The FDA approves Merck’s (NYSE:MRK) Keytruda (pembrolizumab) as monotherapy for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy (bladder removal).
Wednesday, January 8, 2020
Regular Cannabis Use Linked to Cardiac Abnormalities
Regular recreational use of cannabis is associated with potentially adverse features of left ventricular size and subclinical impairment of left ventricular function, compared with rare or no cannabis use, an observational study concludes.
Previous use of recreational cannabis was not associated with such features, suggesting that any deleterious effects may not be permanent.
“These are early data which included a relatively small group of regular cannabis users, and the changes we detected were subtle,” lead author Mohammed Y. Khanji, MBBCh, PhD, William Harvey Research Institute, NIHR Barts Biomedical Center, Queen Mary University of London, and the Barts Heart Center, St Bartholomew’s Hospital, London, United Kingdom, told theheart.org | Medscape Cardiology.
“However, regular users of cannabis may wish to reduce their intake until further systematic research becomes available which will hopefully provide further insight on the long-term effects of recreational cannabis use,” Khanji said.
The study was published online December 21 as a letter in JACC: Cardiovascular Imaging.
However, at least one observer is not convinced. Steven E. Nissen, MD, Lewis and Patricia Dickey Chair in Cardiovascular Medicine and professor of medicine, Cleveland Clinic, Ohio, disagrees with the authors’ conclusion that healthcare professionals should caution patients on regular use of cannabis.
“This very brief manuscript describes a poorly controlled, observational study suggesting differences in cardiac structure and function in regular cannabis users. The findings are unreliable,” Nissen told theheart.org | Medscape Cardiology.
“There were only 47 regular users, and no amount of adjustment can correct for imbalances in the study groups. To conclude that healthcare professionals and policy makers may need to advise caution on regular recreational cannabis use is not warranted based upon these limited data,” he said.
However, addiction psychiatrist Thersilla Oberbarnscheidt, MD, University of Pittsburgh School of Medicine, Pennsylvania, warned that cannabis has not been properly studied and that regular use can have serious health side effects.
“It has been shown before that the frequent use of marijuana increased the risk of myocardial infarction and hypoxemia, but a direct pathological effect on the heart has not been shown until now,” Oberbarnscheidt told theheart.org | Medscape Cardiology.
“We need more studies to look at the organ toxicity of marijuana,” she said. “In the general population, marijuana is seen as natural and ‘harmless.’ As an addiction psychiatrist, I see many patients who smoke marijuana and are not aware of the toxic effects of that substance,” she said.
Khanji said he hopes his study stimulates further research on the cardiovascular health effects of regular cannabis use as well as discussions on the potential public health implications of recreational cannabis.
“Currently, little or no mention of cannabis exists in guidelines on cardiovascular risk assessments or related lifestyle advice guidelines,” he noted.
“Our study does have some limitations, including the fact that the study group were mainly Caucasians and we relied on self-reported cannabis usage, which may not be very accurate. The number of regular cannabis users in our study was relatively small. It’s also unclear whether the associations observed are due to cannabis use alone or other unmeasured confounding factors,” Khanji said.
Discussions of the potential impact of marijuana legalization on public health are hampered by gaps in evidence and variable quality of available data, he added.
Most Widely Produced and Consumed Recreational Drug
A lot has been published about the deleterious effects of smoking cigarettes, but relatively little is known about the effects of recreational cannabis use, the authors say.
“Our team has a clinical and research interest in the prevention of cardiovascular disease. Cannabis is one of the most widely produced and consumed recreational drugs in the world, with over 192 million global users, and so we felt it was important to determine the cardiovascular implication of cannabis use, particularly given the increasing legalization of recreational cannabis,” senior author Steffen E. Petersen, MD, PhD, professor of cardiovascular medicine, Barts Health NHS Trust, London, said in an interview.
To study the association between cannabis use and cardiac structure and function, the investigators analyzed cardiovascular MRI data from individuals who did not have cardiovascular disease and who were participants in the UK Biobank population study.
They then categorized self-reported cannabis use into following three categories:
- “rare/no,” meaning no use or less than monthly usage of cannabis;
- “previous regular,” defined as weekly or daily usage of cannabis up to 5 years prior to the interview; or
- “current regular,” defined as weekly or daily cannabis usage within 5 years of the interview.
The study included 3407 individuals. The average age was 62 years, and 55% were women. Of the participants, 47 individuals reported being current regular cannabis users, 105 said they were previous regular users, and 3255 said they were rare or nonusers.
Those who were current regular users were more likely to be younger, male, current tobacco smokers, and to have experienced greater levels of social deprivation compared to rare/never users and previous regular users. They were also less likely to be taking medications for hypertension, Khanji noted.
Regular cannabis use was associated with larger left ventricular size and early signs of impairment of heart function compared to rare/never cannabis users.
Compared with rare/never users, after controlling for age, sex, body mass index, systolic blood pressure, use of cholesterol medication, diabetes, smoking, and alcohol consumption, regular cannabis use was associated with the following:
- larger indexed left ventricular end-diastolic volume (+5.31 mL/m2; 95% confidence interval [CI], 1.4 – 9.3 mL/m2; P = .008);
- larger end-systolic volume (+3.3 mL/m2; 95% CI, 0.78 – 5.83 mL/m2; P = .010), and
- impaired global circumferential strain (–0.78; 95% CI, –1.47 to – 0.09; P = .026).
There were no differences between the groups with respect to left ventricular myocardial mass, ejection fraction, and stroke volume, nor for right ventricular, left atrial, and right atrial parameters.
Interestingly, parameters were similar for previous cannabis users and rare/no users. “This is encouraging and may suggest a dose response or that changes may be reversible after stopping use, as seen in cigarette smoking,” Khanji said.
These findings should be interpreted with caution; further research is required to understand the potential pathophysiology and dose-response effects of cannabis use, as well as the long-term implications of regular use on the cardiovascular system, the authors state.
“Health care professionals and policy makers may need to advise caution on regular recreational cannabis use until further systematic research is available,” they conclude.
They point out that cannabis use remains illegal in the United Kingdom, “creating additional barriers to reporting usage.”
Khanji, Oberbarnscheidt, and Nissen report no relevant financial relationships. Petersen reports a financial relationship with Circle Cardiovascular Imaging, Inc, Calgary, Canada, and Servier.
JACC Cardiovasc Imaging. Published online December 21, 2019. Full text
Largest Study So Far on Genital Powder and Ovarian Cancer
Results from the largest reported investigation to date indicate there is no statistically significant association between use of powder in the genital area and the risk for ovarian cancer.
The study did not specify the use of talcum powder, although most powder products do include some mineral talc, the authors note.
This is a highly contentious issue, inasmuch as the potential link between talc and ovarian cancer has fueled high-profile litigation cases against Johnson & Johnson, as previously reported by Medscape Medical News.
The new findings come from a pooled analysis of data in four large US cohorts that was published online January 7 in JAMA.
In an accompanying editorial, Dana R. Gossett, MD, MSCI, of the University of California, San Francisco, and Marcela G. del Carmen, MD, MPH, of Harvard University Medical School in Boston, said these study findings may provide some reassurance.
“The overall conclusion [is] that there is no demonstrable statistically significant association between use of powder in the genital area and ovarian cancer risk,” they write. “This is the key finding of the study.”
However, the finding comes with several key caveats, according to both the study authors and outside experts who were approached for comment by Medscape Medical News.
All agreed that no definitive conclusions can be drawn.
The study may have been underpowered to detect small increases or decreases in ovarian cancer rates, the study authors acknowledge.
“Although this is the largest study ever done, our findings are not definitive,” lead author Katie O’Brien, PhD, of the National Institute of Environmental Health Sciences at Research Triangle Park, North Carolina, told Medscape Medical News. “We cannot make any determinations about causation.”
The findings do suggest a small increased risk for women with an intact reproductive tract, O’Brien noted.
However, the editorialists note that this finding (with a hazard ratio of 1.13) “is below the effect size that epidemiologists generally consider important and should not be selectively highlighted by the statistically unsophisticated reader as evidence of a relationship.”
Patency of the reproductive tract remains a key factor in exposure, experts have pointed out. For a woman who has undergone a hysterectomy or tubal ligation, for instance, a carcinogen that comes into contact with the vulva or vagina could not reach the fallopian tubes and ovaries to cause the local inflammation thought to trigger carcinogenesis.
When approached for comment, Don S. Dizon, MD, professor of medicine at Brown University and director of women’s cancers at Lifespan Cancer Institute in Providence, Rhode Island, emphasized that many factors can affect risk
“This is an example of the difficulties in concluding that any one factor increased the risk of ovarian cancer,” Dizon told Medscape Medical News. “The risk is likely to be multifactorial, and there are far better data to support other factors that also determine risk,” he said. As an example, he cited the protective effects of hormonal therapy and the value of genetic risk evaluation and testing for familial cancer predisposition syndromes.
Dizon noted that the study did show a significant association between the use of genital powder and ovarian cancer risk in the subgroup of women who had a patent reproductive tract.
However, Dizon said he remains unconvinced that there is an increased risk for ovarian cancer from the use of talc body powder in the genital area. Even so, he acknowledged that, “short of definitive proof, which would require a randomized controlled trial, the worry about the risk will always persist.”
When discussing the “hows” and “whys” of an ovarian cancer diagnosis with patients and their families, Dizon said he does not include genital talc powder in the discussion of possible risk factors. He simply acknowledges the lack of conclusive evidence that genital use of talc is or is not associated with the risk for ovarian cancer. “I do think that if women are worried about exposures, simply not using these products make sense,” he said.
Study Details
For the study, the researchers created a cohort of more than 252,745 women using prospective observational data pooled from the Nurses’ Health Study II (NHS II), the Sister Study (SIS), and the Women’s Health Initiative Observational Study (WHI-OS).
The NHS, the WHI-OS, and the SIS previously reported associations between genital use of powder and ovarian cancer risk. The current pooled analysis included updated data from additional cases and longer follow-up, the researchers note.
With a median patient age at baseline of 57 years and a median follow-up of 11.2 years, the analysis showed that 2168 women developed ovarian cancer. Among ever-users of genital powder, the incidence of ovarian cancer was 61 cases/100,000 person-years; among never-users, the incidence was 55 cases/100,000 person-years (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.99 – 1.17). By age 70 years, the estimated difference in ovarian cancer risk between powder users and nonusers was 0.09%.
Analyses across subgroups of women that compared those who had an in situ uterus and fallopian tubes with those who had a nonpatent reproductive tract showed that tests for heterogeneity were not statistically significant for any comparisons (HR, 1.13, vs HR, 0.99; P = .15). When frequent users and never-users with a patent reproductive tract were compared, the analysis showed that the HR was 1.19 (95% CI, 1.03 – 1.37; P for trend = .03).
The editorialists agree that the study may have been underpowered to detect small increases or decreases in ovarian cancer rates. They also point out that the cohort studies from which the data were taken “may have lacked the power to detect a true association given the relative rarity of epithelial ovarian cancer.”
Given the the small number of ovarian cancer cases in a study population with 3.8 million person-years of observation, the editorialists suggest that in future, “analyses would be strengthened by focusing on women with intact reproductive tracts.”
Attention should be paid to the timing and duration of genital powder exposure, they add, but they also note that with the present low rates of genital powder use among US women, collecting sufficient data may not be feasible.
Risk for Women With Greatest Exposure
Another expert who was approached for comment, Daniel W. Cramer, MD, ScD, professor of obstetrics, gynecology, and reproductive biology at Brigham and Women’s Hospital, Harvard Medical School, commented: “This study is by no means the final word on the talc story.
“For those who would say that the overall association is too weak to be of public health importance, this study can say nothing about women who had daily talc use for more than 20 years,” Cramer told Medscape Medical News. “I have argued this is the group of women who are at greatest risk for ovarian cancer from this level of exposure.”
Cramer, who has studied the topic for more than 3 decades and has acted as an expert witness for the prosecution in litigation proceedings, advises women not to use talc for genital hygiene.
The current analysis “does not shed any entirely new light on the topic,” he said. The findings must be taken in context with case-control studies that provide substantial data for a stronger association and a dose-response than cohort studies.
It is already known that the cohort studies find a weaker association between genital talc use and ovarian cancer, Cramer said. Exposure measures that combine both frequency and duration of use are not available in these studies.
Physicians have likely formed an opinion on this topic already, and this study may do little to change their minds, he pointed out. “At least I hope that physicians will not suddenly conclude that an elevated hazards ratio can be ignored simply because the hazard ratio did not reach the somewhat arbitrary bar of 5% but may have said, ‘Yes, the association is real’ if the HR were 1.08.”
Cramer noted that in a 2014 editorial entitled “Talc Use and Ovarian Cancer:Between a Rock and a Hard Place,” one of the current study authors suggests it was unlikely that new conventional epidemiologic studies would be able to settle the issue of causality.
This could soon change, Cramer predicted, noting that “there is some emerging laboratory data that I believe can move the bar.”
The study was funded by the Intramural Research Program of National Institutes of Health, the National Institute of Environmental Health Sciences, the Intramural Research Program of the National Cancer Institute, the US Department of Defense, the National Heart, Lung, and Blood Institute, and the US Department of Health and Human Services. O’Brien has disclosed no relevant financial relationships. Several coauthors of the study have reported relationships with industry. Gossett has reported a relationship with Bayer. Del Carmen has disclosed no relevant financial relationships. Cramer has acted as an expert witness on behalf of users of products that contain talc. Dizon has disclosed no relevant financial relationships.
Teva forks over $54M to settle Copaxone, Azilect kickbacks suit
Teva has plenty of lawsuits on its plate, even after resolving a couple of big opioid cases, but now it’s worked its way past another one.
The drugmaker agreed to pay $54 million to settle a years-old whistleblower lawsuit claiming it paid doctors—as speakers or consultants at “sham” events—to prescribe multiple sclerosis drug Copaxone and Parkinson’s med Azilect.
The drugmaker didn’t immediately respond to a request for comment.
Former Teva sales reps Charles Arnstein and Hossam Senousy sued the company in 2013, alleging the company set up a program to pay doctors to prescribe the drugs through speakers’ fees. The events weren’t educational, though, and only served as a conduit for paying docs to prescribe the drugs, according to the whistleblowers.
The next year, the Justice Department declined to intervene in the lawsuit, and the whistleblowers proceeded on their own. Teva tried to get the lawsuit tossed, but a U.S. judge denied its motion for summary judgment earlier this year. The court found that Teva’s written compliance materials contained “all of the right language,” but that didn’t mean the company followed its own guidelines, the court said.
Both meds were covered by federal health programs, so the lawsuit alleged violations of the False Claims Act and the Anti-Kickback Statute.
The settlement comes as Teva undergoes a years-long restructuring with plans to cut down $3 billion in annual costs and pay down its massive debt load. Meanwhile, Teva agreed to pay $85 million to escape an opioid trial in Oklahoma and has offered billions of dollars of free drugs to resolve a big chunk of nationwide opioid litigation, but so far a deal has not been finalized. The drugmaker also settled opioid suits from two Ohio counties for $20 million plus $25 million in free drugs.
Will Clovis’ Rubraca sales shortfall revive talk of a buyout at JP Morgan?
Last year at the annual J.P. Morgan Healthcare Conference, Clovis Oncology CEO Patrick Mahaffy didn’t mince words in his response to questions about whether he would entertain buyout offers for his company, which was considered a hot target because of its sole marketed product: the PARP inhibitor Rubraca to treat ovarian cancer.
“Everybody knows where to find me and every company in this industry is for sale,” he said at the time.
A year later, Clovis is still an independent company with one product—but it’s a drug that’s struggling to live up to Wall Street’s high expectations. So as Clovis heads to San Francisco for this year’s J.P. Morgan confab, that nagging question about whether the company should hang up a “for sale” sign could very well come up again.
Clovis expects Rubraca sales for the fourth quarter to come in between $38.3 million and $39.3 million, missing the consensus analyst expectation of $40.5 million, it said Tuesday. The company’s stock fell 8.4% to $8.47. The slide followed a turbulent 2019, when Clovis’s shares fell from $24 to $3 before starting a late-year climb that may have been partly fueled by M&A speculation.
One main challenge Clovis continues to battle is competition. Rubraca is approved to treat women with recurrent ovarian cancer who have previously responded to chemotherapy, but Clovis has struggled to set the drug apart from GlaxoSmithKline’s Zejula and AstraZeneca and Merck’s Lynparza.
“Despite impressive data, market growth in [maintenance] settings has been slower than we and the market anticipated,” wrote J.P. Morgan analysts in a note to clients following Clovis’s Tuesday announcement. The firm lowered its Rubraca sales expectations for the year, predicting the drug would pull in about $143 million.
Clovis’s biggest opportunity for growth will hinge on its ability to expand the market for Rubraca. During its announcement, the company said it submitted an application to the FDA for the approval of the drug to treat BRCA-positive prostate cancer in November, following up on an earlier promise to make that filing by the end of 2019.
That gives Rubraca a head start on its rivals in prostate cancer, a lead that Clovis hopes to lock up with positive clinical trial data. The company nabbed a breakthrough designation from the FDA in October 2018 after posting results showing Rubraca produced a 44% response rate in prostate cancer patients with BRCA 1/2 mutations.
Still, success in the prostate cancer market is in no way guaranteed for Clovis. In October of last year, the FDA handed Zejula a breakthrough tag in BRCA-positive prostate cancer based on clinical trial data showing a 41% response rate.
AstraZeneca and Merck are shaping up to be tough contenders in the prostate cancer market, too: They presented data at the recent European Society for Medical Oncology (ESMO) annual meeting showing that Lynparza could reduce the risk of death by 66% in men with prostate cancer that carries either BRCA or ATM mutations. J.P. Morgan declared that data “incrementally negative to Clovis.”
Clovis had plans to expand Rubraca’s target market to include bladder cancer, but it pulled the plug on that strategy last April after preliminary data from a trial of the drug as a solo treatment proved disappointing.
Nevertheless, Clovis’ name continued to pop up as a top target of M&A speculation throughout 2019. Last summer, Evercore ISI analysts listed a potential buyout as a major positive for Clovis in a note they sent to investors. And when RBC Capital Markets analysts asked their clients to name the companies they thought were most likely be taken out, Clovis showed up once again.
So how will Mahaffy respond if he faces the M&A question at this year’s J.P. Morgan conference? Stay tuned. The company is scheduled to present there on January 13.
U.S. cancer death rate drops by largest annual margin ever — report
Researchers on Wednesday reported the largest-ever one-year decline in the U.S. cancer death rate, a drop they credited to advances in lung-tumor treatments.
The overall cancer death rate has been falling about 1.5% a year since 1991. It fell 2.2% from 2016 to 2017, according to the new American Cancer Society report. That’s the largest drop ever seen in national cancer statistics going back to 1930, said Rebecca Siegel, the lead author.
“It’s absolutely driven by lung cancer,” which accounts for about a quarter of all cancer deaths, she said. Take lung cancer out of the mix, and the 2017 rate drop is 1.4%, she added.
Government researchers previously reported a slightly lower drop in the cancer death rate for the same period. But the Cancer Society calculates the death rate differently, and on Wednesday said the decline was larger — and record-setting.
Most lung cancer cases are tied to smoking, and decades of declining smoking rates led to falling rates of lung cancer illnesses and deaths.
But the drop in deaths seems to have been accelerated by recent lung cancer treatment advances, Siegel said.
Experts mainly credit advances in treatment. Topping the list are refinements in surgery, better diagnostic scanning, and more precise use of radiation.
They also celebrate the impact of newer drugs. Genetic testing can now identify specific cancer cell mutations, which allow more targeted therapy using newer pharmaceuticals that are a step beyond traditional chemotherapy.
“It’s an exciting time,” said Dr. Jyoti Patel, a Northwestern University lung cancer expert.
Even patients with late-stage cancers are surviving for several years — rather than months — after treatment starts, she said. “That was very, very uncommon a decade ago,” she said.
New immunotherapy drugs could accelerate the death rate decline, Patel said.
Cancer Society researchers also found:
— The overall cancer death rate fell by nearly 30% from 1991 through 2017.
— Death rates from one type of skin cancer dropped even more dramatically than lung cancer — falling 7% a year recently. That decline in melanoma patients is attributed to drugs that came on the market about nine years ago.
— Declines in the death rates from prostate, breast and colon cancer are slowing, for a range of reasons.
— The rising liver cancer death rate seems to have leveled off somewhat. That may be related to better treatment of hepatitis C infections, which are tied to about 25% of liver cancer cases, Siegel said.
Celgene backs out of $55M settlement over alleged efforts to thwart generics
Bristol-Myers Squibb (BMY +0.5%) unit Celgene has apparently backed out of a $55M settlement that it agreed to in July 2019 over its activities to delay generic encroachment on Revlimid (lenalidomide) and Thalomid (thalidomide).
Class action plaintiffs accused the company of using a mandated safety program to deny samples of the drugs to generic firms, preventing them from conducting equivalency studies to support marketing applications and enabling it to maintain high prices.
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