Shares of Karyopharm Therapeutics Inc. KPTI, +36.03% soared 36% in very active trade Wednesday, enough to pace the Nasdaq exchange’s gainers, prior to a trading hold for news. The drug maker focused on cancer treatments disclosed after the close that the U.S. Food and Drug Administration has approved oral XPOVIO in combination with dexamethasone for the treatment of relapsed or refactory multiple myeloma in adult patients. Karyopharm expects XPOVIO to become commercially available in the U.S. on or before July 10, 2019. “With today’s accelerated approval of XPOVIO by the FDA, patients with heavily pretreated multiple myeloma will now have a new therapeutic option to treat their disease,” said Chief Scientific Officer Sharon Shacham. The stock can resume trading at 1:35 p.m. Eastern. The stock has still shed 5.1% year to date, while the S&P 500 SPX, +0.77% has gained 19.5%.
Wednesday, July 3, 2019
Fresenius Medical Care Expands Frenova Clinical Research Activities
Fresenius Medical Care AG & Co. KGaA (FME.XE) said Wednesday that it is expanding its clinical-research activities.
The German health-care company said that Frenova Renal Research–a division offering clinical services in the field of kidney research–will be integrated into Fresenius Medical Care’s newly created global medical office and will expand its presence worldwide. Frenova’s activities were previously limited to North America, the company said.
Frenova Renal Research was formerly a subsidiary of Fresenius Medical Care North America.
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 “immune response,” acute and chronic inflammationare associated with serious conditions and diseases like sepsis, 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 chromosomal protein 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 “drugrepositioning” 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 physical activityhabit,” added first author Leah Schumacher, Ph.D.
More information: Obesity, DOI: 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 exercise 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 regular exercise 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 genes 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 dendritic spines—the site at which synapses form.
In effect, the study showed that an acute burst of exercise is enough to prime the brain 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
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