Scientists find ally in fight against brain tumors: Ebola

Glioblastomas are relentless, hard-to-treat, and often lethal brain tumors. Yale scientists have enlisted a most unlikely ally in efforts to treat this form of cancer—elements of the Ebola virus.

“The irony is that one of the world’s deadliest viruses may be useful in treating one of the deadliest of brain cancers,” said Yale’s Anthony van den Pol, professor of neurosurgery, who describes the Yale efforts Feb. 12 in the Journal of Virology.
The approach takes advantage of a weakness in most cancer tumors and also of an Ebola defense against the immune system response to pathogens.
Unlike normal cells, a large percentage of cancer cells lack the ability to generate an innate immune response against invaders such as viruses. This has led cancer researchers to explore the use of viruses to combat a variety of cancers.
Using viruses carries an obvious risk—they can introduce potentially dangerous infections. To get around this problem, scientists, including van den Pol, have experimented with creating or testing chimeric viruses, or a combination of genes from multiple viruses. They have the ability to target cancer cells without harming patients.
One of the seven genes of the Ebola virus that helps it avoid an immune system response also contributes to its lethality. This intrigued van den Pol.
He and the study’s first author, Xue Zhang, also of Yale, used a chimeric virus containing one of gene from the Ebola virus—a glycoprotein with a mucin-line domain (MLD). In wild-type Ebola virus, the MLD plays a role in hiding Ebola from the immune system. They injected this chimeric virus into the brains of mice with glioblastoma—and found that the MLD helped selectively target and kill deadly glioblastoma brain tumors.
(The team worked with the MLD glycoprotein, not with the full Ebola virus.)
Van den Pol said MLD’s beneficial effect appears to be that it protects normal cells from infection—but not cancer cells, which lack the ability to mount an immune response to pathogens.
A key factor may be that the virus with the glycoprotein MLD replicates less rapidly, potentially making it safer than viruses without the MLD part of the glycoprotein, he said.
In theory, such a virus might be used in conjunction with surgery to eliminate glioblastoma tumors and help prevent a recurrence of cancer, he said.

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Brain tumors may be new targets of Ebola-like virus

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More information: Xue Zhang et al, Mucin-like domain of Ebola virus glycoprotein enhances selective oncolytic actions against brain tumors, Journal of Virology (2020). DOI: 10.1128/JVI.01967-19

https://medicalxpress.com/news/2020-02-scientists-ally-brain-tumors-ebola.html

Treating Sleep Problems in Children With Autism

Identify whether sleep problems in children with autism spectrum disorder (ASD) may be caused by medication or other medical conditions and if so, address these factors, say new recommendations issued this week from the American Academy of Neurology (AAN).
If insomnia and disrupted sleep appear to be more behavioral in nature, a number of strategies may be effective for children and adolescents with autism, advised Ashura Williams Buckley, MD, of the National Institute of Mental Health in Bethesda, Maryland, and co-authors, in a practice guideline published in Neurology.
Up to 40% of children and teens in the general population have sleep problems at some point during childhood, but these typically diminish with age, noted Williams Buckley. But for children and teens with autism, “sleep problems are more common and more likely to persist, resulting in poor health and poor quality of life,” she said in a statement.
While autism symptoms may exacerbate sleep problems, the opposite also may be true, she pointed out. “Sleep problems can make behavioral issues in children and teens with autism even worse,” she said. “That’s why it is important for parents and caregivers to work with healthcare providers to find a way to improve a child’s sleep because we know that good quality sleep can improve overall health and quality of life in all children.”
To develop the guidance, panel members conducted a systematic review of studies about sleep disturbance in children with autism published through December 2017. The review showed a “dearth of evidence-based treatments” for sleep dysregulation in autism, the panelists noted.
Of 1,987 abstracts, 139 were potentially relevant, and 12 met criteria for data extraction. Eight studies were rated Class III or higher and were included in the panel’s review. None examined drug approaches like antidepressants, alpha-adrenergic agonists, benzodiazepines, anti-seizure medicines, or antipsychotics.
Recommendations
The AAN panel’s first recommendation was for healthcare providers to determine whether medications or co-existing conditions underlie sleep problems, and if so, to address them. This is especially important because children with autism have an increased risk of conditions that could contribute to sleep disturbance, such as apnea, epilepsy, depression, anxiety, bipolar disorder, ADHD, and gastrointestinal illness.
The guideline writers also advised clinicians to counsel parents about behavioral strategies, including:

• Setting up a consistent sleep routine with regular bedtimes and wake times
• Developing and adhering to pre-bed calming rituals
• Choosing a bedtime close to the time a child begins to fall asleep

“Behavior-modification strategies are a good place to start because they do not cost anything, there are no side effects, and they have been shown to work for some people,” Williams Buckley pointed out. Family-based cognitive behavioral therapy also may improve aspects of sleep.
If behavioral strategies are not helpful and contributing conditions and medications have been addressed, clinicians should offer melatonin, starting with a low dose. They should advise patients to use a pharmaceutical-grade preparation, if possible. Melatonin is the most commonly dispensed hypnotic drug in children, but melatonin concentrations in over-the-counter formulations differ and some formulations are contaminated with other products like serotonin, they cautioned.
No insomnia drugs are FDA-approved for pediatric use, the guideline authors noted.
Clinicians should counsel patients and parents that melatonin may have adverse effects like morning drowsiness, increased enuresis, headache, or dizziness, and should let them know long-term safety information is lacking.
“Given that many children with ASD use melatonin for months or years, the lack of long-term safety data is concerning,” the authors wrote. “Melatonin affects the hypothalamic–gonadal axis and can potentially influence pubertal development.”
Melatonin alone may be just as helpful for some patients as combining melatonin with behavioral strategies, they added.
Panel members found no evidence that weighted blankets or special mattress technologies improve sleep when used routinely. “If asked about weighted blankets, clinicians should counsel that the trial reported no serious adverse events with blanket use and that blankets could be a reasonable nonpharmacologic approach for some individuals,” they wrote.
Future research is needed about the long-term use of melatonin and about children with ASD and concomitant mood disorders, the authors noted. “Research tying the underlying neurobiology in early-life sleep disruption to behavior might help clinicians and researchers understand which treatments might work for which people with ASD,” they added.

Disclosures

This document was developed with financial support from the American Academy of Neurology.
Authors listed numerous relationships with government agencies, publishing companies, academic centers, and industry.

Primary Source

Neurology

Source Reference: Williams Buckley A, et al “Practice guideline: Treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology” Neurology 2020; DOI: 10.1212/WNL.0000000000009033.

https://www.medpagetoday.com/neurology/autism/84852

Lilly and Novo Nordisk Question FDA’s Draft Guidance on Insulin Biosimilars

In November 2019, the U.S. Food and Drug Administration (FDA) released new draft guidance that would help generic drug companies bring biosimilars to insulin to the market more quickly. And now there are reports that two of the three primary biopharma companies that sell insulin in the U.S. are trying to change that draft guidance.
The key focus of the eight-page draft guidance suggested eliminating the need for comparative clinical immunogenicity studies for potential insulin biosimilars under specific situations. A biosimilar is a generic version of a biologic drug, but because it is not a direct copycat, but is instead “similar,” has to undergo a regulatory pathway very similar to that of branded drugs.
The FDA’s rationale was scientific research suggesting a “lack of clinical impact of immunogenicity with insulin,” and notes that the European Medicines Agency (EMA) made the same recommendation in 2015.
The FDA also stated that there were “decades of clinical experience with approved insulin products, including the lack of a correlation between immunogenicity and safety or effectiveness as reflected in approved product labeling for insulin products.”
The draft guidance was then open for comments from the industry. On January 28, 2020, Novo Nordisk said it had “experienced a circumstance of unexpected immunogenicity in response to a new insulin analog which was encountered during its clinical development.”
It went on to say that this “exemplifies the unpredictable nature of immunogenic reactions in response to insulin formulations. As such, we believe caution needs to be applied regarding the broad assumption” in the draft guidance that argues that “if a comparative analytical assessment based on state-of-the-art technology supports a demonstration of ‘highly similar’ for a proposed biosimilar or interchangeable insulin product, there would be little or no residual uncertainty regarding immunogenicity.”
Eli Lilly argues the FDA should revise the guidance to be more specific about where this immunogenicity testing is applied and when.
“Should FDA intend to apply the Draft Guidance to insulin products which were not approved under a section 505(b)(2) application, Lilly believes that good science dictates some amount of clinical immunogenicity data should be required in order to understand the impact of potential differences in immunogenicity profiles on clinical outcomes,” Lilly stated.
The other big company in the insulins market is Paris-based Sanofi, which did not comment on the draft guidance.
Both companies have been under fire for the price and availability of insulin. In January 2020, Lilly added another lower-priced version of its insulin products to the market in response to the criticism. It is offering cheaper versions of Humalog Mix75/25 KwikPen (insulin lispro protamine and insulin lispro injectable suspension 100 units/mL) and Humalog Junior KwikPen (insulin lispro injection 100 units/mL).
Both will be marked down 50% compared to the branded versions and be made available by mid-April. They are identical to the branded versions and may be substituted at the pharmacy.
This was Lilly’s second attempt at introducing lower-cost insulins. In May 2019, two months after regulatory approval, the company’s authorized generic formulation of Humalog went on sale at a 50% lower price than its branded form of insulin. However, an August analysis indicated patients weren’t getting the cheaper version, partly because of lack of awareness of the product.
All three insulin companies have raised insulin prices significantly over the last 10 years. In 2012, a vial of Lilly’s Humalog went for $130 and in 2016, the price was $255.
Novo Nordisk also launched authorized generics of its insulin products at decreased prices, partly in preparation for biosimilar competition.
https://www.biospace.com/article/lilly-and-novo-nordisk-question-fda-s-draft-guidance-on-insulin-biosimilars/

CVS Swings to Profit, Forecasts 2020 Results in Line With Estimates

CVS Health Corp. turned a profit that beat Wall Street expectations and projected results for 2020 that matched estimates, as it capped its first year of integrating health insurer Aetna Inc.’s operations.
The earnings continued a string of quarters that mark a recovery from a year ago, when CVS’s shares dropped sharply after it offered lackluster 2019 guidance. Shares of CVS rose slightly in trading Wednesday morning on the New York Stock Exchange.
The company also said that the head of its pharmacy-benefits unit, Derica Rice, will leave. His exit comes after the departure earlier this year of Kevin Hourican, the leader of the pharmacy operations, who left to take a CEO job elsewhere.
CVS said Alan Lotvin, currently an executive vice president, will take over the PBM. The company previously said that chief operating officer Jonathan Roberts would temporarily lead the pharmacy unit.
CVS said during a conference call with analysts and investors that it is seeing benefits from its nearly $70 billion takeover of Aetna, which closed in late 2018.
“We have set a clear and bold path for CVS Health to be the most consumer-centric health company, transforming the way care is delivered in the U.S.,” CVS Chief Executive Larry Merlo said. “With over a year of successful integration, we have laid a strong foundation for growth.”
Former Aetna Chief Executive Mark Bertolini, who recently resigned from CVS’s board after publicly saying he was being pushed out, told The Wall Street Journal the integration of the two companies was far from complete.
For 2020, CVS expects per-share earnings from continuing operations of $5.47 to $5.60, or $7.04 to $7.17 on an adjusted basis. It sees operating income of $12.8 billion to $13 billion, or $15.5 billion to $15.8 billion on an adjusted basis.
Analysts polled by FactSet have projected 2020 earnings per share of $5.52, or $7.15 on an adjusted basis.
CVS reported fourth-quarter net income of $1.75 billion, or $1.33 a share, compared with a loss of $419 million, or 37 cents a share, in the comparable quarter a year before. Adjusted earnings were $1.73 a share.
Analysts were looking for earnings of $1.22 a share, or $1.68 a share on an adjusted basis.
CVS said its revenue rose 22.9% to $66.89 billion from the same period the year before as revenue from premiums shot up. Analysts were targeting $63.93 billion.
Revenue in its retail segment, which fulfills prescription medications and sells a range of merchandise, was $22.58 billion, up from $22.03 billion in the year-earlier period. Like competitor Walgreens Boots Alliance Inc., CVS faces pressure on margins in its retail-pharmacy business.
Mr. Merlo said the company’s health-hub stores, which offer a broader array of health services than its traditional pharmacies, are showing higher prescription volume and front-store sales in line with expectations. Yet he didn’t offer financial details on their performance. He said the company would share more information later this year.
CVS is in the process of rolling out around 1,500 of the new stores, which target people with chronic conditions such as diabetes with testing, monitoring and treatment plans.
The company’s health-care benefits business, which includes Aetna, posted revenue of $17.15 billion, up nearly threefold from the prior year. The segment’s medical-loss ratio, which represents the share of premiums paid out in claims, was 85.7% for the quarter.

https://www.marketscreener.com/CVS-HEALTH-CORPORATION-12230/news/CVS-Swings-to-Profit-Forecasts-2020-Results-in-Line-With-Estimates-Update-29987217/

Bayer Strives to End Lawsuits Over Roundup — While Still Selling It

Bayer AG faces an extraordinary challenge as it tries to settle tens of thousands of claims that its Roundup weedkiller causes cancer: The product remains on the shelves, making it almost impossible to put the litigation to rest forever.
Experts say Bayer is in an unusual position compared with other companies that have faced multibillion-dollar lawsuits over their products. To end mass-tort litigation, other companies generally have discontinued or altered their products or added warning labels — all of which are problematic for the German pharmaceutical and agricultural firm.
“If you’re still putting out a product that people claim injures them, I don’t know how they can insulate themselves from future liability,” said Carl Tobias, a University of Richmond law professor who studies product-liability cases. “I think they’re in a bind.”
Bayer is moving closer to a settlement potentially totalling $10 billion, people familiar with the matter said, making it one of the most complex and costly corporate litigation cases ever. Many investors are demanding clarity and expect Bayer to deliver at least a partial solution before the company’s next annual shareholder meeting in late April.
But Bayer’s case is tricky because regulators including the U.S. Environmental Protection Agency have said that glyphosate, the main chemical ingredient in Roundup, doesn’t cause cancer. The agency said last year that manufacturers like Bayer can’t put cancer warnings on glyphosate-based herbicides like Roundup, and that states can’t require such labels. The company also can’t alter the product to remove glyphosate — which plaintiffs claim poses a cancer risk — because it is the herbicide’s main weedkilling chemical.
Bayer has said repeatedly that glyphosate will remain an important product and has applied for re-approval of the chemical in the European Union, where some countries including Germany are banning sales.
Bayer Chief Executive Werner Baumann has said any settlement framework must come “relatively close” to guaranteeing Bayer won’t face a future wave of lawsuits. People familiar with Bayer management’s thinking said the company would take its time to reach such a settlement, even if it angers investors seeking clarity before the annual meeting.
The settlement talks come after Bayer lost its first three trials with juries awarding some $2.4 billion to plaintiffs — later reduced by judges to about $190.5 million. Bayer has appealed, but those processes could take years to play out.
“The trials have gone so spectacularly bad for Bayer that they don’t want to go in front of another jury,” said Adam Zimmerman, a law professor at Loyola Law School, Los Angeles.
Experts said they couldn’t identify another company that has settled yet persisted in selling a product unaltered and without a warning label. Johnson & Johnson has continued selling its talcum powders while defending itself against some 17,000 lawsuits alleging they cause ovarian cancer or mesothelioma, and that J&J failed to properly warn consumers of this purported risk. The company will face similar questions if it decides to settle the cases.
Roundup remains on many hardware store shelves, creating a vast pool of home gardeners who could claim it caused their cancer. Pulling Roundup from the consumer market would cost Bayer about $200 million in annual sales, Bernstein analysts have estimated.
Roundup accounts for around 5% of Bayer’s total sales, the company has estimated — sold mostly to farmers, who have stuck by Roundup despite the cancer litigation.
The Roundup dilemma led investors last year to reject a confidence vote in Mr. Baumann, whom some blamed for the legal problems that followed Bayer’s $63 billion acquisition of biotech seed giant Monsanto Co. in June 2018. Monsanto is the maker of Roundup.
Bayer lost about a third of its market value as the first jury verdicts rolled in. The shares have bounced back since the company and plaintiffs’ attorneys began settlement talks last summer and have agreed along the way to postpone trials. If talks were to collapse and trials resume, Bayer’s share price could get stuck in another rout, analysts say.
Of the $10 billion under consideration in settlement talks, $8 billion would be used to pay current plaintiffs and $2 billion would be set aside as a fund for future claims, according to people familiar with the matter. That would exceed recent big-ticket payouts such as Merck & Co. Inc.’s nearly $5 billion settlement over its painkiller Vioxx and Takeda Pharmaceutical Co. Ltd.’s roughly $2.4 billion settlement over allegations its diabetes drug caused bladder cancer.
Many analysts say a settlement in that range would still be a positive outcome for Bayer. But even then, it is difficult to guarantee such a figure wouldn’t eventually surpass $10 billion, academics and lawyers say. They said the settlement under discussion couldn’t bar future plaintiffs from attempting to sue if they deem the payouts from the $2 billion fund insufficient or if it runs out, potentially exposing Bayer to future liability.
Even if it decided to stop selling Roundup, partially or entirely, plaintiffs could theoretically still sue a few years from now, experts say. Non-Hodgkin lymphoma, the type of cancer plaintiffs say glyphosate causes, can take years to develop.
Experts said certain measures could help discourage future litigants. As part of the settlement, plaintiff attorneys could agree not to advertise and recruit future litigants. The federal judge overseeing the settlement could order that any future litigants each produce their own expert report linking their cancer to Roundup when filing a case. That would be a hurdle for attorneys who file large numbers of cases at once, costing several thousand dollars per expert report.
Bayer could also eventually win its appeals, giving it an upper hand that would discourage future plaintiffs from suing — or even wipe out remaining lawsuits, if a higher court rules that the company can’t warn about a cancer risk that regulators have determined doesn’t exist.
“There is a way to get more peace,” Mr. Zimmerman said. “I just don’t know if it will be global peace.”

https://www.marketscreener.com/BAYER-AG-436063/news/Bayer-Strives-to-End-Lawsuits-Over-Roundup-While-Still-Selling-It-29987691/

NeuroBo up 81%

Thinly traded nano cap NeuroBo Pharmaceuticals (NRBO +81.2%) is up on a 26x surge in volume, albeit on turnover of only 312K shares, on no particular news.

The company, a reverse merger of publicly traded Gemphire Therapeutics and privately held NeuroBo, began trading on December 31, 2019. Shares have rallied almost four-fold since then.

Although no particular news accounts for the action, investors should be wary of a capital raise. NeuroBo closed $24M in Series B financing in July 2019. Gemphire only had $1.9M in cash and equivalents at the end of September 2019.

Funding will be needed to support Phase 3 development of NB-01 for neuropathic pain and early-stage clinical trials for NB-02 for Alzheimer’s disease and tauopathies.

https://seekingalpha.com/news/3541276-neurobo-up-81

CDC tests for coronavirus may be flawed

The WSJ reports that some of the 200 coronavirus test kits developed by the CDC and shipped to U.S. and international laboratories may not work properly.

Some tests may generate “inconclusive” results. The CDC says it will ship new ingredients to labs that encounter problems.

U.S. tally as of today: 420 total suspected samples, 13 positives, 347 negatives and 60 pending.

Selected tickers: CODX, THW, BME, GRX, IXJ, KMED

https://seekingalpha.com/news/3541295-cdc-tests-for-coronavirus-may-be-flawed-wsj