr. Knopman of the Mayo Clinic, Rochester, Minn., with those taking placebo staying relatively stable for some time before the cognitive scores dropped precipitously. "The data were unconvincing to me."

He also pointed out that, although the extensive preclinical data appeared in the recent peer-reviewed Cell Research paper, the phase 3 data have not appeared in any peer-reviewed forum, "even though the trial has been completed for some time now. Furthermore, the duration of the study was inadequate."

Finally, none of the study subjects were taking the standard-of-care Cholinesterase inhibitors, which virtually every AD patient in the United States does take. "This makes it almost completely inapplicable to the U.S.," he said. "It's not bad news. I'm just not convinced."

Dr. Holtzman is a cofounder of C2N Diagnostics. He is on the scientific advisory board of Genentech, Denali, and C2N Diagnostics. He consults for Idorsia. Dr. Knopman is a consultant for the Bluefield Project to Cure Frontotemporal Dementia and for Lundbeck.

Caption: Dr. David Knopman cited the absence of the phase 3 results on GV-971 in any peer-reviewed forum as a shortcoming.

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Title Annotation:NEUROLOGY
Author:Sullivan, Michele G.
Publication:Clinical Psychiatry News
Date:Dec 1, 2019
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