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Wednesday, July 3, 2019

U.S. judge to slash $80 million Roundup jury verdict: court hearing

A U.S. judge on Tuesday said he would reduce an $80 million damage award against Bayer AG to $50 million or less in the case of a man who blamed his cancer on glyphosate-based weed killer Roundup.

U.S. District Judge Vince Chhabria in San Francisco said the jury’s $75 million punitive damages award to plaintiff Edwin Hardeman in March could not stand.
“It’s quite clear that under the Constitution I’m required to reduce the punitive damages award and it’s just a question of how much,” Chhabria said during a court hearing in which lawyers for both sides discussed the company’s request to overturn the verdict. Chhabria said he would issue a ruling by the end of next week.
Following a four-week trial, a federal jury on March 27 awarded $5 million in compensatory and $75 million in punitive damages to Hardeman, who was diagnosed with non-Hodgkin’s lymphoma in 2014.
U.S. Supreme Court rulings limit the ratio of punitive to compensatory damages to 9 to 1.
Chhabria said he was also considering reducing the compensatory damages award because Hardeman was now in full remission and unlikely to suffer as much as he had in the past.
Bayer, which bought Roundup maker Monsanto for $63 billion last year, says Roundup and its active ingredient glyphosate are safe for human use and not carcinogenic.
The company faces lawsuits by more than 13,400 plaintiffs nationwide and a series of Roundup jury verdicts against Bayer have prompted its share price to plummet. Under pressure from activist shareholders, Bayer on Wednesday said it set up a committee to help resolve the litigation and hired an external lawyer to advise its supervisory board.
Bayer had asked Chhabria to completely reverse the jury verdict in Hardeman’s case in light of scientific evidence and assessments by regulators finding glyphosate to be safe.
Brian Stekloff, a lawyer for Bayer, on Tuesday said Monsanto went “above and beyond” to meet regulatory requirements, warranting a complete reversal of the punitive damages award.
But Chhabria disagreed, saying jurors had seen sufficient evidence that Monsanto did not care whether its products cause cancer, instead focusing on undermining people who were raising concerns.
“There was nothing suggesting that anybody at Monsanto viewed this issue objectively or with any consideration for the life of human people,” the judge said.

Glaxo HIV drug receives EU marketing nod

GlaxoSmithKline said its specialist HIV company had received marketing authorization from the European Commission for its drug to treat advanced stage HIV infections in adults and adolescents above the age of 12 and weighing at least 40 kg.
ViiV Healthcare, which is majority owned by GSK and with Pfizer Inc and Shionogi Ltd as shareholders, got the U.S. Food and Drug Administration approval for the treatment Dovato in April.

Using a common anticonvulsant to counteract inflammation

Serious conditions, including sepsis, stem from inflammation in the body, and there is a lack of effective medication for sepsis. A chromosomal protein called high-mobility group box 1 (HMGB1), secreted by immune and dying cells, binds to a specific cellular receptor—receptor for advanced glycation end-products (RAGE)—and triggers the process of inflammation in the body. Through a computer software-based docking study with a structural similarity-based strategy, scientists from Japan, led by senior researcher Prof Sei-ichi Tanuma from Tokyo University of Science (TUS), discovered that the popular anticonvulsant drug papaverine blocks the binding of HMGB1 to this receptor. This kind of “drug repositioning” can be used to find other merits for existing drugs whose safety profiles are known. This novel approach used for the first time here is unique to TUS and is described in the paper published in Biochemical and Biophysical Research Communications. Prof Tanuma states, “Our research group has been trying to identify compounds, preferably based on existing drugs, that block the binding of irritants to cellular receptors. We want to find novel drugs to treat inflammation-based conditions.”
Inflammation is the body’s response to injury or irritation. Although it is technically an “,” acute and chronic are associated with serious conditions and diseases like , rheumatoid arthritis, diabetes, Alzheimer’s disease, and even cancer. One of the many molecular-level processes underlying inflammation is the binding of a RAGE, to a “ligand” (e.g., HMGB1, amyloid β) or irritant. The  HMGB1, which is secreted by immune and dying cells, specifically binds to RAGE and triggers the production of molecules that promote inflammation. These molecules are called pro-inflammatory cytokines (PICs), and this entire cellular mechanism has been implicated in the onset of the diseases and conditions mentioned above.
Sepsis, which is a manifestation of acute infection and inflammation, is a particularly serious concern. Septic shock results in fatal multi-organ dysfunction, and there is still a need for effective drugs to treat septic shock.
This means that molecules that can block the interaction between HMGB1 and RAGE could be a novel class of therapeutics for treating such conditions, especially sepsis. However, it easily takes more than 10 years to get new drugs screened, evaluated, and approved. The concept of “repositioning” can be used to overcome this problem. Drug repositioning basically means finding new merits for existing drugs that have known safety profiles. This approach was the basis of this high-profile study done by Prof Tanuma and his colleagues.
The scientists first designed a unique cyclic “peptide” (small protein) called Pepb2 to mimic the RAGE-binding domain of HMGB1, using their computer software called “COSMOS.” They found that Pepb2 competed with HMGB1 to bind to RAGE, and thus “competitively inhibited” the HMGB1-RAGE interaction. Then, they screened for Pepb2 mimetic compounds (compounds that are structurally similar to Pepb2) in the DrugBank library. They found that papaverine, a popular vasodilating and anticonvulsant drug extracted from poppy seeds, was structurally similar to Pepb2.
In the laboratory, the researchers then found that papaverine directly blocks the binding of HMGB1 to RAGE and consequently lowers the production of PICs such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This proves that papaverine prevents irritants from binding to their receptors and thus suppresses inflammation. Prof Tanuma and colleagues also found that papaverine considerably reduced death rates in model mice with induced sepsis. Prof Tanuma summarizes this research by saying, “This in silico drug design approach, to find novel effects of papaverine, is a unique strategy employed for the first time only by TUS researchers.”
In another related study that was also headed by Prof Tanuma, the scientists found that papaverine canceled out the tumor-promoting effects of HMGB1 in tumor microenvironment. They also found that papaverine suppressed the growth and migration of cancer cells. This study, published in PLOS ONE, showed that papaverine may also be a potential anticancer drug.
These findings about papaverine could be a breakthrough in the treatment of diseases like Alzheimer’s, diabetes, and cancer, and even sepsis, which is a critical issue in geriatric medicine and emergency medicine. Prof Tanuma concludes, “Drug repositioning using the in silico drug discovery approach used in our research can repurpose existing drugs into novel therapeutic agents. Also, because the cost of ‘designing’ a novel drug is saved, such approaches can also radically reduce the cost of medical treatment. The next step is to understand the degree to which papaverine blocks HMGB1-RAGE interaction in the human body. We are now trying to optimize the structure of papaverine to design a more ‘effective’ drug for the future.”

Explore further

More information: Kenya Tamada et al, Papaverine identified as an inhibitor of high mobility group box 1/receptor for advanced glycation end-products interaction suppresses high mobility group box 1-mediated inflammatory responses, Biochemical and Biophysical Research Communications (2019). DOI: 10.1016/j.bbrc.2019.01.136Mana Inada et al. Anticancer effects of a non-narcotic opium alkaloid medicine, papaverine, in human glioblastoma cells, PLOS ONE (2019). DOI: 10.1371/journal.pone.0216358

Timing of exercise may be key to successful weight loss

In a study of 375 adults who have successfully maintained weight loss and who engage in moderate-to-vigorous intensity physical activity, most reported consistency in the time of day that they exercised, with early morning being the most common time.
The Obesity study also found that being consistent in the timing of physical activity was associated with higher physical activity levels, regardless of whether people exercised consistently during the morning, afternoon, or evening.
“Our findings warrant future experimental research to determine whether promoting consistency in the time of day that planned and structured physical activity is performed can help individuals achieve and sustain higher levels of physical activity,” said senior author Dale Bond, Ph.D. of the Brown Alpert Medical School. “It will also be important to determine whether there is a specific time of day that is more advantageous for individuals who have initial low physical activity levels to develop a habit,” added first author Leah Schumacher, Ph.D.

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More information: ObesityDOI: 10.1002/oby.22535

Short bout of exercise enhances brain function

Most people know that regular exercise is good for your health. New research shows it may make you smarter, too.
Neuroscientists at OHSU in Portland, Oregon, working with mice, have discovered that a short burst of  directly boosts the function of a gene that increases connections between neurons in the hippocampus, the region of the brain associated with learning and memory.
The research is published online in the journal eLife.
“Exercise is cheap, and you don’t necessarily need a fancy gym membership or have to run 10 miles a day,” said co-senior author Gary Westbrook, M.D., senior scientist at the OHSU Vollum Institute and Dixon Professor of Neurology in the OHSU School of Medicine.
Previous research in animals and in people shows that  promotes general brain health. However, it’s hard to untangle the overall benefits of exercise to the heart, liver and muscles from the specific effect on the brain. For example, a healthy heart oxygenates the whole body, including the brain.
“Previous studies of exercise almost all focus on sustained exercise,” Westbrook said. “As neuroscientists, it’s not that we don’t care about the benefits on the heart and muscles but we wanted to know the brain-specific benefit of exercise.”
So the scientists designed a study in mice that specifically measured the brain’s response to single bouts of exercise in otherwise sedentary mice that were placed for short periods on running wheels. The mice ran a few kilometers in two hours.
The study found that short-term bursts of exercise—the human equivalent of a weekly game of pickup basketball, or 4,000 steps—promoted an increase in synapses in the hippocampus. Scientists made the key discovery by analyzing  that were increased in single neurons activated during exercise.
One particular gene stood out: Mtss1L. This gene had been largely ignored in prior studies in the brain.
“That was the most exciting thing,” said co-lead author Christina Chatzi, Ph.D.
The Mtss1L gene encodes a protein that causes bending of the cell membrane. Researchers discovered that when this gene is activated by short bursts of exercise, it promotes small growths on neurons known as —the site at which synapses form.
In effect, the study showed that an acute burst of exercise is enough to prime the  for learning.
In the next stage of research, scientists plan to pair acute bouts of exercise with learning tasks to better understand the impact on learning and memory.

Explore further

More information: Christina Chatzi et al, Exercise-induced enhancement of synaptic function triggered by the inverse BAR protein, Mtss1L, eLife(2019). DOI: 10.7554/eLife.45920

Genentech: Positive Results in Phase 3 1-dose XOFLUZA in Children With Flu

– The MINISTONE-2 study showed XOFLUZA, given as a new oral suspension, is a well-tolerated and effective potential treatment for the flu in otherwise healthy children aged one to less than 12 years –
– Approximately one in three children develop the flu every year and they are often contagious longer than adults – treating children may therefore help reduce symptoms and prevent the spread of the flu to the wider community –
Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the Phase III MINISTONE-2 study met its primary endpoint, demonstrating that XOFLUZA™ (baloxavir marboxil) was well-tolerated in children with the flu. The study also showed that XOFLUZA is comparable to oseltamivir – a proven effective treatment for children with the flu – at reducing the duration of flu symptoms, including fever. The study assessed XOFLUZA versus an active comparator (oseltamivir) in children aged between one and less than 12 years old with the flu. Full results from MINISTONE-2 will be presented at an upcoming medical meeting.
“Children need new medicines for the flu because they are at higher risk of developing the flu and more likely to have complications such as breathing problems and pneumonia. These flu complications, which in some cases can be fatal, lead to approximately one million children under five being admitted to the hospital globally every year,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “As a one-dose oral suspension medicine, XOFLUZA could potentially provide a convenient treatment option for children with the flu, and we look forward to sharing these data with health authorities around the world.”
The safety and efficacy of XOFLUZA in children with the flu under the age of one is also being studied in the global Phase III MINISTONE-1 study (NCT03653364). XOFLUZA is the first and only one-dose oral medicine approved to treat the flu and the first new flu medicine with a novel proposed mechanism of action approved by the U.S. Food and Drug Administration (FDA) in nearly 20 years. XOFLUZA is also the only flu treatment shown to be efficacious in both otherwise healthy people with the flu (CAPSTONE-1) and people at high risk of complications from the flu (CAPSTONE-2), as well as a preventive measure against developing the flu following exposure to an infected household member (BLOCKSTONE).
XOFLUZA is currently approved in several countries, including Japan for the treatment of influenza types A and B in children, adolescents and adults, and in the U.S. for the treatment of acute, uncomplicated influenza in people 12 years of age and older. In addition, the FDA recently accepted a supplemental New Drug Application (sNDA) for XOFLUZA as a one-dose oral treatment for people at high risk of complications from the flu. The FDA is expected to decide on whether to approve this additional indication by November 4, 2019.

Austria Ban Deals Blow to Bayer

Austrian lawmakers Tuesday banned the key chemical in Roundup — a first in Europe and a fresh blow to Bayer AG, which has lost several lawsuits in the U.S. alleging that the potent herbicide causes cancer.
The German chemicals and pharmaceuticals company completed the acquisition of Roundup inventor Monsanto Co. last year, but saw its share price plummet after a jury ruled against it for the first time. Thousands of cancer patients have since filed similar suits seeking damages.
Lawmakers in Austria were voting on a proposal by the opposition Social Democratic Party to ban use of the chemical glyphosate, the world’s most widely used herbicide, which Bayer insists doesn’t cause cancer if used as indicated.
“We want to be a role model for other countries in the EU and the world, ” said Erwin Preiner, a member of the Austrian parliament for the Social Democrats who worked on the proposed ban.
Bayer is currently facing lawsuits from over 13,000 plaintiffs alleging that Roundup gave them cancer. While the Austrian decision has no direct bearing on the suits and the country is a negligibly small market for Roundup, the ban could complicate Bayer’s public efforts to defend the use of the product as safe and environmentally friendly.
Bayer has argued that regulators around the world, including the U.S. Environmental Protection Agency and the European Chemicals Agency, have declared glyphosate to be safe and not carcinogenic.
But the chemical has faced growing skepticism since a 2015 decision by the International Agency for Research on Cancer, a World Health Organization unit, classifying it as likely having the potential to cause cancer in humans.
Other countries outside of Europe have adopted total and partial glyphosate bans in the past, such as Colombia and El Salvador. Sri Lanka in 2015 was the first country to issue a national ban, but it later revoked the law because the country’s tea exports plummeted.
The vote in Austria came despite glyphosate having been cleared for sale and use in the entire European Union until 2022, which some critics say could make any national ban illegal under EU law.
A report commissioned by Austria’s Ministry for Sustainability and Tourism published Monday concluded that a total ban didn’t conform to EU law. The sponsors of the bill reject this argument, pointing to examples of other member states banning specific compounds. The European Commission has three months to object the Austrian measure, according to a Commission spokeswoman.
Bayer said the Austrian parliament’s decision was contrary to scientific findings on glyphosate, ignored the safety assessment of Austria’s food-safety authority and the existing EU-wide license of the chemical.
“We expect the European Commission to review this decision critically, as it may be inconsistent with mandatory legal and procedural requirements and scientific reasoning,” said a spokesman for Bayer’s crop science unit.
A ban in the small Alpine republic where use of glyphosate-based herbicides amounts to a few hundred tons a year, would have close to no direct impact on Roundup sales, analysts say.
Annual sales of glyphosate herbicides, including by competitors, totaled around $5 billion in 2016, according to Sanford C. Bernstein. The bulk of that is generated in the U.S. and South America, where Bayer relies heavily on selling seeds genetically engineered to resist glyphosate.
But Austria’s move highlights the growing popular and political backlash against the chemical in Bayer’s own European backyard, where protecting the environment is rising up the list of voters’ concerns.
President Emmanuel Macron of France, the EU’s largest grain producer, has pledged to gradually phase out glyphosate and wants to make French vineyards the first glyphosate-free vineyards of the world. Earlier this year, a French court also banned one form of Roundup.
In Germany, Environment Minister Svenja Schulze has proposed a plan for a gradual phasing out of glyphosate. Public railway operator Deutsche Bahn AG, the country’s largest user of glyphosate, said it was setting up a research project to find alternatives to combat weeds along its 33,000 kilometers of tracks.
“We will come to a point where glyphosate isn’t used anymore,” German Chancellor Angela Merkel told the lower house of parliament last week.
All of this could make it harder for the chemical to see its EU clearance renewed in 2022. In 2017, the bloc would likely have banned glyphosate without a last-minute change of tack by Germany, which threw its weight behind the chemical, tilting the balance of the vote. The surprise move prompted grass-roots protests that forced the EU to make the process for authorizing pesticides more transparent.
“People have learned a lot about how pesticides are regulated so the process will be highly scrutinized,” said Nina Holland, a researcher with Corporate Europe Observatory, a Brussels-based think tank that has been fighting glyphosate for years.