Incontinence Drug May Cut Hot Flashes in Breast Cancer Survivors

Hot flashes, a common curse in menopause, can be especially bothersome after breast cancer. But a new study suggests an existing medication may help.

The drug is oxybutynin (Ditropan XL), long used to treat urinary incontinence.

The study found that women taking the medicine had an average of five fewer hot flashes a week, compared with three fewer among women taking a placebo.

“Oxybutynin is an option that can control these symptoms and improve quality of life,” said lead researcher Dr. Roberto Leon-Ferre, an assistant professor of oncology at the Mayo Clinic in Rochester, Minn.

There are a couple of reasons for severe hot flashes after breast cancer. Chemotherapy may induce early menopause, and drugs that reduce estrogen levels may make hot flashes worse, the research team noted.

Hormone replacement therapy, which is often recommended for menopausal symptoms, is generally not advised for breast cancer survivors. That’s left women who can’t take hormones at a disadvantage.

Oxybutynin blocks a substance in the brain, and one of its side effects is decreased sweating, Leon-Ferre noted.

“Because of this, we can take advantage of the ‘side effect’ and decrease involuntary sweating associated with hot flashes, and decrease the hot flashes as well,” he explained.

The drug could be game-changing for certain women, said Dr. Alice Police, regional director of breast surgery at Northwell Health Cancer Institute in Sleepy Hollow, N.Y.

“This is a really important advance in survivorship and compassionate cancer care,” added Police, who wasn’t involved in the study.

Because oxybutynin is already available for other conditions, Leon-Ferre said doctors could prescribe it off-label.

However, he cautioned that its long-term effects aren’t known. Drugs in this class — called anticholinergics — have been linked with mental decline, he said.

For example, the drugs may raise the risk for problems with short-term memory, reasoning and confusion, and may also hike the risk for dementia among older patients, studies indicate.

For the new study, Leon-Ferre and his colleagues randomly assigned 150 women who experienced at least 28 hot flashes a week to oxybutynin or a placebo.

Almost two-thirds were also taking drugs to prevent a return of breast cancer, either tamoxifen or an aromatase inhibitor.

The women were randomly assigned to one of three groups: low-dose oxybutynin twice a day for six weeks; low-dose oxybutynin for one week followed by an increased dose; or a placebo.

Both doses appeared to reduce hot flashes better than the placebo.

And oxybutynin doesn’t interfere with the metabolism of tamoxifen, Leon-Ferre said, calling that an important consideration for breast cancer survivors.

Most insurance covers oxybutynin, and a month’s supply can range from $21 to $42. With insurance, copays would be less, he added.

Side effects included constipation, mild diarrhea, dry mouth, dry eyes, episodes of confusion and difficulty urinating, the researchers found.

Women taking oxybutynin also reported improvement in work, social activities, leisure activities, sleep and overall quality of life.

These are vital issues, Police said. “I will never forget the first time a patient said, ‘Thank you for curing my breast cancer, but you ruined my life,’ ” she said.

The patient said endocrine therapy had caused hot flashes so severe that she could not sleep. As a result, she was having trouble at work and in all other aspects of her life, Police recalled.

“Her intimate relationship was also suffering, as nighttime had become a battleground between her and her internal temperature control,” Police said.

The patient said she was willing to stop her hormone therapy and risk the return of breast cancer rather than live with her current symptoms, she said.

“This study makes me hopeful that these patients may have a way out of their dilemma,” Police said. “Instead of just telling them they should be happy to be alive, we may be able to offer a reliable treatment for some of the debilitating side effects of our treatments for breast cancer.”

The research was scheduled to be presented Friday at the San Antonio Breast Cancer Symposium in Texas. Studies presented at meetings are usually considered preliminary until peer-reviewed for publication in a medical journal.

More information

The U.S. National Cancer Institute has more about hot flashes and cancer survivors.

SOURCES: Roberto Leon-Ferre, M.D., assistant professor, oncology, Mayo Clinic, Rochester, Minn.; Alice Police, M.D., regional director, breast surgery, Northwell Health Cancer Institute, Sleepy Hollow, N.Y.; Dec. 7, 2018, presentation, San Antonio Breast Cancer Symposium, Texas

https://consumer.healthday.com/women-s-health-information-34/menopause-and-postmenopause-news-472/incontinence-drug-may-cut-hot-flashes-in-breast-cancer-survivors-740325.html

Regenerating insulin-producing cells with zinc could tackle base cause of diabetes

Most current diabetes treatments, from insulin injections to newer GLP-1 agonists, don’t solve the underlying cause of the disease. The ability to regenerate insulin-producing cells in the pancreas would do the job, but that has so far proven to be an elusive target. A team of Stanford University scientists is now searching for a solution in a common nutrient: zinc.

As it turns out, insulin-producing beta cells have a particularly strong taste for zinc. The researchers are leveraging that affinity to zinc as a way to guide regenerative medicine towards the cells.

Diabetes happens when the body can’t produce enough insulin, so the study’s senior author, Stanford University endocrinologist Justin Annes, M.D., Ph.D., has been trying to develop drugs that can help regenerate insulin-producing beta cells. His team did find such a candidate recently in a known cancer drug, JNK inhibitor CC-401.

According to Annes’ recent study published in the journal Endocrinology, CC-401 induced beta-cell replication in vitro and in rodents. However, there was one major problem: The drug’s mechanism of action also increased the expression of many genes that are normally suppressed. That touch off an uncontrolled replication of off-target cells, which could cause serious side effects.

So Annes turned his attention to zinc. Scientists know that beta cells take in about 1,000 times more zinc than surrounding cells, and that trait has been used to help scientists visually identify beta cells in pancreatic tissues. That means zinc holds potential as a “lighthouse” for beta-cell regenerative drug, Annes figured.

With help from medicinal chemists, Annes’ team came up with a strategy based on a well-established technique known as chelation, which is generally used to treat lead and mercury poisoning. Chelation involves a drug that clumps with the metals, which can then be excreted from the body.

The Stanford team used a zinc-chelating agent that can accumulate in beta cells and linked it with a beta-cell regenerating therapy. They showed that in rat cells the combo helped the beta cells replicate about 250% more than other cell types. Studies in human cells returned a smaller yet still significant 130% advantage, the team reported in the journal Cell Chemical Biology.

Various ideas for regenerating beta cells are being explored by other scientists as potential treatments or even cures for diabetes. AstraZeneca and Ionis are investigating the use of antisense oligonucleotides in beta cells to silence genes that disrupt insulin production, for example. And scientists at the University of Miami have recently found a source of pancreatic stem cells that can turn into—and therefore replenish—beta cells.

The Stanford team still has a long way to go to prove that their zinc-chelating approach can deliver regenerative therapy. “This is the first demonstration of a selectively delivered replication molecule in beta cells,” said Annes in a statement. One challenge is that zinc is found in cells throughout the body, so there’s a risk that the treatment will find its way to other organs, causing side effects. The researchers plan to work on improving the beta-cell selectivity of the technique in the hopes of further developing it to treat diabetes.

https://www.fiercebiotech.com/research/honing-regenerative-diabetes-drug-zinc

‘Chemo brain’ caused by malfunction in three types of brain cells

More than half of cancer survivors suffer from cognitive impairment from chemotherapy that lingers for months or years after the cancer is gone. In a new study explaining the cellular mechanisms behind this condition, scientists at the Stanford University School of Medicine have demonstrated that a widely used chemotherapy drug, methotrexate, causes a complex set of problems in three major cell types within the brain’s white matter.

The study, which will be published online Dec. 6 in Cell, also identifies a potential remedy. A drug now in clinical trials for other indications reversed symptoms of “chemo brain,” as the condition is known, in a mouse model, the researchers found.

Chemo brain is becoming more common as cancer therapies increasingly allow patients to live many years beyond their diagnoses. There are 15.5 million cancer survivors alive today in the United States, a figure expected to reach 20 million by 2026, according to the National Cancer Institute. But the cognitive side effects of cancer treatment can be debilitating and prolonged: Adults may be unable to return to work, and children often struggle in school.

“It’s wonderful that they’re alive, but their quality of life is really suffering,” said the study’s lead author, Erin Gibson, PhD, a research scientist at Stanford. “If we can do anything to improve that, there is a huge population that could benefit.”

Scientists have long known that drugs like methotrexate impair all of the body’s rapidly dividing cells, but how such drugs affect the function of brain cells has been poorly understood.

“Cognitive dysfunction after cancer therapy is a real and recognized syndrome,” said Michelle Monje, MD, PhD, associate professor of neurology and neurological sciences and the study’s senior author. “In addition to existing symptomatic therapies — which many patients don’t know about — we are now homing in on potential interventions to promote normalization of the disorders induced by cancer drugs. There’s real hope that we can intervene, induce regeneration and prevent damage in the brain.”

Chemo brain is especially severe in childhood cancer patients, Monje added, and children have the most to gain from better remedies.

Inside the white matter

In addition to neurons, which transmit nerve impulses, the brain’s white matter contains other cells that help the neurons function. The research focused on three types of those cells: oligodendrocytes, which produce and maintain myelin, the fatty insulating sheath around nerve fibers; astrocytes, which link neurons to their blood supply, promote proper connections between neurons and maintain the neurons’ environment; and microglia, immune cells that can engulf and destroy foreign invaders in the brain, as well as sculpt neural circuitry.

Comparing postmortem frontal lobe brain tissue from children who had and had not received chemotherapy, the researchers showed that there were far fewer oligodendrocyte lineage cells in the brains of the chemotherapy-treated children.

To figure out what was happening to these cells, the researchers injected young mice with methotrexate at levels designed to replicate human exposures during cancer treatment. The mice received three doses at weekly intervals. Four weeks later, the researchers compared the mice’s brains to those of mice that had not received the drug.

Methotrexate chemotherapy was found to damage the brain’s populations of oligodendrocyte precursor cells. Normally, these cells can quickly divide to replace any that are lost, but after methotrexate was administered, this self-renewal process did not happen correctly. More precursor cells than normal were starting down the path of maturation to oligodendrocytes, but they were getting stuck in an intermediate, immature state. The same problem was seen in mouse brains six months after methotrexate was administered.

Transmission electron microscopy of the mouse brains after methotrexate administration revealed deficiencies in the thickness of the myelin insulation around nerve fibers, similar to changes in the brains of humans who have received chemotherapy. Mice exposed to methotrexate also exhibited behavioral problems after four weeks that were similar to humans with chemo brain, including motor impairment (slower movement of their forepaws), signs of anxiety on an “open field” test used to assess how threatened the animal feels in an unsheltered environment, and impaired attention and short-term memory function, evidenced by the inability to discern between novel and familiar objects — a symptom that persisted for six months after methotrexate was given.

The researchers injected oligodendrocyte precursor cells from healthy animals into the brains of animals that had received methotrexate to see if the cells’ maturation problems were caused by some aspect of the brain environment after chemotherapy. The precursor cells still began maturing at higher-than-normal rates but did not get stuck partway through the maturation process, indicating that the brain environment was partly responsible for the cells’ abnormal maturation.

Microglial activation

Further study showed that microglia, the brain’s immune cells, were persistently activated after methotrexate exposure for at least six months. The activated microglia caused problems for astrocytes, the cells that help neurons get nutrients and function properly. Administering a drug that selectively depleted microglia to mice that had been treated with methotrexate reversed many of the cognitive symptoms of chemo brain and reversed the abnormalities in maturation of oligodendrocyte precursor cells, activation of astrocytes and myelin thickness.

“The biology of this disease really underscores how important intercellular crosstalk is,” Monje said. “Every major neural cell type is affected in this pathophysiology.” She suspects this type of complex dysfunction may also underlie other cognitive disorders. “I think that is probably more the rule than the exception,” she said.

More research is needed to understand exactly how the different cell types are signaling to each other, as well as when and how medications could be best deployed against chemo brain.

“If we understand the cellular and molecular mechanisms that contribute to cognitive dysfunction after cancer therapy, that will help us develop strategies for effective treatment,” Monje said. “It’s an exciting moment.”

The study’s other Stanford co-authors are MD-PhD student Surya Nagaraja; undergraduate students Alfonso Ocampo, Lydia Tam, Andrea Goldstein, Praveen Pallegar and Jacob Greene; former medical student Lauren Wood, MD; postdoctoral scholar Anna Geraghty, PhD; research assistants Lijun Ni and Pamelyn Woo; the late Ben Barres, MD, PhD, professor of neurobiology, of developmental biology and of neurology and neurological sciences; former postdoctoral scholar Shane Liddelow, PhD; and Hannes Vogel, MD, professor of pathology and of pediatrics.

Monje is a member of Stanford Bio-X, the Stanford Maternal and Child Health Research Institute, the Stanford Institute for Stem Cell Biology and Regenerative Medicine, and the Wu Tsai Neurosciences Institute at Stanford. Monje and Vogel are both members of the Stanford Cancer Institute.

The research was funded by the California Institute for Regenerative Medicine, Unravel Pediatric Cancer, the McKenna Claire Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the National Institute of Neurological Disorders and Stroke (grant R01NS092597), the Stanford Medical Scientist Training Program, the Stanford Neuroscience Institute, the Maternal and Child Health Research Institute, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, the Stanford Clinical and Translational Science Award (grant UL1RR025744), Stanford Bio-X, a Katharine McCormick fellowship, the Stanford MedScholars Program, the Christopher and Dana Reeve Foundation, the Novartis Institute for Biomedical Research, the JPB Foundation, the Cure Alzheimer’s Fund, the Glenn Foundation, the Esther B. O’Keeffe Charitable Foundation, the Australian National Health and the Medical Research Council.

Stanford’s Department of Neurology and Neurological Sciences also supported the work.

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Story Source:

Materials provided by Stanford Medicine. Original written by Erin Digitale. Note: Content may be edited for style and length.

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Journal Reference:

1. Erin M. Gibson, Surya Nagaraja, Alfonso Ocampo, Lydia T. Tam, Lauren S. Wood, Praveen N. Pallegar, Jacob J. Greene, Anna C. Geraghty, Andrea K. Goldstein, Lijun Ni, Pamelyn J. Woo, Ben A. Barres, Shane Liddelow, Hannes Vogel, Michelle Monje. Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. Cell, 2018; DOI: 10.1016/j.cell.2018.10.049

https://www.sciencedaily.com/releases/2018/12/181206120032.htm

Exercise test predicts risk of death from cardiovascular disease and cancer

Performance on an exercise test predicts the risk of death from cardiovascular disease, cancer, and other causes, reports a study presented today at EuroEcho-Imaging 2018.1 Good performance on the test equates to climbing three floors of stairs very fast, or four floors fast, without stopping. The findings underline the importance of fitness for longevity.

The study included 12,615 participants with known or suspected coronary artery disease. Participants underwent treadmill exercise echocardiography, in which they were asked to walk or run, gradually increasing the intensity, and continue until exhaustion. The test also generates images of the heart to check its function.

During a median 4.7-year follow-up, there were 1,253 cardiovascular deaths, 670 cancer deaths, and 650 deaths from other causes. After adjusting for age, sex, and other factors that could potentially influence the relationship, each MET (metabolic equivalent)* achieved was independently associated with 9%, 9%, and 4% lower risks of cardiovascular death, cancer death, and other causes of death during follow-up.

The death rate from cardiovascular disease was nearly three times higher in participants with poor compared to good functional capacity (3.2% versus 1.2%, p<0.001). Non-cardiovascular and non-cancer deaths were also nearly three-fold higher in those with poor compared to good functional capacity (1.7% versus 0.6%, p<0.001). Cancer deaths were almost double in participants with poor compared to good functional capacity (1.5% versus 0.8%, p<0.001).

As expected, the imaging part of the examination was predictive of cardiovascular death, but not of deaths caused by cancer or other conditions.

Study author Dr Jesús Peteiro, a cardiologist at University Hospital A Coruña, A Coruña, Spain, said: “Our results provide further evidence of the benefits of exercise and being fit on health and longevity. In addition to keeping body weight down, physical activity has positive effects on blood pressure and lipids, reduces inflammation, and improves the body’s immune response to tumours.”

Dr Peteiro said people do not need to undergo exercise echocardiography to check their fitness level. “There are much cheaper ways to estimate if you could achieve ten METs on the treadmill test,” he said. “If you can walk very fast up three floors of stairs without stopping, or fast up four floors without stopping, you have good functional capacity. If not, it’s a good indication that you need more exercise.”

ESC guidelines recommend at least 150 minutes a week of moderate aerobic physical activity or 75 minutes a week of vigorous aerobic physical activity, or a combination of the two intensities.2

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Story Source:

Materials provided by European Society of Cardiology. Note: Content may be edited for style and length.

https://www.sciencedaily.com/releases/2018/12/181206120043.htm

Novartis: data on Kisqali combo in advanced breast cancer

*Subgroup analyses of three pivotal Phase III MONALEESA trials showed Kisqali plus endocrine therapy extended PFS in all patients with and without visceral involvement compared to endocrine therapy alone; consistent with the overall study populations[3] * In patients with visceral metastasis, increased PFS benefit was seen regardless of burden of disease (=< 3 or > 3 lesions)[3]

* Approximately 41% of postmenopausal women with HR+ advanced breast cancer will develop their first metastasis in visceral organs, such as the lungs or liver, which is often associated with a poor prognosis[1],[2]

Basel, December 8, 2018 – Novartis today announced data from subgroup analyses of the three pivotal Phase III MONALEESA trials showing that Kisqali(®) (ribociclib) plus endocrine therapy extended progression-free survival (PFS) compared to endocrine therapy alone, regardless of the presence of visceral metastases in pre-, peri- and postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer[1]. These data will be presented today at the San Antonio Breast Cancer Symposium (SABCS) (Abstract #P6-18-07).

“Nearly 60% of patients enrolled in the MONALEESA clinical trials had visceral metastases, and all benefited from treatment with ribociclib in combination with endocrine therapy,” said Denise Yardley, MD, Principal Investigator, Sarah Cannon Research Institute. “These results, coupled with the NCCN and ABC4 recommended treatment guidelines for HR+ advanced breast cancer patients with visceral metastases, support the use of ribociclib combination therapy as a standard of care in this patient population.”

In patients with visceral metastases, Kisqali plus endocrine therapy extended median PFS by 11.5 months in MONALEESA-2 (24.9 months vs 13.4 months) and 13.4 months in MONALEESA-7 (23.8 months vs 10.4 months) compared to endocrine therapy alone. Median PFS for patients with visceral metastases in the MONALEESA-3 trial still has not been reached compared to 16.5 months median PFS in patients receiving endocrine therapy alone.

Kisqali plus endocrine therapy demonstrated consistent efficacy across the MONALEESA trials in patients with and without visceral metastases. In patients with visceral metastases and measurable disease, the overall response rate (ORR) in patients who received Kisqali plus endocrine therapy compared to endocrine therapy alone was 53% vs 40% (MONALEESA-2), 50% vs 38% (MONALEESA-7) and 48% vs 31% (MONALEESA-3). Patients without visceral disease showed an ORR of 59% vs 35%, 52% vs 32% and 49% vs 39% in the respective MONALEEA-2, MONALEESA-7 and MONALEESA-3 trials[3].

“Patients living with HR+/HER2- advanced breast cancer who have visceral metastases often have a poorer prognosis and are at higher risk for treatment resistance and disease progression than those without,” said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. “These sub analyses reaffirm that it is critical to treat HR+ advanced breast cancer with a CDK4/6 combination therapy, such as Kisqali plus fulvestrant or an aromatase inhibitor, to give all patients, especially those with visceral metastases, the strongest option for delaying disease progression.”

https://www.marketscreener.com/NOVARTIS-9364983/news/Novartis-data-demonstrates-consistent-efficacy-and-tolerability-of-Kisqali-combination-therapy-in-27726821/

Moderna Declines in Market Debut

Moderna Inc. on Friday lodged one of the worst-performing opening days for a company going public this year, as investors sold the risky biotechnology firm amid broad market declines.

The stock, trading on the Nasdaq Stock Market under the symbol MRNA, dropped 19% to $18.60, well below its initial-public-offering price of $23. That makes it the fifth-worst performer on its first day among all U.S.-listed IPOs this year, according to Dealogic. Its drop was the biggest among companies worth more than $1 billion at the time of their IPO since April 2017, when Carvana Co. fell 26%.

On Thursday, the Cambridge, Mass., company’s stock sale to investors was strong: It sold 26.3 million shares — more than expected — and priced in line with expectations. It raised $604.3 million, giving the company a valuation of more than $7.5 billion.

Launching an IPO into such a rocky stock market was a gamble for Moderna. The S&P 500 has fallen roughly 4% since the company began its roadshow, where management meets with potential investors to pitch the IPO. Moderna’s shares priced Thursday after a late rally nearly erased the day’s prior deep declines. On Friday, the stock selloff deepened.

Still, Moderna’s decline was much sharper than that of the broader markets. It lost nearly a fifth of its value, while the S&P 500 finished the day down 2.3%.

From the start of the roadshow last week, the company and its underwriters assured potential investors they could complete the deal, according to a person familiar with the offering.

One reason for their confidence was the many so-called testing-the-water meetings Moderna management had with fund managers and analysts in the years leading up to the IPO. Some fund managers said they skipped the company’s IPO roadshow because they already understood Moderna’s business from those past meetings.

Moderna’s debut, one of the largest biotechnology IPOs, is considered to be one of the last big deals in a year that has brought in more than 200 new U.S. listings and raised more than $58 billion.

It has also been a banner year for biotech offerings. More than 60 biotech and pharmaceutical companies have listed shares in the U.S. this year, raising $7.1 billion, according to Dealogic. That makes it the second-biggest year on record for the industry and the biggest since 2014.

Moderna, which was founded in 2010, has 21 drug and vaccine research programs, including 10 that have progressed beyond the laboratory and are being tested in humans.

The company has drawn much fanfare, luring investors on the promise that its messenger RNA technology will bring new treatments for cancer, heart disease and other diseases. Critics have raised concerns that there is not much public information out about the company and that some of its programs remain relatively unproven since many are still in the earlier stages of clinical testing.

Before it began trading, Moderna’s IPO process had drawn some controversy. The company disclosed on Tuesday that it had dropped an underwriter, claiming the firm had made “unauthorized communications” about the offering.

https://www.marketscreener.com/MODERNA-INC-47437573/news/Moderna-Declines-in-Market-Debut-WSJ-27726378/

Altria: Seeks Growth With Edgy Bets

Marlboro maker set to invest in vaping, cannabis

Altria Group Inc., faced with slumping cigarette sales and the threat of new federal regulations, is placing some big bets in search of growth beyond dominant its Marlboro brand.

On Friday, the biggest U.S. tobacco company said it would invest $1.8 billion in a Canadian marijuana grower, pushing into a nascent business that is illegal on the federal level in the U.S. but could unlock international markets.

Altria also said it would discontinue its e-cigarette alternatives to its familiar Marlboro, Virginia Slims and Parliament cigarettes. Altria has been developing and marketing e-cigarettes for years but failed to get traction with consumers.

The tobacco company isn’t giving up on the vaping business that threatens to undermine its roughly $20 billion in annual cigarette revenue. Altria is in talks to invest billions of dollars to take a significant stake in Juul Labs Inc., acontroversial but fast-growing San Francisco e-cigarette startup, according to people familiar with the matter.

Although Altria dominates U.S. cigarette sales with 46% of the market, the Richmond, Va., company is under pressure to shift strategies because of the decline in adult smokers and a proposed U.S. ban on menthol-flavored cigarettes. Its shares have declined more than 20% this year.

It has been “an exceedingly challenging year as growth from e-cigarettes, and Juul in particular, seem to finally be weighing on cigarette consumption,” Cowen analyst Vivien Azer said.

For years, Altria and its U.S. rivals have been able to boost profits, despite falling cigarette volumes, by raising prices . But the surge in e-cigarette sales over the past year threatens to further shrink the pool of adult smokers and undercut cigarette pricing.

For the year ended Nov. 17, Altria’s cigarette volumes fell 4.5%, and the rate steepened to 7.6% in the most recent four weeks, according to a Wells Fargo analysis of Nielsen data. Altria’s long-term cigarette volume forecast had been a decline of between 3% and 4%.

Altria CEO Howard Willard, in an October conference call, attributed the accelerated decline to higher gas prices, which reduce discretionary spending, and e-cigarettes’ growing popularity. “It’s hard to tell how long it’s going to persist,” he said of the slide. “I think we’re going to have to wait and see what happens with both gas prices…and whether or not the growth rate of e-vapor slows down.”

A significant investment in Juul, which has captured roughly three-quarters of the U.S. e-cigarette market, would be one way to counter the slide. It would come at a steep price: Juul, with roughly $2 billion in sales, was valued at $16 billion in a funding round over the summer.

Altria’s own e-cigarette brands, MarkTen and Green Smoke, had captured just a small slice of the market. On Friday, Altria said it would take a $200 million charge to discontinue that business and its Verve nicotine gum.

“We do not see a path to leadership with these particular products and believe that now is the time to refocus our resources,” Mr. Willard said in a news release. He said the company is still committed to e-cigarettes and other cigarette alternatives.

Altria is awaiting Food and Drug Administration approval of a heat-not-burn tobacco product called IQOS, which it hopes to market in the U.S. in a partnership with Philip Morris International. The companies say the device is less harmful than cigarettes.

Mr. Willard, a 26-year company veteran, took over as Altria’s chairman and CEO in May. He played a role in the company’s 2009 acquisition of smokeless tobacco company UST Inc. and its 2007 acquisition of cigar maker John Middleton.

Altria’s discussions with Juul have met resistance within the startup, which pitches itself as an alternative to big tobacco but has come under fire for the popularity of its fruit-flavored products with teens. In response to a surge in underage use, the FDA recently announced sharp restrictions on retail sales of such products.

At Juul, some employees are concerned about a partnership with a cigarette maker. At an all-hands meeting Wednesday, Juul’s CEO said the startup wouldn’t do a deal that didn’t align with its mission of helping adult cigarette smokers switch to less harmful products.

Meanwhile, Altria agreed Friday to pay $1.8 billion for a 45% stake in Toronto-based cannabis company Cronos Group Inc. It grows and sells medical and recreational marijuana products mainly in Canada, with smaller medical growing and distribution operations in such countries as Germany and Australia.

Altria and Cronos plan to work together to design vaporizers for cannabis use, according to Cronos CEO Michael Gorenstein. He said vaporizers are one of the fastest growing products in Colorado and California, where pot is legal, and a vaping device is a priority for both companies.

Canada legalized recreational pot sales in October, and a number of other countries have legalized medical marijuana sales.

In the U.S., recreational marijuana is legal in 10 states and medical marijuana is legal in more than 30.

Altria said the cannabis industry “is poised for rapid growth over the next decade” and called cannabis “an adjacent category” for its tobacco operations. Cronos had just US$7.5 million in revenue for the nine months ended Sept. 30.

Cronos is one of several Canadian marijuana growers to attract a big investment from established U.S. companies. In August, Corona brewer Constellation Brands Inc. invested $4 billion to expand its stake in Canopy Growth Inc., which is developing both medical and recreational products.

Altria is paying C$16.25 for each Cronos share, a 40% roughly premium to where the stock was trading last week. Altria has a warrant to buy more Cronos shares at C$19 a share that would give it control of the company with a total stake of 55%. Cronos’s board will be expanded from five directors to seven and Altria will get to nominate four directors.

https://www.marketscreener.com/ALTRIA-GROUP-4837/news/Altria-Seeks-Growth-With-Edgy-Bets-27726373/