l*******2
发帖数: 1 | 1 07 Nov 2019
Just as the clamor about Biogen’s seeking FDA approval for aducanumab with
one positive Phase 3 trial started to die down, a Chinese company garnered a
regulatory thumbs-up for its drug, also with one Phase 3 trial. On November
2, Shanghai Green Valley Pharmaceuticals announced that China’s National
Medical Product Administration (NMPA) had conditionally approved GV-971, aka
oligomannate, for the treatment of mild to moderate Alzheimer’s disease.
Full approval, expected to come in spring 2020, hinges on the company
submitting animal safety studies that have already been completed, according
to a spokesperson for the company.
GV-971 conditionally approved in China to treat AD.
Drug met its one primary, but not secondary endpoints, in a single Phase 3
trial.
Global Phase 3 trial slated to begin in 2020, in United States, Europe,
China.
A single Phase 3 study apparently found that GV-971, reported to alter the
gut microbiome, slowed cognitive decline in people with AD. The trajectory
of cognitive change in the nine-month trial raised some eyebrows—for one,
the placebo group did unusually well for weeks before their cognitive scores
plummeted. A global Phase 3 trial, slated to begin in 2020, will test if GV
-971 passes muster in the United States, Europe, and China.
Green Valley has developed carbohydrate-based drugs for a number of chronic
diseases since 1997. It touts GV-971, a mixture of oligosaccharides derived
from brown algae, as restoring balance to the gut microbiota. A recent study
led by the drug’s discoverer, Meiyu Geng at the Chinese Academy of
Sciences in Shanghai, reported that the bacterial flora inhabiting the guts
of 5xFAD and other mouse models of AD differed from the flora of wild-type
animals. This triggered infiltration of T cells into the brain, where they
stoked microglial activation and led to damaging neuroinflammation. GV-971
reportedly altered the microbiome such that it no longer triggered
neuroinflammation. Furthermore, the saccharide reportedly reduced Aβ burden
, tau hyperphosphorylation, and cognitive deficits in the mice (Wang et al.,
2019).
Since news of GV-971’s approval burst onto the scene, some commentators
have scrutinized this preclinical data. They noted instances of image
duplication in previous studies published by Geng’s lab, and recalled
regulatory troubles with Green Valley from the past (see Science
Translational Medicine blog).
Liping Zhao, a microbiome researcher at Rutgers University, New Jersey,
noted that in the preclinical study, treatment of 5xFAD mice with GV-971
appeared to boost the growth of certain taxa that contain opportunistic
pathogens that could aggravate inflammation, and suppressed others known to
pump out inflammation-soothing short-chain fatty acids. “Taken together,
the microbiome data … did not support the hypothesis that part of the
mechanism for GV-971 to alleviate AD might be reducing inflammation by way
of modulating the gut microbiota,” he wrote in a comment to Alzforum. “On
the contrary, the microbiome data provided in the Cell Research paper
indicates a possibility that GV-971 may aggravate the dysbiosis of the gut
microbiota and thus potentially increase inflammation in AD mice.” (See
full comment below.)
Green Valley has been studying this oligosaccharide in people for some years
. In 2008, the company completed a Phase 1 study in healthy men, followed by
a Phase 2 study in 255 people with mild to moderate AD that began in 2011.
Results of that Phase 2 study were presented at the Clinical Trials in
Alzheimer’s Disease (CTAD) meeting in 2014. While a 900 mg daily dose of GV
-971 had not significantly altered the trajectory of ADAS-Cog12 scores over
24 weeks, i.e., had failed the primary endpoint, it did appear to have
slowed decline on Clinician's Interview-Based Impression of Change Plus
Caregiver Input (CIBIC-Plus), a secondary endpoint (see Dec 2014 Medscape
news story). As yet, no clinical trial data on GV-971 are published in the
peer-reviewed literature.
Geng presented findings from the Phase 3 trial, which started in 2014, at
the last CTAD conference in 2018, and Green Valley filed for approval
shortly thereafter, according to the company spokesperson (Nov 2018 news).
Conducted at 34 sites in China, this trial enrolled 818 people clinically
diagnosed with mild to moderate AD. Roughly half were randomized to twice-
daily doses of 450 mg of GV-971, the others to placebo. Participants could
not take cholinesterase inhibitors, the standard of care in many countries,
during the trial. Change in ADAS-Cog12 performance at 36 weeks served as the
primary endpoint. Secondary endpoints—none of which were met—included
changes on the CIBIC, activities of daily living (ADL), neuropsychiatric
inventory (NPI), and FDG-PET. Neither amyloid PET scans nor fluid biomarkers
were used anywhere in the trial.
Curious Curves. ADAS-Cog12 scores similarly improved in both treatment and
placebo groups, with a group difference at four weeks sharply increasing at
36 weeks. [Courtesy of Shanghai Green Valley Pharmaceuticals.]
GV-971 was safe and well-tolerated, with comparable side effects to placebo,
according to the company press release. Compared with baseline scores, both
the treatment and placebo groups improved on the ADAS-Cog12 by four weeks,
though those on GV-971 improved slightly more than those on placebo. At 12
and 24 weeks, both groups essentially maintained their scores. At 36 weeks,
the gap widened as placebo-group scores plummeted to just above baseline,
while those in the treatment group reportedly bettered their baseline scores
by 2.70 points, making for a 2.54-point difference between the groups.
This is slightly larger than differences reported for cholinesterase
inhibitors, said Jeffrey Cummings of the Cleveland Clinic, Lou Ruvo Center
for Brain Health in Las Vegas, who is a scientific adviser to Green Valley.
Separation between groups was largest—with a 4.55 ADAS-Cog point difference
—in participants with the lowest MMSE scores at baseline, i.e., those whose
dementia was most advanced.
Lon Schneider of the University of Southern California, Los Angeles, said
the trajectories were unusual, noting that the placebo group would be
expected to worsen by around 1.5 points on the ADAS-Cog over six months. He
noted that a similar placebo response was observed over the 24-week Phase 2
trial. “In the Phase 3 trial, after closely tracking the oligomannate group
for 24 weeks, the placebo group took a nosedive, returning to its baseline
by week 36. This unexpected and unexplained inflection point for the placebo
group accounts for the significance on the ADAS-Cog12 at week 36,” he
wrote.
Cummings also found the performance of the placebo groups in both trials odd
. One possible explanation is the relatively low standard of healthcare in
China. Regular doctor visits are not the norm there, and might by themselves
have a salubrious effect on trial participants. Cummings said he was
convinced that the trial was well-conducted, with standards typical of those
in the United States and European Union.
The mechanism of this compound remains unclear, Cummings said. While the gut
microbiome, which is reportedly altered in people with AD, could be
involved, Cummings thinks it will be important to consider other
possibilities. According to unpublished data from Green Valley scientists,
GV-971 also binds to and de-aggregates various forms of Aβ.
Eric Siemers, Siemers Integration LLC, Zionsville, Indiana, stressed the
need for another, larger study. Siemers agreed that the trajectory in the
placebo group was unusual and that the drug’s mechanism of action remains
unclear. He added that the group separation at the first few time points was
small. Siemers asked how much of this rather large oligosaccharide crosses
into the brain, and whether it has been shown to affect the gut microbiome
in people. Positive findings in a second trial would indicate the drug most
likely offers symptomatic relief, he said.
“While the drug in question may soon be available in Chinese markets and
there are efforts to initiate global level trials, extreme caution is
warranted before the scientific and medical community can embrace this new
drug for treating AD patients,” wrote Malú Tansey and Paramita Chakrabarty
of the University of Florida in Gainesville, in a joint comment to Alzforum
. They stressed the importance of nailing down the drug’s mechanism of
action, and of evaluating it in diverse populations, especially since the
microbiome varies across ethnicities.
The drug will be available to people in China by the end of 2019. Green
Valley plans to seek marketing authorization in other countries as well. It
farms its own seaweed, from which it extracts the oligosaccharides that make
up GV-971, according to the company.
In the United States, the FDA sometimes approves drugs pending further data
linking a biomarker response to a meaningful clinical outcome. In this case,
by contrast, the Chinese NMPA approved GV-971 on the condition of reviewing
further animal safety reports. It is unclear how the drug’s approval in
China could be affected by a potential failure in the global trial, Cummings
said.
That global trial is slated to begin in 2020, and will include more than 1,
000 participants from the United States, Western Europe, and China, Cummings
said. In the meantime, will people outside of China be able to obtain the
drug? Cummings said the company is considering asking the FDA to create a
compassionate-use indication, which could theoretically give people with AD
access to the drug. Without a legitimate pathway for expanded use outside of
China, counterfeiting is likely to take place, he said.
“Approval in China for a new treatment for Alzheimer’s disease is
encouraging,” wrote Stephen Salloway of Brown University in Providence,
Rhode Island. “We await publication of the study that led to approval.”
Salloway noted that people who took cholinesterase inhibitors were excluded
from the trial. “Further study is needed in the United States and elsewhere
that includes the background use of cholinesterase inhibitors, the current
standard of care,” he added.
David Holtzman of Washington University in St. Louis agreed. “It will also
be important to sort out whether the effects observed in humans are through
neurotransmitter modulation accounting for a symptomatic benefit, or whether
they are due to altering the microbiome, with secondary effects on the
brain as has been recently seen in mouse models with GV-971,” he added.
Holtzman co-authored an editorial about the recently published preclinical
studies (Seo et al., 2019).
Cummings told Alzforum that Green Valley has not yet completed a trial to
assess interactions between GV-971 and cholinesterase inhibitors, but that
one is planned. Therefore, the upcoming global Phase 3 trial will likely
prohibit use of cholinesterase inhibitors among its participants, a factor
he acknowledged could hinder enrollment.—Jessica Shugart
COMMENTS
User Profile ImageStephen Salloway
Brown University
Posted: 07 Nov 2019
Approval in China for a new treatment for Alzheimer’s disease is
encouraging. We await publication of the study that led to approval. From
the data presented at CTAD, cholinesterase inhibitors were not allowed and
the drug worked best for those with a Mini Mental State Exam score of 11-15.
There was improvement relative to placebo on the ADAS-Cog but not on the
Activities of Daily Living scale and with a trend on the Clinician’s Global
Impression of Change. The mechanism of action is novel, but it is hard to
know the exact mechanism that might provide clinical benefits. Further study
is needed in the United States and elsewhere that includes the background
use of cholinesterase inhibitors, the current standard of care.…MORE
VIEW ALL COMMENTS BY STEPHEN SALLOWAY
User Profile ImageDavid Holtzman
Washington University
Posted: 07 Nov 2019
The compound GV-971, Sodium oligomannate, was recently tested in a people
who, based on clinical criteria, had mild to moderate dementia believed to
be due to Alzheimer’s disease. Over a 36-week period, participants on GV-
971 performed better than placebo-treated individuals by ~2.5 points on the
ADAS-Cog test. This is a similar effect on this test to studies using
cholinesterase inhibitors such as donepezil. Based on this and other data,
GV-971 was approved to treat patients with mild to moderate dementia of the
Alzheimer’s type in China.
It is exciting that a new treatment is being approved for mild to moderate
dementia in China. To my knowledge, the patients who participated in the
trials in China were not on cholinesterase inhibitors or memantine. It will
be important in future studies in the United States, Europe, and other
places to compare the effects of GV-971 to the currently utilized treatments
in the field, or when added to these treatments. It will also be important
to sort out whether the effects observed in humans are through
neurotransmitter modulation accounting for a symptomatic benefit, or whether
they are due to altering the microbiome with secondary effects on the brain
as has been recently seen in mouse models with GV-971.…MORE
VIEW ALL COMMENTS BY DAVID HOLTZMAN
User Profile ImageLon S. Schneider
University of Southern California Keck School of Medicine
Posted: 07 Nov 2019
The conditional marketing approval by China’s FDA, the NMPA, for GV-971
also limited its price to twice that of donepezil. If donepezil is as cheap
in China as it is at Costco (i.e., $30.30 per year with a GoodRx coupon),
then $60.60 is a steal for this plant-derived product, whether or not it’s
effective and as long as it’s safe. The prior Phase 2 study and this Phase
3 trial report adverse events generally lower than placebo, suggesting that
oligomannate is remarkably safe and perhaps without side effects.
However, the company provides curious and tenuous results for its efficacy,
even if we accept the outcomes at face value. The Phase 2, 24-week trial of
255 patients showed significance on the CIBIC+, but not on any other outcome
(presented at CTAD in 2014, results at clinicaltrials.gov). The Phase 3, 36
-week P3 trial with 788 patients reported a significant 2.54 ADAS-cog12
point advantage over placebo at 36 weeks, but also was not supported by any
other outcome (presented at CTAD 2018). Both trials looked rather similar up
to 24 weeks, showing substantial improvement for both drug and placebo on
the ADAS-cog12 within four weeks and stabilization of this improvement in
both treatment groups over 24 weeks, with very small and questionably
clinically meaningful drug-placebo differences of 1.1 and 0.7 ADAS-cog12
points. In the P3 trial, after closely tracking the oligomannate group for
24 weeks, the placebo group took a nosedive, returning to its baseline by
week 36. This unexpected and unexplained inflection point for the placebo
group accounts for the significance on the ADAS-cog12 at week 36. …MORE
Some features of the study may have a bearing on its external validity. They
include an apparent marked practice effect on the ADAS-cog12 when patients
with dementia often don’t show much, and the lack of cognitive decline over
24 to 36 weeks, as seen in the vast majority of mild to moderate AD trials
(Schneider and Sano, 2009). There also may be issues with internal validity
that would become evident once we know more about the statistical analyses.
They might include the rather small standard errors suggesting smaller-than-
expected standard deviations and less variance in the ADAS-cog outcomes than
in other trials.Patients for this study were not allowed to take
cholinesterase inhibitors, and as has been demonstrated in U.S. samples, the
differences in clinical characteristics and course between those taking
AChEIs and those not taking them may affect outcomes. Any trial in the
United States likely would have to enroll patients on AChEIs. The lack of
clarity and details inherent in conference presentations and press releases
limits inferences we can make.References:Schneider LS, Sano M. Current
Alzheimer's disease clinical trials: methods and placebo outcomes.
Alzheimers Dement. 2009 Sep;5(5):388-97. PubMed.VIEW ALL COMMENTS BY LON S.
SCHNEIDER
User Profile ImageMalu G. Tansey
The University of Florida College of Medicine
User Profile ImageParamita Chakrabarty
University of Florida
Posted: 07 Nov 2019
The research team reports that the initial results from the Phase 3 trial
look very promising. The team claims that the drug was extremely well-
tolerated, with literally no side effects; that it stabilized the decrease
in ADAS-Cog within four weeks of initiation. Yet without data on other
measures, such as CSF biomarker levels, FDG-PET and Aβ PET signals, plasma
levels of cytokines and some indication as to how the microbiome is
progressively changed in these patients, the outcome of this trial should be
treated as promising but preliminary. Other critical information, such as
whether these patients were on any other cognitive enhancers or undergoing
neurocognitive therapies, was not included in their reports and is needed to
evaluate whether the positive outcomes can be attributed directly to GV-971
. Although preclinical studies have hinted that GV-971 has multifaceted
roles in AD mouse models, such as altering Aβ metabolism, controlling
neuroinflammation, and normalizing gut microbiome, we do not yet know to
what extent these parameters changed in these patients.…MORE
While the drug in question may soon be available in Chinese markets, and
there are efforts to initiate global level trials, extreme caution is
warranted before the scientific and medical community can embrace this new
drug for treating AD patients. Specifically, there should be concerted
efforts to nail down the mechanism of action as well as establishing
reproducibility of the beneficial effects in a larger cohort of patients of
different ethnicities since ethnic differences influence gut microbiome
composition.That said, if these results can be replicated in additional,
larger cohorts of diverse ethnicities, this drug may hold promise in other
neurological disorders where disruption of the gut-brain axis and dysbiosis
has been implicated in etiology, including autism spectrum disorders and
Parkinson’s disease. VIEW ALL COMMENTS BY MALU G. TANSEY VIEW ALL COMMENTS
BY PARAMITA CHAKRABARTY
User Profile ImageLiping Zhao
Rutgers University
Posted: 07 Nov 2019
Out of curiosity, I read the preclinical Cell Research paper on how GV-971
modulated the gut microbiota of transgenic (Tg) mice (Wang et al., 2019).
I was surprised to find out that the microbiome data did not support the
hypothesis that GV-971 may alleviate inflammation via modulation of the gut
microbiota.
This relevant data is in Fig. 4.
Fig. 4a is a principal coordinate analysis of the gut microbiome composition
at the species level (operational taxonomic units) based on the Bray-Curtis
distance for Tg and GV-971-treated Tg mice. This shows that these two
groups of mice have significantly different gut microbiota. This could mean
that GV-971 changed the gut microbiota of Tg mice.…MORE
Fig. 4b is a heat map of significantly changed gut bacteria represented at
the genus level between Tg and GV-971-treated Tg mice. Among the taxa that
were significantly promoted by GV-971 were those that contained
opportunistic pathogens that may aggravate inflammation. A typical example
is the family Desulfovibrionaceae. Members of this family, when found in
human or animal gut, are endotoxin and hydrogen sulfide producers, which can
induce or aggravate inflammation. This means that potentially
proinflammatory gut bacteria were promoted by GV-971. Among the taxa that
were significantly diminished by GV-971 were those that can produce short-
chain fatty acids such as Roseburia spp. Members of genus Roseburia can
produce butyrate that can mitigate inflammation. Increased abundance of this
genus has been associated with weight loss and reduced insulin resistance
in mice. Astonishingly, this potentially beneficial, anti-inflammatory group
of gut bacteria was reduced by GV-971.Taken together, the microbiome data
provided in the Cell Research paper, being associative in nature, do not
support the hypothesis that part of the mechanism for GV-971 alleviating AD
might be by reducing inflammation by way of modulating the gut microbiota.On
the contrary, the microbiome data provided in the Cell Research paper
indicates a possibility that GV-971 may aggravate the dysbiosis of the gut
microbiota and thus potentially increase inflammation in AD mice.References:
Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, Xie Z, Chu X, Yang J, Wang
H, Chang S, Gong Y, Ruan L, Zhang G, Yan S, Lian W, Du C, Yang D, Zhang Q,
Lin F, Liu J, Zhang H, Ge C, Xiao S, Ding J, Geng M. 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.VIEW ALL COMMENTS
BY LIPING ZHAO
User Profile ImageNam Chul Kim
University of Minnesota
Posted: 08 Nov 2019
In the method section, the authors claimed that GV-971 targets Aβ
aggregation. GV-971 is a mixture of oligosaccharides with the degree of
polymerization (dp) from 2 to 10. This preclinical study showed that GV-971
penetrates the blood-brain-barrier (BBB) in its original form. Type 1
glucose transporter (GLUT1) was identified as one of the transporters
accounting for its penetration mechanism of BBB. GV-971 could directly bind
to multiple subregions of Aβ to inhibit Aβ fibril formation and
destabilize the preformed fibrils into non-toxic monomers. Through targeting
Aβ, GV-971 promoted microglia-mediated Aβ phagocytosis in vitro, and
reversed cognition impairment in multiple AD models.…MORE | l*******2
发帖数: 1 | 2 大概意思就是说这个药分子机理还没有搞清楚，老鼠的肠道菌群改善不明显
这个药可以透过血脑屏障，能不能Ab蛋白结合还不清楚
部分人质疑临川实验结果，认为中国的health care 很差，导致安慰剂组数据不是那么
可靠
还有人在拔Dr.geng 的旧账，说他造假历史
anyway, 这个药全球临床实验2020年开始，是骡子是马迁出来溜溜 | f******t
发帖数: 19544 | 3 不死人，有钱人不妨吃吃。睡前消息里督工这么说的。 | l*******2
发帖数: 1 | 4 就是这么个道理
再说海藻里的多糖提取物估计也不会贵到哪里去
还可以带动一个产业链
【在 f******t 的大作中提到】
: 不死人，有钱人不妨吃吃。睡前消息里督工这么说的。
| P**C
发帖数: 4333 | 5 绿谷这个“药厂”最有名的要就是中华灵芝宝，那就是一个伪药，臭名昭著。这药估计
基本上也是一个伪药品，属于吃不死人的安慰药。 |
|
