Pharmacology

CHARLOTTE, N.C. – RBX2660 could be a new option for people who experience recurrent, debilitating Clostridioides difficile infections.

Following a standard course of antibiotics, a one-time treatment with RBX2660 was successful for three quarters of participants at 8 weeks, according to a new study. It also prevented additional bouts, with 84% of these initial responders remaining free of C. difficile infection at 6 months.

The ongoing phase 3, open-label PUNCH CD3-OLS study expands on clinical trial experience by treating more “real-world” patients. People who might have been excluded from previous research because of comorbidities, such as irritable bowel syndrome, inflammatory bowel disease, and immunosuppression, were included.

The study also placed no limit on the number of previous rounds of C. difficile infections.

“Even when you expand the patient population to make it more generalizable, we’re still seeing both a high cure rate and a high success rate,” Sahil Khanna, MBBS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minn., said in an interview.

“We also are not seeing any kind of safety signals that can be attributed to this particular product,” he said.

Dr. Khanna presented the findings during the annual meeting of the American College of Gastroenterology, which were also published simultaneously in the journal Drugs. The research by Dr. Khanna and associates received an ACG Outstanding Research Award in the colon category.
 

Study design and results

RBX2660 (Rebyota) is a microbiota-based live biotherapeutic in development from Ferring Pharmaceuticals. The treatment contains human stool collected from prescreened, qualified donors and is prepared according to good manufacturing standards.

After standard-of-care antibiotics and a 72-hour washout period, participants received a single 150-mL dose rectally by enema. RBX2660 is administered by a health care professional.

The median age of study participants was 63 years, with 45% aged 65 years or older, and 70% were women. Overall, 37% of participants had Crohn’s disease and 4% had ulcerative colitis.

At the time of screening, about half of participants had a history of one or two infections with C. difficile, and the remaining half reported three or more episodes.

Of the 402 participants whose outcomes could be analyzed, 75% reported treatment success, meaning no further C. difficile infections at 8 weeks. This was consistent with the 75% of 60 participants free of C. difficile in the interim analysis reported in 2021. Efficacy results were based on a modified intent-to-treat analysis.

Of the 300 participants who responded to RBX2660 at 8 weeks, 262 were followed up to 6 months, with 84% of these reporting no C. difficile recurrence.

“If you succeeded to 8 weeks, there was a high likelihood that you would succeed up to 6 months,” Dr. Khanna said.

For the subset of participants with inflammatory bowel disease, Dr. Khanna noted that the success rates were in the 80% range, which is higher than what is seen in clinic fecal microbiota transplantation programs.
 

Adverse events

Of the participants, 63% reported treatment-emergent adverse events. Most events were mild to moderate in severity, the researchers reported, with diarrhea and abdominal pain being the most common.

“When you look at the treatment-emergent adverse events, it’s important to put them into context in terms of this patient population,” Dr. Khanna said. “This recurrent population has developed underlying gastrointestinal symptoms like abdominal pain, diarrhea, nausea, vomiting, and weight loss.”

Some of these adverse events persist beyond resolution of the C. difficile infection, and the adverse-event profile with RBX2660 is consistent with what is seen following fecal microbiota transplantation, he added.

The serious adverse events “were very, very few,” Dr. Khanna said.

Overall, 11% of participants reported a serious adverse event. The majority were related to the C. difficile infection or an underlying comorbidity, he noted.
 

“Excruciating for patients to deal with”

Traditionally, there could be “some hesitation on the patient’s part [to undergo therapy] just because it’s delivered rectally,” session comoderator Lisa Malter, MD, said in an interview.

However, C. difficile can be “excruciating for patients to deal with,” said Dr. Malter, a gastroenterologist and professor of medicine at New York University Langone Health. They “may be more than willing to take [this agent] because it gets them feeling better.”

“This is a positive adjunct to our current therapies for C. diff in terms of trying to knock it out once a standard course of antibiotics has been administered,” she added.

Currently, people with recurrent C. difficile seek fecal microbiota material from a biobank or from a close friend or loved one.

But Dr. Malter noted that asking someone you know to donate fecal matter for transplantation requires several steps. Donors are screened to make sure they are free of gastrointestinal illness, are not taking any contraindicated medications, and do not have active infection.

Fecal microbiota samples from a biobank are more standardized, but there have been intermittent shutdowns and availability has been limited during the pandemic, she said.

Dr. Malter added that one unanswered question is how much of the colon is covered by therapy delivery via enema compared with colonoscope delivery during fecal microbiota transplantation.

“If it’s delivered colonoscopically, you get the entire colon. In contrast with an enema, you really only hit the left side of the colon,” she said.
 

FDA advisory committee nod

On Sept. 26, the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee reviewed evidence for RBX2660. The committee voted 13 to 4 that data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults following antibiotic treatment for recurrent infections.

Members also voted 12 to 4, with one abstention, that the data were adequate to support the product’s safety.

The FDA often follows its advisory committee recommendations but is not required to do so.

“The hope would be that this would get through the usual FDA pipeline of an approval in the near future,” Dr. Khanna said.

The study was funded by Ferring Pharmaceuticals. Dr. Khanna reported receiving grant and research funding from Ferring. Dr. Malter reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHARLOTTE, N.C. – RBX2660 could be a new option for people who experience recurrent, debilitating Clostridioides difficile infections.

Following a standard course of antibiotics, a one-time treatment with RBX2660 was successful for three quarters of participants at 8 weeks, according to a new study. It also prevented additional bouts, with 84% of these initial responders remaining free of C. difficile infection at 6 months.

The ongoing phase 3, open-label PUNCH CD3-OLS study expands on clinical trial experience by treating more “real-world” patients. People who might have been excluded from previous research because of comorbidities, such as irritable bowel syndrome, inflammatory bowel disease, and immunosuppression, were included.

The study also placed no limit on the number of previous rounds of C. difficile infections.

“Even when you expand the patient population to make it more generalizable, we’re still seeing both a high cure rate and a high success rate,” Sahil Khanna, MBBS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minn., said in an interview.

“We also are not seeing any kind of safety signals that can be attributed to this particular product,” he said.

Dr. Khanna presented the findings during the annual meeting of the American College of Gastroenterology, which were also published simultaneously in the journal Drugs. The research by Dr. Khanna and associates received an ACG Outstanding Research Award in the colon category.
 

Study design and results

RBX2660 (Rebyota) is a microbiota-based live biotherapeutic in development from Ferring Pharmaceuticals. The treatment contains human stool collected from prescreened, qualified donors and is prepared according to good manufacturing standards.

After standard-of-care antibiotics and a 72-hour washout period, participants received a single 150-mL dose rectally by enema. RBX2660 is administered by a health care professional.

The median age of study participants was 63 years, with 45% aged 65 years or older, and 70% were women. Overall, 37% of participants had Crohn’s disease and 4% had ulcerative colitis.

At the time of screening, about half of participants had a history of one or two infections with C. difficile, and the remaining half reported three or more episodes.

Of the 402 participants whose outcomes could be analyzed, 75% reported treatment success, meaning no further C. difficile infections at 8 weeks. This was consistent with the 75% of 60 participants free of C. difficile in the interim analysis reported in 2021. Efficacy results were based on a modified intent-to-treat analysis.

Of the 300 participants who responded to RBX2660 at 8 weeks, 262 were followed up to 6 months, with 84% of these reporting no C. difficile recurrence.

“If you succeeded to 8 weeks, there was a high likelihood that you would succeed up to 6 months,” Dr. Khanna said.

For the subset of participants with inflammatory bowel disease, Dr. Khanna noted that the success rates were in the 80% range, which is higher than what is seen in clinic fecal microbiota transplantation programs.
 

Adverse events

Of the participants, 63% reported treatment-emergent adverse events. Most events were mild to moderate in severity, the researchers reported, with diarrhea and abdominal pain being the most common.

“When you look at the treatment-emergent adverse events, it’s important to put them into context in terms of this patient population,” Dr. Khanna said. “This recurrent population has developed underlying gastrointestinal symptoms like abdominal pain, diarrhea, nausea, vomiting, and weight loss.”

Some of these adverse events persist beyond resolution of the C. difficile infection, and the adverse-event profile with RBX2660 is consistent with what is seen following fecal microbiota transplantation, he added.

The serious adverse events “were very, very few,” Dr. Khanna said.

Overall, 11% of participants reported a serious adverse event. The majority were related to the C. difficile infection or an underlying comorbidity, he noted.
 

“Excruciating for patients to deal with”

Traditionally, there could be “some hesitation on the patient’s part [to undergo therapy] just because it’s delivered rectally,” session comoderator Lisa Malter, MD, said in an interview.

However, C. difficile can be “excruciating for patients to deal with,” said Dr. Malter, a gastroenterologist and professor of medicine at New York University Langone Health. They “may be more than willing to take [this agent] because it gets them feeling better.”

“This is a positive adjunct to our current therapies for C. diff in terms of trying to knock it out once a standard course of antibiotics has been administered,” she added.

Currently, people with recurrent C. difficile seek fecal microbiota material from a biobank or from a close friend or loved one.

But Dr. Malter noted that asking someone you know to donate fecal matter for transplantation requires several steps. Donors are screened to make sure they are free of gastrointestinal illness, are not taking any contraindicated medications, and do not have active infection.

Fecal microbiota samples from a biobank are more standardized, but there have been intermittent shutdowns and availability has been limited during the pandemic, she said.

Dr. Malter added that one unanswered question is how much of the colon is covered by therapy delivery via enema compared with colonoscope delivery during fecal microbiota transplantation.

“If it’s delivered colonoscopically, you get the entire colon. In contrast with an enema, you really only hit the left side of the colon,” she said.
 

FDA advisory committee nod

On Sept. 26, the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee reviewed evidence for RBX2660. The committee voted 13 to 4 that data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults following antibiotic treatment for recurrent infections.

Members also voted 12 to 4, with one abstention, that the data were adequate to support the product’s safety.

The FDA often follows its advisory committee recommendations but is not required to do so.

“The hope would be that this would get through the usual FDA pipeline of an approval in the near future,” Dr. Khanna said.

The study was funded by Ferring Pharmaceuticals. Dr. Khanna reported receiving grant and research funding from Ferring. Dr. Malter reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHARLOTTE, N.C. – RBX2660 could be a new option for people who experience recurrent, debilitating Clostridioides difficile infections.

Following a standard course of antibiotics, a one-time treatment with RBX2660 was successful for three quarters of participants at 8 weeks, according to a new study. It also prevented additional bouts, with 84% of these initial responders remaining free of C. difficile infection at 6 months.

The ongoing phase 3, open-label PUNCH CD3-OLS study expands on clinical trial experience by treating more “real-world” patients. People who might have been excluded from previous research because of comorbidities, such as irritable bowel syndrome, inflammatory bowel disease, and immunosuppression, were included.

The study also placed no limit on the number of previous rounds of C. difficile infections.

“Even when you expand the patient population to make it more generalizable, we’re still seeing both a high cure rate and a high success rate,” Sahil Khanna, MBBS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minn., said in an interview.

“We also are not seeing any kind of safety signals that can be attributed to this particular product,” he said.

Dr. Khanna presented the findings during the annual meeting of the American College of Gastroenterology, which were also published simultaneously in the journal Drugs. The research by Dr. Khanna and associates received an ACG Outstanding Research Award in the colon category.
 

Study design and results

RBX2660 (Rebyota) is a microbiota-based live biotherapeutic in development from Ferring Pharmaceuticals. The treatment contains human stool collected from prescreened, qualified donors and is prepared according to good manufacturing standards.

After standard-of-care antibiotics and a 72-hour washout period, participants received a single 150-mL dose rectally by enema. RBX2660 is administered by a health care professional.

The median age of study participants was 63 years, with 45% aged 65 years or older, and 70% were women. Overall, 37% of participants had Crohn’s disease and 4% had ulcerative colitis.

At the time of screening, about half of participants had a history of one or two infections with C. difficile, and the remaining half reported three or more episodes.

Of the 402 participants whose outcomes could be analyzed, 75% reported treatment success, meaning no further C. difficile infections at 8 weeks. This was consistent with the 75% of 60 participants free of C. difficile in the interim analysis reported in 2021. Efficacy results were based on a modified intent-to-treat analysis.

Of the 300 participants who responded to RBX2660 at 8 weeks, 262 were followed up to 6 months, with 84% of these reporting no C. difficile recurrence.

“If you succeeded to 8 weeks, there was a high likelihood that you would succeed up to 6 months,” Dr. Khanna said.

For the subset of participants with inflammatory bowel disease, Dr. Khanna noted that the success rates were in the 80% range, which is higher than what is seen in clinic fecal microbiota transplantation programs.
 

Adverse events

Of the participants, 63% reported treatment-emergent adverse events. Most events were mild to moderate in severity, the researchers reported, with diarrhea and abdominal pain being the most common.

“When you look at the treatment-emergent adverse events, it’s important to put them into context in terms of this patient population,” Dr. Khanna said. “This recurrent population has developed underlying gastrointestinal symptoms like abdominal pain, diarrhea, nausea, vomiting, and weight loss.”

Some of these adverse events persist beyond resolution of the C. difficile infection, and the adverse-event profile with RBX2660 is consistent with what is seen following fecal microbiota transplantation, he added.

The serious adverse events “were very, very few,” Dr. Khanna said.

Overall, 11% of participants reported a serious adverse event. The majority were related to the C. difficile infection or an underlying comorbidity, he noted.
 

“Excruciating for patients to deal with”

Traditionally, there could be “some hesitation on the patient’s part [to undergo therapy] just because it’s delivered rectally,” session comoderator Lisa Malter, MD, said in an interview.

However, C. difficile can be “excruciating for patients to deal with,” said Dr. Malter, a gastroenterologist and professor of medicine at New York University Langone Health. They “may be more than willing to take [this agent] because it gets them feeling better.”

“This is a positive adjunct to our current therapies for C. diff in terms of trying to knock it out once a standard course of antibiotics has been administered,” she added.

Currently, people with recurrent C. difficile seek fecal microbiota material from a biobank or from a close friend or loved one.

But Dr. Malter noted that asking someone you know to donate fecal matter for transplantation requires several steps. Donors are screened to make sure they are free of gastrointestinal illness, are not taking any contraindicated medications, and do not have active infection.

Fecal microbiota samples from a biobank are more standardized, but there have been intermittent shutdowns and availability has been limited during the pandemic, she said.

Dr. Malter added that one unanswered question is how much of the colon is covered by therapy delivery via enema compared with colonoscope delivery during fecal microbiota transplantation.

“If it’s delivered colonoscopically, you get the entire colon. In contrast with an enema, you really only hit the left side of the colon,” she said.
 

FDA advisory committee nod

On Sept. 26, the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee reviewed evidence for RBX2660. The committee voted 13 to 4 that data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults following antibiotic treatment for recurrent infections.

Members also voted 12 to 4, with one abstention, that the data were adequate to support the product’s safety.

The FDA often follows its advisory committee recommendations but is not required to do so.

“The hope would be that this would get through the usual FDA pipeline of an approval in the near future,” Dr. Khanna said.

The study was funded by Ferring Pharmaceuticals. Dr. Khanna reported receiving grant and research funding from Ferring. Dr. Malter reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Josie Tenore, MD, and Paul Hinds were introduced by a mutual friend in 2017 and hadn’t been going out long when she laid down the law: He had to get a physical.

“I don’t date people who don’t take care of their health,” said Dr. Tenore, who practices cosmetic dermatology and functional medicine in suburban Chicago.

One of Mr. Hinds’ blood tests that summer came back with an alarming result: His prostate-specific antigen (PSA), level was very high. A biopsy confirmed he had advanced prostate cancer.

There aren’t a lot of comfortable alternatives for treating prostate cancer, which generally progresses as long as testosterone levels remain high. Marijuana appears to lower testosterone levels, so after his diagnosis, he dosed a liquid form of cannabis for several weeks. That cut his PSA in half, but Mr. Hinds, a cybersecurity expert who likes yoga and bicycling, “was stoned out of his mind and couldn’t function,” Dr. Tenore recalled.

With Dr. Tenore guiding his decisions, Mr. Hinds next tried high-frequency ultrasound treatment, but it failed. And in the summer of 2019 doctors removed his prostate gland. Still, the PSA levels climbed again, and doctors assessed that the cancer had metastasized. The only alternative was to drastically lower Mr. Hinds’ testosterone levels – either via surgery or drugs that block all testosterone. In May 2021, he got his first intramuscular shot of Lupron Depot, a brand name for leuprolide, designed to suppress the prostate gland’s release of the hormone for 3 months. That August, he got his second shot.

And then the bills came.

The patient: Paul Hinds, now 60, is covered by United Healthcare through a COBRA plan from his former employer.

Medical service: Two 3-month Lupron Depot injections for metastatic prostate cancer.

Service provider: University of Chicago Medicine, a 900-physician nonprofit system that includes an 811-bed medical center, a suburban hospital, the Pritzker School of Medicine, and outpatient clinics and physician offices throughout the Chicago area.

Total bill: $73,812 for the two shots ($35,414 for the first, $38,398 for the second), including lab work and physician charges. United Healthcare’s negotiated rate for the two shots plus associated fees was $27,568, of which the insurer paid $19,567. After Mr. Hinds haggled with the hospital and insurer for more than a year, his share of the bills was determined to be nearly $7,000.

What gives: The first issue is unrelenting price increases on old drugs that have remained branded as manufacturers find ways to extend patents for decades and maintain sales through marketing.

Though Lupron was invented in 1973, its manufacturer got patent extensions in 1989 by offering a slow-release version. Drugmakers commonly use this tactic to extend their exclusive rights to sell a product.

The development of Lupron Depot as an intramuscular shot that suppressed testosterone for months at a time improved patient compliance and also enabled its maker, Abbott Laboratories, and its Japanese partner, Takeda, to extend their patents on the drug into the 2000s, said Gerald Weisberg, MD, a former Abbott scientist who has been critical of the company’s pricing policies.

In subsequent years, Abbott and Takeda, in a joint venture called TAP Pharmaceuticals, steadily marked up the price of their slow-release product. In 2000, the average wholesale U.S. price for a 3-month shot was $1,245; currently that figure is $5,866. (It is manufactured in the United States by AbbVie now.)

In the United Kingdom, where health care is generally free and Takeda sells the drug under the name Prostap, all physicians can purchase a 3-month dose for about $260.

It’s likely that Chicago Medicine, where Mr. Hinds got his shots, paid something close to the British price. That’s because the health system’s hospital on Chicago’s South Side participates in a federal program called 340B, which allows hospitals that serve low-income populations to purchase drugs at deep discounts.

Lupron Depot is given as a simple injection into the muscle. It takes minutes for a nurse or doctor to administer. Yet hospital systems like Chicago Medicine can and typically do charge lavishly for such services, to enhance revenue, said Morgan Henderson, principal data scientist at the Hilltop Institute at the University of Maryland-Baltimore County. Chicago Medicine declined to say what it paid for the drug.

While U.S. drugmakers can price their drugs however they please, TAP has gotten into trouble for its Lupron sales policies in the past. In 2001, after a Justice Department probe, it paid an $875 million settlement for illegally stimulating sales by giving urologists free and discounted vials of the drug while enabling them to charge Medicare full price.

Since then, many other drugs aimed at lowering testosterone levels have entered the market, including a pill, relugolix (Orgovyx). So why wouldn’t a patient use them?

Lupron Depot is long acting, is easy to prepare and store, and employs a small needle, which some patients prefer, said Brian McNeil, MD, chief of urology at University Hospital of Brooklyn. Orgovyx is convenient, but “a patient has to be very compliant. They have to take it every day around the same time,” he said. “Some people just forget.”

But there is another important factor that may well explain Lupron Depot’s ongoing popularity among medical providers: Doctors and hospitals can earn tens of thousands of dollars each visit by marking up its price and administration fees – as they did with Mr. Hinds. If they merely write a prescription for a drug that can be taken at home, they earn nothing.

Asked about this high patient charge and the possibility of using alternatives, United spokesperson Maria Gordon Shydlo said payment was “appropriately based on the hospital’s contract and the member’s benefit plan,” adding that the insurer encourages customers to shop around for the best quality and price.

Resolution: In addition to leaving Mr. Hinds listless, the Lupron Depot shots were, literally, a pain in the rear end. “Each time he was miserable for 2 weeks,” Dr. Tenore said. After looking over his first bill for the Lupron shot, Dr. Tenore told Mr. Hinds he should ask his doctor whether there was a less expensive drug that was easier to take.

After the second shot, in August 2021, a pharmacist told him he could instead receive the pill. His doctor prescribed Mr. Hinds 3 months’ worth of Orgovyx last November, for which he paid $216 and the insurer paid over $6,000. The drug’s list price is about $2,700 a month. There is evidence that Orgovyx works a little better than leuprolide.

Orgovyx was a “no-brainer,” Mr. Hinds said. “Why would you want a sore ass for two weeks when you can take a pill that kicks in sooner, functions the same way, and clears your body of testosterone faster?”

While Orgovyx is increasingly used for prostate cancer, Lupron and other injections usually remain the standard of care, hospital spokesperson Ashley Heher said. Clinicians “work with patients to determine what treatments are the most medically effective and, when necessary, to find reasonable alternatives that may be less financially burdensome due to insurance coverage limitations.”

Mr. Hinds was baffled by the size of the charges. During months of phone calls and emails, the hospital reversed and then reapplied part of the charge, and then in July agreed to a $666.34 monthly payment plan. After Hinds had made two payments, however, the hospital announced Aug. 29 it was canceling the agreement and sending the remainder of his bill to a collection agency. Two weeks later, the hospital reinstated the payment plan – after KHN asked about the cancellation.

As for Mr. Hinds, he remains active, though his bike rides have been shortened from 50 or 60 miles to about 30, he said.

He’s grateful to have Dr. Tenore as a free consultant and empathizes with those who lack a knowledgeable guide through their disease and health care’s financial maze.

“I’ve got Dr. Josie as an advocate who knows the system,” Mr. Hinds said.

The takeaway: First tip: If you are prescribed an infusion or injection, ask your physician if there are cheaper oral medications to treat your condition. Also, many drugs that are given by injection – ones that are given “subcutaneously,” rather than into a muscle – can be administered by a patient at home, avoiding hefty administration fees. Drugs like Dupixent for eczema fall into this category.

Keep in mind that where you get treatment could make a big difference in your charges: A study found that leading U.S. cancer centers charge enormous markups to private insurers for drug injections or infusions. Another study found that hospital systems charge an average of 86% more than private clinics for cancer drug infusions. And the percentage of cancer infusions done in hospital-operated clinics increased from 6% in 2004 to 43% in 2014, and has grown since.

Under a law that took effect in 2021, hospitals are required to list their charges, though they currently do so in a way that is not user friendly. But it’s worth taking a look at the price list – the hospital chargemaster – to try to decipher the pricing and markup for your medicine. If you’re about to get an injection, infusion, or procedure done in a hospital system, ask ahead of time for an estimate of what you will owe.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Josie Tenore, MD, and Paul Hinds were introduced by a mutual friend in 2017 and hadn’t been going out long when she laid down the law: He had to get a physical.

“I don’t date people who don’t take care of their health,” said Dr. Tenore, who practices cosmetic dermatology and functional medicine in suburban Chicago.

One of Mr. Hinds’ blood tests that summer came back with an alarming result: His prostate-specific antigen (PSA), level was very high. A biopsy confirmed he had advanced prostate cancer.

There aren’t a lot of comfortable alternatives for treating prostate cancer, which generally progresses as long as testosterone levels remain high. Marijuana appears to lower testosterone levels, so after his diagnosis, he dosed a liquid form of cannabis for several weeks. That cut his PSA in half, but Mr. Hinds, a cybersecurity expert who likes yoga and bicycling, “was stoned out of his mind and couldn’t function,” Dr. Tenore recalled.

With Dr. Tenore guiding his decisions, Mr. Hinds next tried high-frequency ultrasound treatment, but it failed. And in the summer of 2019 doctors removed his prostate gland. Still, the PSA levels climbed again, and doctors assessed that the cancer had metastasized. The only alternative was to drastically lower Mr. Hinds’ testosterone levels – either via surgery or drugs that block all testosterone. In May 2021, he got his first intramuscular shot of Lupron Depot, a brand name for leuprolide, designed to suppress the prostate gland’s release of the hormone for 3 months. That August, he got his second shot.

And then the bills came.

The patient: Paul Hinds, now 60, is covered by United Healthcare through a COBRA plan from his former employer.

Medical service: Two 3-month Lupron Depot injections for metastatic prostate cancer.

Service provider: University of Chicago Medicine, a 900-physician nonprofit system that includes an 811-bed medical center, a suburban hospital, the Pritzker School of Medicine, and outpatient clinics and physician offices throughout the Chicago area.

Total bill: $73,812 for the two shots ($35,414 for the first, $38,398 for the second), including lab work and physician charges. United Healthcare’s negotiated rate for the two shots plus associated fees was $27,568, of which the insurer paid $19,567. After Mr. Hinds haggled with the hospital and insurer for more than a year, his share of the bills was determined to be nearly $7,000.

What gives: The first issue is unrelenting price increases on old drugs that have remained branded as manufacturers find ways to extend patents for decades and maintain sales through marketing.

Though Lupron was invented in 1973, its manufacturer got patent extensions in 1989 by offering a slow-release version. Drugmakers commonly use this tactic to extend their exclusive rights to sell a product.

The development of Lupron Depot as an intramuscular shot that suppressed testosterone for months at a time improved patient compliance and also enabled its maker, Abbott Laboratories, and its Japanese partner, Takeda, to extend their patents on the drug into the 2000s, said Gerald Weisberg, MD, a former Abbott scientist who has been critical of the company’s pricing policies.

In subsequent years, Abbott and Takeda, in a joint venture called TAP Pharmaceuticals, steadily marked up the price of their slow-release product. In 2000, the average wholesale U.S. price for a 3-month shot was $1,245; currently that figure is $5,866. (It is manufactured in the United States by AbbVie now.)

In the United Kingdom, where health care is generally free and Takeda sells the drug under the name Prostap, all physicians can purchase a 3-month dose for about $260.

It’s likely that Chicago Medicine, where Mr. Hinds got his shots, paid something close to the British price. That’s because the health system’s hospital on Chicago’s South Side participates in a federal program called 340B, which allows hospitals that serve low-income populations to purchase drugs at deep discounts.

Lupron Depot is given as a simple injection into the muscle. It takes minutes for a nurse or doctor to administer. Yet hospital systems like Chicago Medicine can and typically do charge lavishly for such services, to enhance revenue, said Morgan Henderson, principal data scientist at the Hilltop Institute at the University of Maryland-Baltimore County. Chicago Medicine declined to say what it paid for the drug.

While U.S. drugmakers can price their drugs however they please, TAP has gotten into trouble for its Lupron sales policies in the past. In 2001, after a Justice Department probe, it paid an $875 million settlement for illegally stimulating sales by giving urologists free and discounted vials of the drug while enabling them to charge Medicare full price.

Since then, many other drugs aimed at lowering testosterone levels have entered the market, including a pill, relugolix (Orgovyx). So why wouldn’t a patient use them?

Lupron Depot is long acting, is easy to prepare and store, and employs a small needle, which some patients prefer, said Brian McNeil, MD, chief of urology at University Hospital of Brooklyn. Orgovyx is convenient, but “a patient has to be very compliant. They have to take it every day around the same time,” he said. “Some people just forget.”

But there is another important factor that may well explain Lupron Depot’s ongoing popularity among medical providers: Doctors and hospitals can earn tens of thousands of dollars each visit by marking up its price and administration fees – as they did with Mr. Hinds. If they merely write a prescription for a drug that can be taken at home, they earn nothing.

Asked about this high patient charge and the possibility of using alternatives, United spokesperson Maria Gordon Shydlo said payment was “appropriately based on the hospital’s contract and the member’s benefit plan,” adding that the insurer encourages customers to shop around for the best quality and price.

Resolution: In addition to leaving Mr. Hinds listless, the Lupron Depot shots were, literally, a pain in the rear end. “Each time he was miserable for 2 weeks,” Dr. Tenore said. After looking over his first bill for the Lupron shot, Dr. Tenore told Mr. Hinds he should ask his doctor whether there was a less expensive drug that was easier to take.

After the second shot, in August 2021, a pharmacist told him he could instead receive the pill. His doctor prescribed Mr. Hinds 3 months’ worth of Orgovyx last November, for which he paid $216 and the insurer paid over $6,000. The drug’s list price is about $2,700 a month. There is evidence that Orgovyx works a little better than leuprolide.

Orgovyx was a “no-brainer,” Mr. Hinds said. “Why would you want a sore ass for two weeks when you can take a pill that kicks in sooner, functions the same way, and clears your body of testosterone faster?”

While Orgovyx is increasingly used for prostate cancer, Lupron and other injections usually remain the standard of care, hospital spokesperson Ashley Heher said. Clinicians “work with patients to determine what treatments are the most medically effective and, when necessary, to find reasonable alternatives that may be less financially burdensome due to insurance coverage limitations.”

Mr. Hinds was baffled by the size of the charges. During months of phone calls and emails, the hospital reversed and then reapplied part of the charge, and then in July agreed to a $666.34 monthly payment plan. After Hinds had made two payments, however, the hospital announced Aug. 29 it was canceling the agreement and sending the remainder of his bill to a collection agency. Two weeks later, the hospital reinstated the payment plan – after KHN asked about the cancellation.

As for Mr. Hinds, he remains active, though his bike rides have been shortened from 50 or 60 miles to about 30, he said.

He’s grateful to have Dr. Tenore as a free consultant and empathizes with those who lack a knowledgeable guide through their disease and health care’s financial maze.

“I’ve got Dr. Josie as an advocate who knows the system,” Mr. Hinds said.

The takeaway: First tip: If you are prescribed an infusion or injection, ask your physician if there are cheaper oral medications to treat your condition. Also, many drugs that are given by injection – ones that are given “subcutaneously,” rather than into a muscle – can be administered by a patient at home, avoiding hefty administration fees. Drugs like Dupixent for eczema fall into this category.

Keep in mind that where you get treatment could make a big difference in your charges: A study found that leading U.S. cancer centers charge enormous markups to private insurers for drug injections or infusions. Another study found that hospital systems charge an average of 86% more than private clinics for cancer drug infusions. And the percentage of cancer infusions done in hospital-operated clinics increased from 6% in 2004 to 43% in 2014, and has grown since.

Under a law that took effect in 2021, hospitals are required to list their charges, though they currently do so in a way that is not user friendly. But it’s worth taking a look at the price list – the hospital chargemaster – to try to decipher the pricing and markup for your medicine. If you’re about to get an injection, infusion, or procedure done in a hospital system, ask ahead of time for an estimate of what you will owe.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Josie Tenore, MD, and Paul Hinds were introduced by a mutual friend in 2017 and hadn’t been going out long when she laid down the law: He had to get a physical.

“I don’t date people who don’t take care of their health,” said Dr. Tenore, who practices cosmetic dermatology and functional medicine in suburban Chicago.

One of Mr. Hinds’ blood tests that summer came back with an alarming result: His prostate-specific antigen (PSA), level was very high. A biopsy confirmed he had advanced prostate cancer.

There aren’t a lot of comfortable alternatives for treating prostate cancer, which generally progresses as long as testosterone levels remain high. Marijuana appears to lower testosterone levels, so after his diagnosis, he dosed a liquid form of cannabis for several weeks. That cut his PSA in half, but Mr. Hinds, a cybersecurity expert who likes yoga and bicycling, “was stoned out of his mind and couldn’t function,” Dr. Tenore recalled.

With Dr. Tenore guiding his decisions, Mr. Hinds next tried high-frequency ultrasound treatment, but it failed. And in the summer of 2019 doctors removed his prostate gland. Still, the PSA levels climbed again, and doctors assessed that the cancer had metastasized. The only alternative was to drastically lower Mr. Hinds’ testosterone levels – either via surgery or drugs that block all testosterone. In May 2021, he got his first intramuscular shot of Lupron Depot, a brand name for leuprolide, designed to suppress the prostate gland’s release of the hormone for 3 months. That August, he got his second shot.

And then the bills came.

The patient: Paul Hinds, now 60, is covered by United Healthcare through a COBRA plan from his former employer.

Medical service: Two 3-month Lupron Depot injections for metastatic prostate cancer.

Service provider: University of Chicago Medicine, a 900-physician nonprofit system that includes an 811-bed medical center, a suburban hospital, the Pritzker School of Medicine, and outpatient clinics and physician offices throughout the Chicago area.

Total bill: $73,812 for the two shots ($35,414 for the first, $38,398 for the second), including lab work and physician charges. United Healthcare’s negotiated rate for the two shots plus associated fees was $27,568, of which the insurer paid $19,567. After Mr. Hinds haggled with the hospital and insurer for more than a year, his share of the bills was determined to be nearly $7,000.

What gives: The first issue is unrelenting price increases on old drugs that have remained branded as manufacturers find ways to extend patents for decades and maintain sales through marketing.

Though Lupron was invented in 1973, its manufacturer got patent extensions in 1989 by offering a slow-release version. Drugmakers commonly use this tactic to extend their exclusive rights to sell a product.

The development of Lupron Depot as an intramuscular shot that suppressed testosterone for months at a time improved patient compliance and also enabled its maker, Abbott Laboratories, and its Japanese partner, Takeda, to extend their patents on the drug into the 2000s, said Gerald Weisberg, MD, a former Abbott scientist who has been critical of the company’s pricing policies.

In subsequent years, Abbott and Takeda, in a joint venture called TAP Pharmaceuticals, steadily marked up the price of their slow-release product. In 2000, the average wholesale U.S. price for a 3-month shot was $1,245; currently that figure is $5,866. (It is manufactured in the United States by AbbVie now.)

In the United Kingdom, where health care is generally free and Takeda sells the drug under the name Prostap, all physicians can purchase a 3-month dose for about $260.

It’s likely that Chicago Medicine, where Mr. Hinds got his shots, paid something close to the British price. That’s because the health system’s hospital on Chicago’s South Side participates in a federal program called 340B, which allows hospitals that serve low-income populations to purchase drugs at deep discounts.

Lupron Depot is given as a simple injection into the muscle. It takes minutes for a nurse or doctor to administer. Yet hospital systems like Chicago Medicine can and typically do charge lavishly for such services, to enhance revenue, said Morgan Henderson, principal data scientist at the Hilltop Institute at the University of Maryland-Baltimore County. Chicago Medicine declined to say what it paid for the drug.

While U.S. drugmakers can price their drugs however they please, TAP has gotten into trouble for its Lupron sales policies in the past. In 2001, after a Justice Department probe, it paid an $875 million settlement for illegally stimulating sales by giving urologists free and discounted vials of the drug while enabling them to charge Medicare full price.

Since then, many other drugs aimed at lowering testosterone levels have entered the market, including a pill, relugolix (Orgovyx). So why wouldn’t a patient use them?

Lupron Depot is long acting, is easy to prepare and store, and employs a small needle, which some patients prefer, said Brian McNeil, MD, chief of urology at University Hospital of Brooklyn. Orgovyx is convenient, but “a patient has to be very compliant. They have to take it every day around the same time,” he said. “Some people just forget.”

But there is another important factor that may well explain Lupron Depot’s ongoing popularity among medical providers: Doctors and hospitals can earn tens of thousands of dollars each visit by marking up its price and administration fees – as they did with Mr. Hinds. If they merely write a prescription for a drug that can be taken at home, they earn nothing.

Asked about this high patient charge and the possibility of using alternatives, United spokesperson Maria Gordon Shydlo said payment was “appropriately based on the hospital’s contract and the member’s benefit plan,” adding that the insurer encourages customers to shop around for the best quality and price.

Resolution: In addition to leaving Mr. Hinds listless, the Lupron Depot shots were, literally, a pain in the rear end. “Each time he was miserable for 2 weeks,” Dr. Tenore said. After looking over his first bill for the Lupron shot, Dr. Tenore told Mr. Hinds he should ask his doctor whether there was a less expensive drug that was easier to take.

After the second shot, in August 2021, a pharmacist told him he could instead receive the pill. His doctor prescribed Mr. Hinds 3 months’ worth of Orgovyx last November, for which he paid $216 and the insurer paid over $6,000. The drug’s list price is about $2,700 a month. There is evidence that Orgovyx works a little better than leuprolide.

Orgovyx was a “no-brainer,” Mr. Hinds said. “Why would you want a sore ass for two weeks when you can take a pill that kicks in sooner, functions the same way, and clears your body of testosterone faster?”

While Orgovyx is increasingly used for prostate cancer, Lupron and other injections usually remain the standard of care, hospital spokesperson Ashley Heher said. Clinicians “work with patients to determine what treatments are the most medically effective and, when necessary, to find reasonable alternatives that may be less financially burdensome due to insurance coverage limitations.”

Mr. Hinds was baffled by the size of the charges. During months of phone calls and emails, the hospital reversed and then reapplied part of the charge, and then in July agreed to a $666.34 monthly payment plan. After Hinds had made two payments, however, the hospital announced Aug. 29 it was canceling the agreement and sending the remainder of his bill to a collection agency. Two weeks later, the hospital reinstated the payment plan – after KHN asked about the cancellation.

As for Mr. Hinds, he remains active, though his bike rides have been shortened from 50 or 60 miles to about 30, he said.

He’s grateful to have Dr. Tenore as a free consultant and empathizes with those who lack a knowledgeable guide through their disease and health care’s financial maze.

“I’ve got Dr. Josie as an advocate who knows the system,” Mr. Hinds said.

The takeaway: First tip: If you are prescribed an infusion or injection, ask your physician if there are cheaper oral medications to treat your condition. Also, many drugs that are given by injection – ones that are given “subcutaneously,” rather than into a muscle – can be administered by a patient at home, avoiding hefty administration fees. Drugs like Dupixent for eczema fall into this category.

Keep in mind that where you get treatment could make a big difference in your charges: A study found that leading U.S. cancer centers charge enormous markups to private insurers for drug injections or infusions. Another study found that hospital systems charge an average of 86% more than private clinics for cancer drug infusions. And the percentage of cancer infusions done in hospital-operated clinics increased from 6% in 2004 to 43% in 2014, and has grown since.

Under a law that took effect in 2021, hospitals are required to list their charges, though they currently do so in a way that is not user friendly. But it’s worth taking a look at the price list – the hospital chargemaster – to try to decipher the pricing and markup for your medicine. If you’re about to get an injection, infusion, or procedure done in a hospital system, ask ahead of time for an estimate of what you will owe.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

New efficacy and safety data from the monarchE study show that chemotherapy administered before treatment with abemaciclib and estrogen therapy, led to a clinically meaningful improvement in invasive disease-free survival and distant relapse-free survival for women with HR-positive, ERBB2-negative, node-positive, early breast cancer at high risk of recurrence.

The study was published earlier this year in JAMA Oncology.

Neoadjuvant chemotherapy is often provided to such patients in hopes of achieving breast-conserving surgery. Although pathologic complete response rates can be higher than 50% after chemotherapy treatment in triple-negative and ERBB2-positive breast cancer, most patients with HR-positive and ERBB2-negative breast cancer have residual tumor at surgery after neoadjuvant chemotherapy, which is associated with an increased risk of recurrence.

Adjuvant estrogen therapy can reduce the risk of recurrence in this population, but a significant hazard remains.

“To our knowledge, abemaciclib is the first agent added to standard adjuvant estrogen therapy that has been shown to reduce the risk of recurrence in patients with HR-positive, ERBB2-negative early breast cancer with residual disease after neoadjuvant chemotherapy,” wrote the authors, who were led by Miguel Martin, MD, PhD, Hospital General Universitario Gregorio Marañon, Spain.

In 2021, Food and Drug Administration approved abemaciclib (Verzenio, Lilly) with endocrine therapy for the treatment of HR-positive/ERBB2-negative, node-positive, high-risk early breast cancer. Their decision was based on data from the monarchE study.

The study is at odds with the previously published Penelope-B study, which found no benefit from treatment with the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) after 42.8 months of follow-up. The authors suggest that the disparate outcomes may be due to pharmacological differences between the two drugs as well as different dosing schedules: In monarchE, patients received abemaciclib on a continuous basis, while patients in Penelope-B received palbociclib for 21 days, followed by 7 days off. The treatment duration was 2 years in monarchE and 1 year in Penelope-B. Abemaciclib can be dosed continuously because it is a stronger inhibitor of CDK4 versus CDK6 compared to abemaciclib, and in vitro studies suggest that continuous dosing could be a key factor in creating profound inhibition of DNA synthesis.

The monarchE study included 5,637 patients who were randomized to receive standard of care estrogen therapy for 5 years with or without abemaciclib (150 mg, twice per day) for 2 years; 36.5% received abemaciclib. The mean age was 49.9 years; 70.8% were White, 22.8% Asian, and 2.7% Black.

The abemaciclib group had a clinically and statistically significant benefit in invasive disease-free survival (IDFS) (hazard ratio, 0.61; nominal P < .001) and distant relapse-free survival (DRFS) (HR, 0.61; nominal P < .001). At 2 years, DRFS was 89.5% in the abemaciclib group and 82.8% in the estrogen therapy–only group. IDFS was 87.2% and 80.6%, respectively. Patients who underwent neoadjuvant chemotherapy had a similar safety profile to the estrogen therapy–only group, although there was a higher incidence of treatment-emergent adverse events. The most common were diarrhea, infections, neutropenia, and fatigue. The most frequent grade treatment-emergent adverse events (of at least 3) were neutropenia and leucopenia.

The researchers noted that patients who underwent neoadjuvant chemotherapy had a worse prognosis than the intent-to-treat arm, as evidenced by a higher risk of 2-year recurrence (19% versus 11%). Exploratory subgroup analyses revealed that treatment with abemaciclib and estrogen therapy conferred IDFS and DRFS benefits regardless of the pathological tumor size and number of positive axillary lymph nodes.

The study was limited by the fact that it was open label, and the subgroup analyses were not powered to find statistically significant associations.

Dr. Martin has received grants from Eli Lilly, which funded monarchE.

New efficacy and safety data from the monarchE study show that chemotherapy administered before treatment with abemaciclib and estrogen therapy, led to a clinically meaningful improvement in invasive disease-free survival and distant relapse-free survival for women with HR-positive, ERBB2-negative, node-positive, early breast cancer at high risk of recurrence.

The study was published earlier this year in JAMA Oncology.

Neoadjuvant chemotherapy is often provided to such patients in hopes of achieving breast-conserving surgery. Although pathologic complete response rates can be higher than 50% after chemotherapy treatment in triple-negative and ERBB2-positive breast cancer, most patients with HR-positive and ERBB2-negative breast cancer have residual tumor at surgery after neoadjuvant chemotherapy, which is associated with an increased risk of recurrence.

Adjuvant estrogen therapy can reduce the risk of recurrence in this population, but a significant hazard remains.

“To our knowledge, abemaciclib is the first agent added to standard adjuvant estrogen therapy that has been shown to reduce the risk of recurrence in patients with HR-positive, ERBB2-negative early breast cancer with residual disease after neoadjuvant chemotherapy,” wrote the authors, who were led by Miguel Martin, MD, PhD, Hospital General Universitario Gregorio Marañon, Spain.

In 2021, Food and Drug Administration approved abemaciclib (Verzenio, Lilly) with endocrine therapy for the treatment of HR-positive/ERBB2-negative, node-positive, high-risk early breast cancer. Their decision was based on data from the monarchE study.

The study is at odds with the previously published Penelope-B study, which found no benefit from treatment with the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) after 42.8 months of follow-up. The authors suggest that the disparate outcomes may be due to pharmacological differences between the two drugs as well as different dosing schedules: In monarchE, patients received abemaciclib on a continuous basis, while patients in Penelope-B received palbociclib for 21 days, followed by 7 days off. The treatment duration was 2 years in monarchE and 1 year in Penelope-B. Abemaciclib can be dosed continuously because it is a stronger inhibitor of CDK4 versus CDK6 compared to abemaciclib, and in vitro studies suggest that continuous dosing could be a key factor in creating profound inhibition of DNA synthesis.

The monarchE study included 5,637 patients who were randomized to receive standard of care estrogen therapy for 5 years with or without abemaciclib (150 mg, twice per day) for 2 years; 36.5% received abemaciclib. The mean age was 49.9 years; 70.8% were White, 22.8% Asian, and 2.7% Black.

The abemaciclib group had a clinically and statistically significant benefit in invasive disease-free survival (IDFS) (hazard ratio, 0.61; nominal P < .001) and distant relapse-free survival (DRFS) (HR, 0.61; nominal P < .001). At 2 years, DRFS was 89.5% in the abemaciclib group and 82.8% in the estrogen therapy–only group. IDFS was 87.2% and 80.6%, respectively. Patients who underwent neoadjuvant chemotherapy had a similar safety profile to the estrogen therapy–only group, although there was a higher incidence of treatment-emergent adverse events. The most common were diarrhea, infections, neutropenia, and fatigue. The most frequent grade treatment-emergent adverse events (of at least 3) were neutropenia and leucopenia.

The researchers noted that patients who underwent neoadjuvant chemotherapy had a worse prognosis than the intent-to-treat arm, as evidenced by a higher risk of 2-year recurrence (19% versus 11%). Exploratory subgroup analyses revealed that treatment with abemaciclib and estrogen therapy conferred IDFS and DRFS benefits regardless of the pathological tumor size and number of positive axillary lymph nodes.

The study was limited by the fact that it was open label, and the subgroup analyses were not powered to find statistically significant associations.

Dr. Martin has received grants from Eli Lilly, which funded monarchE.

New efficacy and safety data from the monarchE study show that chemotherapy administered before treatment with abemaciclib and estrogen therapy, led to a clinically meaningful improvement in invasive disease-free survival and distant relapse-free survival for women with HR-positive, ERBB2-negative, node-positive, early breast cancer at high risk of recurrence.

The study was published earlier this year in JAMA Oncology.

Neoadjuvant chemotherapy is often provided to such patients in hopes of achieving breast-conserving surgery. Although pathologic complete response rates can be higher than 50% after chemotherapy treatment in triple-negative and ERBB2-positive breast cancer, most patients with HR-positive and ERBB2-negative breast cancer have residual tumor at surgery after neoadjuvant chemotherapy, which is associated with an increased risk of recurrence.

Adjuvant estrogen therapy can reduce the risk of recurrence in this population, but a significant hazard remains.

“To our knowledge, abemaciclib is the first agent added to standard adjuvant estrogen therapy that has been shown to reduce the risk of recurrence in patients with HR-positive, ERBB2-negative early breast cancer with residual disease after neoadjuvant chemotherapy,” wrote the authors, who were led by Miguel Martin, MD, PhD, Hospital General Universitario Gregorio Marañon, Spain.

In 2021, Food and Drug Administration approved abemaciclib (Verzenio, Lilly) with endocrine therapy for the treatment of HR-positive/ERBB2-negative, node-positive, high-risk early breast cancer. Their decision was based on data from the monarchE study.

The study is at odds with the previously published Penelope-B study, which found no benefit from treatment with the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) after 42.8 months of follow-up. The authors suggest that the disparate outcomes may be due to pharmacological differences between the two drugs as well as different dosing schedules: In monarchE, patients received abemaciclib on a continuous basis, while patients in Penelope-B received palbociclib for 21 days, followed by 7 days off. The treatment duration was 2 years in monarchE and 1 year in Penelope-B. Abemaciclib can be dosed continuously because it is a stronger inhibitor of CDK4 versus CDK6 compared to abemaciclib, and in vitro studies suggest that continuous dosing could be a key factor in creating profound inhibition of DNA synthesis.

The monarchE study included 5,637 patients who were randomized to receive standard of care estrogen therapy for 5 years with or without abemaciclib (150 mg, twice per day) for 2 years; 36.5% received abemaciclib. The mean age was 49.9 years; 70.8% were White, 22.8% Asian, and 2.7% Black.

The abemaciclib group had a clinically and statistically significant benefit in invasive disease-free survival (IDFS) (hazard ratio, 0.61; nominal P < .001) and distant relapse-free survival (DRFS) (HR, 0.61; nominal P < .001). At 2 years, DRFS was 89.5% in the abemaciclib group and 82.8% in the estrogen therapy–only group. IDFS was 87.2% and 80.6%, respectively. Patients who underwent neoadjuvant chemotherapy had a similar safety profile to the estrogen therapy–only group, although there was a higher incidence of treatment-emergent adverse events. The most common were diarrhea, infections, neutropenia, and fatigue. The most frequent grade treatment-emergent adverse events (of at least 3) were neutropenia and leucopenia.

The researchers noted that patients who underwent neoadjuvant chemotherapy had a worse prognosis than the intent-to-treat arm, as evidenced by a higher risk of 2-year recurrence (19% versus 11%). Exploratory subgroup analyses revealed that treatment with abemaciclib and estrogen therapy conferred IDFS and DRFS benefits regardless of the pathological tumor size and number of positive axillary lymph nodes.

The study was limited by the fact that it was open label, and the subgroup analyses were not powered to find statistically significant associations.

Dr. Martin has received grants from Eli Lilly, which funded monarchE.

Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.

While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.

“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.

Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.

American Heart Association

The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.

Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.

“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”

In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.

At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).

“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.

Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
 

Causal mechanisms deserve a closer look

Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.

“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”

Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.

Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.

“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”

Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.

“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”

Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.

“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”

The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.

Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.

While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.

“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.

Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.

American Heart Association

The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.

Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.

“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”

In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.

At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).

“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.

Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
 

Causal mechanisms deserve a closer look

Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.

“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”

Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.

Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.

“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”

Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.

“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”

Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.

“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”

The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.

Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.

While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.

“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.

Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.

American Heart Association

The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.

Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.

“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”

In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.

At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).

“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.

Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
 

Causal mechanisms deserve a closer look

Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.

“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”

Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.

Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.

“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”

Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.

“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”

Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.

“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”

The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.

The results of a phase 2 clinical trial of durvalumab with add-on therapies oleclumab or monalizumab, suggest this novel combination may prove beneficial in patients with unresectable stage 3 non–small-cell lung cancer.

Combinations of the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab led to improved overall response rate and progression-free survival compared to durvalumab alone.

The findings support further study in a phase 3 clinical trial, according to the authors of the study recently published in the Journal of Clinical Oncology.

Durvalumab is the standard treatment following consolidation therapy of chemoradiotherapy in unresectable stage 3 non–small-cell lung cancer (NSCLC). Although it extended progression-free survival (PFS) and overall survival in the PACIFIC phase 3 study, some patients experience a recurrence, which has led to exploration of immunotherapy combinations.

Oleclumab inhibits the enzyme CD73, found on the surfaces of both tumor and immune cells. Its activity leads to an immunosuppressive effect in the tumor microenvironment, and preclinical studies have shown that it can have an additive antitumor effect when combined with PD-1 or PD-L1 inhibitors. A phase 1 study also suggested efficacy. Monalizumab blocks interactions between major histocompatibility complex-E (HLA-E) and an inhibitor receptor. A number of tumors overexpress HLA-E, triggering inhibitor signals that inhibit natural killer and CD8+ T cells.

“COAST was an interesting study that, although not definitive, suggested that the combination of durvalumab with oleclumab or with monalizumab was more effective than durvalumab alone in the consolidation setting after definitive concurrent chemoradiation for patients with stage 3 unresectable NSCLC,” said Nathan Pennell, MD, PhD, who wrote an accompanying editorial.

Despite the positive signal, Dr. Pennell expressed some skepticism that the combinations would pass a phase 3 test. He questioned the choice of response rate as the primary endpoint of the phase 2 study, and noted that the durvalumab arm had worse progression-free survival (PFS) than the previous PACIFIC trial. It could be that the clinical characteristics of the study population differed between the two trials, in which case the improved objective response rate (ORR) and PFS results should be encouraging. It’s also possible the COAST trial’s small sample size led to a mismatch between the control and treatment group despite randomization, in which case the findings may not be valid.

“These are the kinds of issues that keep drug developers up at night. There really is no way to know which scenario is correct without doing the larger trial. I do hope though that the phase 3 trials have robust biomarker analysis including PDL1 to make sure the arms are as well matched for known prognostic and predictive markers as possible,” said Dr. Pennell, who is vice chair of clinical research at Taussig Cancer Institute.
 

The study details

The researchers randomized 189 patients to durvalumab, durvalumab plus oleclumab, or durvalumab plus monalizumab between January 2019 and July 2020. After a median follow-up of 11.5 months, there was a higher confirmed objective response rate in the durvalumab plus oleclumab group (30.0%; 95% confidence interval, 18.8%-43.2%) and the durvalumab plus monalizumab group (35.5%; 95% CI, 23.7%-48.7%) versus durvalumab alone (17.9%; 95% CI, 9.6%-29.2%).

Compared to durvalumab alone, there was improved PFS in both durvalumab plus oleclumab (stratified hazard ratio, 0.44; 95% CI, 0.26-0.75) and durvalumab plus monalizumab (HR, 0.42; 95% CI, 0.24-0.72). At 12 months, PFS was 62.6% (95% CI, 48.1-74.2%) for durvalumab plus oleclumab, 72.7% (95% CI, 58.8-82.6%) for durvalumab plus monalizumab, and 33.9% (95% CI, 21.2-47.1%) for durvalumab alone.

The study was funded by AstraZeneca.

The results of a phase 2 clinical trial of durvalumab with add-on therapies oleclumab or monalizumab, suggest this novel combination may prove beneficial in patients with unresectable stage 3 non–small-cell lung cancer.

Combinations of the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab led to improved overall response rate and progression-free survival compared to durvalumab alone.

The findings support further study in a phase 3 clinical trial, according to the authors of the study recently published in the Journal of Clinical Oncology.

Durvalumab is the standard treatment following consolidation therapy of chemoradiotherapy in unresectable stage 3 non–small-cell lung cancer (NSCLC). Although it extended progression-free survival (PFS) and overall survival in the PACIFIC phase 3 study, some patients experience a recurrence, which has led to exploration of immunotherapy combinations.

Oleclumab inhibits the enzyme CD73, found on the surfaces of both tumor and immune cells. Its activity leads to an immunosuppressive effect in the tumor microenvironment, and preclinical studies have shown that it can have an additive antitumor effect when combined with PD-1 or PD-L1 inhibitors. A phase 1 study also suggested efficacy. Monalizumab blocks interactions between major histocompatibility complex-E (HLA-E) and an inhibitor receptor. A number of tumors overexpress HLA-E, triggering inhibitor signals that inhibit natural killer and CD8+ T cells.

“COAST was an interesting study that, although not definitive, suggested that the combination of durvalumab with oleclumab or with monalizumab was more effective than durvalumab alone in the consolidation setting after definitive concurrent chemoradiation for patients with stage 3 unresectable NSCLC,” said Nathan Pennell, MD, PhD, who wrote an accompanying editorial.

Despite the positive signal, Dr. Pennell expressed some skepticism that the combinations would pass a phase 3 test. He questioned the choice of response rate as the primary endpoint of the phase 2 study, and noted that the durvalumab arm had worse progression-free survival (PFS) than the previous PACIFIC trial. It could be that the clinical characteristics of the study population differed between the two trials, in which case the improved objective response rate (ORR) and PFS results should be encouraging. It’s also possible the COAST trial’s small sample size led to a mismatch between the control and treatment group despite randomization, in which case the findings may not be valid.

“These are the kinds of issues that keep drug developers up at night. There really is no way to know which scenario is correct without doing the larger trial. I do hope though that the phase 3 trials have robust biomarker analysis including PDL1 to make sure the arms are as well matched for known prognostic and predictive markers as possible,” said Dr. Pennell, who is vice chair of clinical research at Taussig Cancer Institute.
 

The study details

The researchers randomized 189 patients to durvalumab, durvalumab plus oleclumab, or durvalumab plus monalizumab between January 2019 and July 2020. After a median follow-up of 11.5 months, there was a higher confirmed objective response rate in the durvalumab plus oleclumab group (30.0%; 95% confidence interval, 18.8%-43.2%) and the durvalumab plus monalizumab group (35.5%; 95% CI, 23.7%-48.7%) versus durvalumab alone (17.9%; 95% CI, 9.6%-29.2%).

Compared to durvalumab alone, there was improved PFS in both durvalumab plus oleclumab (stratified hazard ratio, 0.44; 95% CI, 0.26-0.75) and durvalumab plus monalizumab (HR, 0.42; 95% CI, 0.24-0.72). At 12 months, PFS was 62.6% (95% CI, 48.1-74.2%) for durvalumab plus oleclumab, 72.7% (95% CI, 58.8-82.6%) for durvalumab plus monalizumab, and 33.9% (95% CI, 21.2-47.1%) for durvalumab alone.

The study was funded by AstraZeneca.

The results of a phase 2 clinical trial of durvalumab with add-on therapies oleclumab or monalizumab, suggest this novel combination may prove beneficial in patients with unresectable stage 3 non–small-cell lung cancer.

Combinations of the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab led to improved overall response rate and progression-free survival compared to durvalumab alone.

The findings support further study in a phase 3 clinical trial, according to the authors of the study recently published in the Journal of Clinical Oncology.

Durvalumab is the standard treatment following consolidation therapy of chemoradiotherapy in unresectable stage 3 non–small-cell lung cancer (NSCLC). Although it extended progression-free survival (PFS) and overall survival in the PACIFIC phase 3 study, some patients experience a recurrence, which has led to exploration of immunotherapy combinations.

Oleclumab inhibits the enzyme CD73, found on the surfaces of both tumor and immune cells. Its activity leads to an immunosuppressive effect in the tumor microenvironment, and preclinical studies have shown that it can have an additive antitumor effect when combined with PD-1 or PD-L1 inhibitors. A phase 1 study also suggested efficacy. Monalizumab blocks interactions between major histocompatibility complex-E (HLA-E) and an inhibitor receptor. A number of tumors overexpress HLA-E, triggering inhibitor signals that inhibit natural killer and CD8+ T cells.

“COAST was an interesting study that, although not definitive, suggested that the combination of durvalumab with oleclumab or with monalizumab was more effective than durvalumab alone in the consolidation setting after definitive concurrent chemoradiation for patients with stage 3 unresectable NSCLC,” said Nathan Pennell, MD, PhD, who wrote an accompanying editorial.

Despite the positive signal, Dr. Pennell expressed some skepticism that the combinations would pass a phase 3 test. He questioned the choice of response rate as the primary endpoint of the phase 2 study, and noted that the durvalumab arm had worse progression-free survival (PFS) than the previous PACIFIC trial. It could be that the clinical characteristics of the study population differed between the two trials, in which case the improved objective response rate (ORR) and PFS results should be encouraging. It’s also possible the COAST trial’s small sample size led to a mismatch between the control and treatment group despite randomization, in which case the findings may not be valid.

“These are the kinds of issues that keep drug developers up at night. There really is no way to know which scenario is correct without doing the larger trial. I do hope though that the phase 3 trials have robust biomarker analysis including PDL1 to make sure the arms are as well matched for known prognostic and predictive markers as possible,” said Dr. Pennell, who is vice chair of clinical research at Taussig Cancer Institute.
 

The study details

The researchers randomized 189 patients to durvalumab, durvalumab plus oleclumab, or durvalumab plus monalizumab between January 2019 and July 2020. After a median follow-up of 11.5 months, there was a higher confirmed objective response rate in the durvalumab plus oleclumab group (30.0%; 95% confidence interval, 18.8%-43.2%) and the durvalumab plus monalizumab group (35.5%; 95% CI, 23.7%-48.7%) versus durvalumab alone (17.9%; 95% CI, 9.6%-29.2%).

Compared to durvalumab alone, there was improved PFS in both durvalumab plus oleclumab (stratified hazard ratio, 0.44; 95% CI, 0.26-0.75) and durvalumab plus monalizumab (HR, 0.42; 95% CI, 0.24-0.72). At 12 months, PFS was 62.6% (95% CI, 48.1-74.2%) for durvalumab plus oleclumab, 72.7% (95% CI, 58.8-82.6%) for durvalumab plus monalizumab, and 33.9% (95% CI, 21.2-47.1%) for durvalumab alone.

The study was funded by AstraZeneca.

The Food and Drug Administration has approved a new immunotherapy combination for use in the treatment of unresectable hepatocellular carcinoma (HCC), the most common type of liver cancer.

The new combination comprises a single dose of tremelimumab (Imjudo, AstraZeneca) followed by treatment with durvalumab (Imfinzi, AstraZeneca) in what is known as the STRIDE (single-tremelimumab regular-interval durvalumab) regimen.

This marks the first worldwide approval for tremelimumab, which is a CTLA-4 antibody.

The other drug in the combination, durvalumab, is an anti-PDL1 antibody and is already approved by the FDA for use in several tumor types, including lung cancer, bladder cancer, and biliary tract cancers.

The STRIDE regimen is composed of a single 300-mg dose of tremelimumab followed by durvalumab 1,500 mg given every 4 weeks.

This regimen was used in the HIMALAYA phase 3 trial, which was published in June 2022 in the New England Journal of Medicine.

Results from this trial showed that 30% of patients treated with that combination were still alive at 3 years, compared with 20% of patients who were treated with the standard regimen, sorafenib.

“In addition to this regimen demonstrating a favorable 3-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease,” commented the principal investigator of this trial, Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center, New York.

“Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival,” he commented in a press release from the drug’s manufacturer, AstraZeneca.

When the results from this trial were presented earlier this year at the ASCO Gastrointestinal Cancers meeting, the discussant for that abstract, Anthony B. El-Khoueiry, MD, from the University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, suggested that the STRIDE regimen offers a new first-line treatment option for patients with advanced HCC.

He also made several comments about the design of the HIMALAYA trial, which has a third treatment arm in which patients received durvalumab alone. Dr. El-Khoueiry noted that single-agent durvalumab was noninferior to sorafenib, but he added that no conclusions could be drawn about the STRIDE regimen in comparison with durvalumab as a single agent, because the trial was not powered for that.

The STRIDE regimen showed a lower risk of bleeding in comparison with combinations that include VEGF inhibitors (such as bevacizumab), he said, but he also pointed out that this trial excluded patients with main portal vein thrombosis, who are at high risk of bleeding.

Details of adverse events

In the NEJM article, the trialists report that grade 3/4 treatment-emergent adverse events occurred in 50.5% of patients with STRIDE, 37.1% with durvalumab alone, and 52.4% of patients with sorafenib.

The manufacturer noted that severe and fatal immune-mediated adverse reactions may occur, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic reactions, and others.

The company also noted that among the patients with unresectable HCC in the HIMALAYA study who received the STRIDE regimen, the most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.

Serious adverse reactions occurred in 41% of patients and included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%).

Fatal adverse reactions occurred in 8% of patients who received the combination, including death (1%), intracranial hemorrhage (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%).

Permanent discontinuation of the treatment regimen because of an adverse reaction occurred in 14% of patients.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved a new immunotherapy combination for use in the treatment of unresectable hepatocellular carcinoma (HCC), the most common type of liver cancer.

The new combination comprises a single dose of tremelimumab (Imjudo, AstraZeneca) followed by treatment with durvalumab (Imfinzi, AstraZeneca) in what is known as the STRIDE (single-tremelimumab regular-interval durvalumab) regimen.

This marks the first worldwide approval for tremelimumab, which is a CTLA-4 antibody.

The other drug in the combination, durvalumab, is an anti-PDL1 antibody and is already approved by the FDA for use in several tumor types, including lung cancer, bladder cancer, and biliary tract cancers.

The STRIDE regimen is composed of a single 300-mg dose of tremelimumab followed by durvalumab 1,500 mg given every 4 weeks.

This regimen was used in the HIMALAYA phase 3 trial, which was published in June 2022 in the New England Journal of Medicine.

Results from this trial showed that 30% of patients treated with that combination were still alive at 3 years, compared with 20% of patients who were treated with the standard regimen, sorafenib.

“In addition to this regimen demonstrating a favorable 3-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease,” commented the principal investigator of this trial, Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center, New York.

“Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival,” he commented in a press release from the drug’s manufacturer, AstraZeneca.

When the results from this trial were presented earlier this year at the ASCO Gastrointestinal Cancers meeting, the discussant for that abstract, Anthony B. El-Khoueiry, MD, from the University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, suggested that the STRIDE regimen offers a new first-line treatment option for patients with advanced HCC.

He also made several comments about the design of the HIMALAYA trial, which has a third treatment arm in which patients received durvalumab alone. Dr. El-Khoueiry noted that single-agent durvalumab was noninferior to sorafenib, but he added that no conclusions could be drawn about the STRIDE regimen in comparison with durvalumab as a single agent, because the trial was not powered for that.

The STRIDE regimen showed a lower risk of bleeding in comparison with combinations that include VEGF inhibitors (such as bevacizumab), he said, but he also pointed out that this trial excluded patients with main portal vein thrombosis, who are at high risk of bleeding.

Details of adverse events

In the NEJM article, the trialists report that grade 3/4 treatment-emergent adverse events occurred in 50.5% of patients with STRIDE, 37.1% with durvalumab alone, and 52.4% of patients with sorafenib.

The manufacturer noted that severe and fatal immune-mediated adverse reactions may occur, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic reactions, and others.

The company also noted that among the patients with unresectable HCC in the HIMALAYA study who received the STRIDE regimen, the most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.

Serious adverse reactions occurred in 41% of patients and included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%).

Fatal adverse reactions occurred in 8% of patients who received the combination, including death (1%), intracranial hemorrhage (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%).

Permanent discontinuation of the treatment regimen because of an adverse reaction occurred in 14% of patients.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved a new immunotherapy combination for use in the treatment of unresectable hepatocellular carcinoma (HCC), the most common type of liver cancer.

The new combination comprises a single dose of tremelimumab (Imjudo, AstraZeneca) followed by treatment with durvalumab (Imfinzi, AstraZeneca) in what is known as the STRIDE (single-tremelimumab regular-interval durvalumab) regimen.

This marks the first worldwide approval for tremelimumab, which is a CTLA-4 antibody.

The other drug in the combination, durvalumab, is an anti-PDL1 antibody and is already approved by the FDA for use in several tumor types, including lung cancer, bladder cancer, and biliary tract cancers.

The STRIDE regimen is composed of a single 300-mg dose of tremelimumab followed by durvalumab 1,500 mg given every 4 weeks.

This regimen was used in the HIMALAYA phase 3 trial, which was published in June 2022 in the New England Journal of Medicine.

Results from this trial showed that 30% of patients treated with that combination were still alive at 3 years, compared with 20% of patients who were treated with the standard regimen, sorafenib.

“In addition to this regimen demonstrating a favorable 3-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease,” commented the principal investigator of this trial, Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center, New York.

“Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival,” he commented in a press release from the drug’s manufacturer, AstraZeneca.

When the results from this trial were presented earlier this year at the ASCO Gastrointestinal Cancers meeting, the discussant for that abstract, Anthony B. El-Khoueiry, MD, from the University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, suggested that the STRIDE regimen offers a new first-line treatment option for patients with advanced HCC.

He also made several comments about the design of the HIMALAYA trial, which has a third treatment arm in which patients received durvalumab alone. Dr. El-Khoueiry noted that single-agent durvalumab was noninferior to sorafenib, but he added that no conclusions could be drawn about the STRIDE regimen in comparison with durvalumab as a single agent, because the trial was not powered for that.

The STRIDE regimen showed a lower risk of bleeding in comparison with combinations that include VEGF inhibitors (such as bevacizumab), he said, but he also pointed out that this trial excluded patients with main portal vein thrombosis, who are at high risk of bleeding.

Details of adverse events

In the NEJM article, the trialists report that grade 3/4 treatment-emergent adverse events occurred in 50.5% of patients with STRIDE, 37.1% with durvalumab alone, and 52.4% of patients with sorafenib.

The manufacturer noted that severe and fatal immune-mediated adverse reactions may occur, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic reactions, and others.

The company also noted that among the patients with unresectable HCC in the HIMALAYA study who received the STRIDE regimen, the most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.

Serious adverse reactions occurred in 41% of patients and included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%).

Fatal adverse reactions occurred in 8% of patients who received the combination, including death (1%), intracranial hemorrhage (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%).

Permanent discontinuation of the treatment regimen because of an adverse reaction occurred in 14% of patients.

A version of this article first appeared on Medscape.com.

Researchers have developed a computer program to identify drugs for other diseases that might be repurposed to treat type 2 diabetes and/or obesity by targeting genetic pathways for these two conditions.

The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.

Their findings suggest that:

• Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.
• Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.
• Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.
• Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.

Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research during an oral session at the International Congress on Obesity, the biennial congress of the World Obesity Federation, in Melbourne.

“New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity,” senior coauthor Murray Cairns, PhD, said in a press release from the ICO.   

“Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders,” said Dr. Cairns, from the school of biomedical sciences and pharmacy at the University of Newcastle.

Matchmaking between individual, their genetic traits, and drugs

Dr. Cairns and senior coauthor William Reay, PhD, also from the school of biomedical sciences and pharmacy, have cofounded a company called PolygenRx.

The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is “essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors.”

It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, “are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene,” Dr. Cairns explained in an email.

“Complex traits,” he noted, “are associated with thousands of [genetic] variants that are common in people and have a cumulative effect.”

For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.

“By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions with controls, these studies have revealed regions of the genome and genes associated with the condition,” Dr. Cairns noted.

The pharmagenic enrichment score integrates a person’s genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.

“We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless),” Dr. Cairns explained.

From the PES score, “we have an estimate of each individual’s likelihood of a positive response to said drug,” he noted. “We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants.”

With this research, “we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk” for obesity and type 2 diabetes.

“Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans,” he said.

Next steps: Raising funds for clinical trials

“We would like to progress some of these compounds to preclinical and clinical trials,” Dr. Cairns said, “but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates.”

The authors have reported no relevant financial relationships. Dr. Reay and Dr. Cairns are cofounders of PolygenRx.

A version of this article first appeared on Medscape.com.

Researchers have developed a computer program to identify drugs for other diseases that might be repurposed to treat type 2 diabetes and/or obesity by targeting genetic pathways for these two conditions.

The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.

Their findings suggest that:

• Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.
• Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.
• Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.
• Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.

Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research during an oral session at the International Congress on Obesity, the biennial congress of the World Obesity Federation, in Melbourne.

“New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity,” senior coauthor Murray Cairns, PhD, said in a press release from the ICO.   

“Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders,” said Dr. Cairns, from the school of biomedical sciences and pharmacy at the University of Newcastle.

Matchmaking between individual, their genetic traits, and drugs

Dr. Cairns and senior coauthor William Reay, PhD, also from the school of biomedical sciences and pharmacy, have cofounded a company called PolygenRx.

The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is “essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors.”

It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, “are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene,” Dr. Cairns explained in an email.

“Complex traits,” he noted, “are associated with thousands of [genetic] variants that are common in people and have a cumulative effect.”

For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.

“By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions with controls, these studies have revealed regions of the genome and genes associated with the condition,” Dr. Cairns noted.

The pharmagenic enrichment score integrates a person’s genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.

“We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless),” Dr. Cairns explained.

From the PES score, “we have an estimate of each individual’s likelihood of a positive response to said drug,” he noted. “We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants.”

With this research, “we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk” for obesity and type 2 diabetes.

“Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans,” he said.

Next steps: Raising funds for clinical trials

“We would like to progress some of these compounds to preclinical and clinical trials,” Dr. Cairns said, “but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates.”

The authors have reported no relevant financial relationships. Dr. Reay and Dr. Cairns are cofounders of PolygenRx.

A version of this article first appeared on Medscape.com.

Researchers have developed a computer program to identify drugs for other diseases that might be repurposed to treat type 2 diabetes and/or obesity by targeting genetic pathways for these two conditions.

The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.

Their findings suggest that:

• Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.
• Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.
• Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.
• Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.

Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research during an oral session at the International Congress on Obesity, the biennial congress of the World Obesity Federation, in Melbourne.

“New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity,” senior coauthor Murray Cairns, PhD, said in a press release from the ICO.   

“Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders,” said Dr. Cairns, from the school of biomedical sciences and pharmacy at the University of Newcastle.

Matchmaking between individual, their genetic traits, and drugs

Dr. Cairns and senior coauthor William Reay, PhD, also from the school of biomedical sciences and pharmacy, have cofounded a company called PolygenRx.

The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is “essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors.”

It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, “are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene,” Dr. Cairns explained in an email.

“Complex traits,” he noted, “are associated with thousands of [genetic] variants that are common in people and have a cumulative effect.”

For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.

“By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions with controls, these studies have revealed regions of the genome and genes associated with the condition,” Dr. Cairns noted.

The pharmagenic enrichment score integrates a person’s genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.

“We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless),” Dr. Cairns explained.

From the PES score, “we have an estimate of each individual’s likelihood of a positive response to said drug,” he noted. “We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants.”

With this research, “we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk” for obesity and type 2 diabetes.

“Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans,” he said.

Next steps: Raising funds for clinical trials

“We would like to progress some of these compounds to preclinical and clinical trials,” Dr. Cairns said, “but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates.”

The authors have reported no relevant financial relationships. Dr. Reay and Dr. Cairns are cofounders of PolygenRx.

A version of this article first appeared on Medscape.com.

Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.

The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.

These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.

More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.

“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.

Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.

Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).

These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
 

Findings from Echo ORAL Surveillance

“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”

Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.

He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.

“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”

Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.

“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.

Boxed warnings encourage caution, lock treatment sequence

Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.

“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”

If these risks aren’t discussed, he noted, patient trust may falter.

“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”

Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.

Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.

“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”

The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.

A version of this article first appeared on Medscape.com.

Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.

The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.

These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.

More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.

“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.

Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.

Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).

These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
 

Findings from Echo ORAL Surveillance

“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”

Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.

He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.

“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”

Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.

“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.

Boxed warnings encourage caution, lock treatment sequence

Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.

“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”

If these risks aren’t discussed, he noted, patient trust may falter.

“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”

Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.

Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.

“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”

The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.

A version of this article first appeared on Medscape.com.

Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.

The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.

These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.

More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.

“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.

Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.

Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).

These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
 

Findings from Echo ORAL Surveillance

“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”

Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.

He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.

“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”

Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.

“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.

Boxed warnings encourage caution, lock treatment sequence

Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.

“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”

If these risks aren’t discussed, he noted, patient trust may falter.

“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”

Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.

Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.

“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”

The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.

A version of this article first appeared on Medscape.com.

The drug fezolinetant, a selective neurokinin-3 receptor antagonist under investigation for treatment of menopausal vasomotor symptoms, showed acceptable long-term safety and tolerability during a 1-year phase 3 randomized controlled trial, according to data presented at the annual meeting of the North American Menopause Society. The study, called SKYLIGHT 4, examined fezolinetant treatment, especially in terms of endometrial health.

The findings mean that fezolinetant “may help bridge a gap in the management of vasomotor symptoms,” according to lead author Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

This study was an important step in fezolinetant’s path toward potential approval by the Food and Drug Administration for vasomotor symptoms.

”Moderate and severe vasomotor symptoms can adversely affect quality of life of those affected and result in sleep disruption as well as increased risk for heart disease and other high-risk medical problems,” Dr. Neal-Perry said. “Although menopausal hormone therapy significantly improves vasomotor symptoms, it may not be desired or it may not be safe for some women,” resulting in gaps in care and a need for targeted, nonhormonal therapies for hot flashes. A planned study will also assess the safety of the drug in patients with a diagnosis of hormone-sensitive cancer and disorders that increase the risk for blood clots.

”Fezolinetant has a low side effect profile, it is a nonhormonal option, and it is selective for the neurons that trigger and mediate hot flashes,” Dr. Neal-Perry said.

Hot flashes are caused by kisspeptin, neurokinin B, and dynorphin neurons located in the hypothalamus. Fezolinetant works by selectively blocking the neurokinin 3 receptor (NK3R), which regulates a person’s sense of temperature, Dr. Neal-Perry explained. Overactivation of NK3R, resulting from low estrogen levels, plays a role in the hot flashes and cold sweats women experience during menopause.

Drug development for hot flashes ”has been hampered by a lack of knowledge regarding the biological cause,” Dr. Neal-Perry said. “Now that we have a robust understanding of the basic biology of hot flashes, we can develop novel, highly effective, and targeted therapy.”

This safety study involved 1,830 women, ages 40-65, who were experiencing menopausal vasomotor symptoms and were randomly assigned to one of three arms for 52 weeks: 45 mg of fezolinetant, 30 mg of fezolinetant, or a placebo once daily.

The primary endpoints included the percentage of women with endometrial hyperplasia, the percentage of women with endometrial cancer, and the frequency and severity of treatment-emergent adverse events (TEAEs). To meet the primary safety endpoint, no more than 1% of participants could have hyperplasia or malignancy, with an upper confidence interval boundary not greater than 4%. Women who met prespecified criteria for their endometrial health to be assessed, underwent endometrial biopsies at baseline and at the end of the study. Three independent pathologists analyzed the tissue without knowledge of which study arm each sample came from. Among the 599 endometrial biopsy samples, 0.5% of the 203 participants taking 45 mg fezolinetant had hyperplasia while none of the women in the other two arms did. Among the 210 women taking 30 mg of fezolinetant, 0.5% had a malignancy; no malignancies occurred in the other two arms.

Overall adverse events were similar across all three arms, including rates of adverse events leading to discontinuation. The most common adverse events were headache and COVID-19. TEAEs related to the drug were 18.1% in the 45-mg arm, 15.4% in the 30-mg arm, and 17.4% in the placebo arm. Serious adverse events were similar across all three arms, and only 0.5% of participants in the 45-mg arm experienced drug-related serious adverse events, compared with none of the women in the 30-mg arm and 0.2% of women in the placebo group.

”The frequency of transaminase elevations was low, and these TEAEs were generally isolated, transient, and resolved on treatment or with discontinuation,” the authors reported.

The next steps for fezolinetant will be to assess its effect on mood and quality of life measures related to vasomotor symptoms, Dr. Neal-Perry said.

Samantha Dunham, MD, a NAMS-certified menopause practitioner and an associate professor of obstetrics and gynecology at New York University, suggested the drug’s safety in the study is encouraging.

”As a medication that treats menopausal symptoms, the study confirmed there are no issues with the endometrium, or lining of the uterus, not that one would expect issues given the mechanism of action,” Dr. Dunham, also codirector of NYU Langone’s Center for Midlife Health and Menopause, said in an interview. Dr. Dunham was not involved in the study.

”Earlier versions of medication in this class have caused liver enzyme elevation.” The trial of this medication showed that there were only transient elevations in liver enzymes, which resolved upon cessation of the medication. Dr. Dunham said. ”If the medicine proves to be safe over long periods of time in different populations, this will be a very significant medication for treating menopausal vasomotor symptoms.”

The research was funded by Astellas Pharma. Dr. Dunham had no disclosures. Dr. Neal-Perry is a scientific advisory board member for Astellas and Ferring Pharmaceuticals, and has received research funding from Merck and Overa.

The drug fezolinetant, a selective neurokinin-3 receptor antagonist under investigation for treatment of menopausal vasomotor symptoms, showed acceptable long-term safety and tolerability during a 1-year phase 3 randomized controlled trial, according to data presented at the annual meeting of the North American Menopause Society. The study, called SKYLIGHT 4, examined fezolinetant treatment, especially in terms of endometrial health.

The findings mean that fezolinetant “may help bridge a gap in the management of vasomotor symptoms,” according to lead author Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

This study was an important step in fezolinetant’s path toward potential approval by the Food and Drug Administration for vasomotor symptoms.

”Moderate and severe vasomotor symptoms can adversely affect quality of life of those affected and result in sleep disruption as well as increased risk for heart disease and other high-risk medical problems,” Dr. Neal-Perry said. “Although menopausal hormone therapy significantly improves vasomotor symptoms, it may not be desired or it may not be safe for some women,” resulting in gaps in care and a need for targeted, nonhormonal therapies for hot flashes. A planned study will also assess the safety of the drug in patients with a diagnosis of hormone-sensitive cancer and disorders that increase the risk for blood clots.

”Fezolinetant has a low side effect profile, it is a nonhormonal option, and it is selective for the neurons that trigger and mediate hot flashes,” Dr. Neal-Perry said.

Hot flashes are caused by kisspeptin, neurokinin B, and dynorphin neurons located in the hypothalamus. Fezolinetant works by selectively blocking the neurokinin 3 receptor (NK3R), which regulates a person’s sense of temperature, Dr. Neal-Perry explained. Overactivation of NK3R, resulting from low estrogen levels, plays a role in the hot flashes and cold sweats women experience during menopause.

Drug development for hot flashes ”has been hampered by a lack of knowledge regarding the biological cause,” Dr. Neal-Perry said. “Now that we have a robust understanding of the basic biology of hot flashes, we can develop novel, highly effective, and targeted therapy.”

This safety study involved 1,830 women, ages 40-65, who were experiencing menopausal vasomotor symptoms and were randomly assigned to one of three arms for 52 weeks: 45 mg of fezolinetant, 30 mg of fezolinetant, or a placebo once daily.

The primary endpoints included the percentage of women with endometrial hyperplasia, the percentage of women with endometrial cancer, and the frequency and severity of treatment-emergent adverse events (TEAEs). To meet the primary safety endpoint, no more than 1% of participants could have hyperplasia or malignancy, with an upper confidence interval boundary not greater than 4%. Women who met prespecified criteria for their endometrial health to be assessed, underwent endometrial biopsies at baseline and at the end of the study. Three independent pathologists analyzed the tissue without knowledge of which study arm each sample came from. Among the 599 endometrial biopsy samples, 0.5% of the 203 participants taking 45 mg fezolinetant had hyperplasia while none of the women in the other two arms did. Among the 210 women taking 30 mg of fezolinetant, 0.5% had a malignancy; no malignancies occurred in the other two arms.

Overall adverse events were similar across all three arms, including rates of adverse events leading to discontinuation. The most common adverse events were headache and COVID-19. TEAEs related to the drug were 18.1% in the 45-mg arm, 15.4% in the 30-mg arm, and 17.4% in the placebo arm. Serious adverse events were similar across all three arms, and only 0.5% of participants in the 45-mg arm experienced drug-related serious adverse events, compared with none of the women in the 30-mg arm and 0.2% of women in the placebo group.

”The frequency of transaminase elevations was low, and these TEAEs were generally isolated, transient, and resolved on treatment or with discontinuation,” the authors reported.

The next steps for fezolinetant will be to assess its effect on mood and quality of life measures related to vasomotor symptoms, Dr. Neal-Perry said.

Samantha Dunham, MD, a NAMS-certified menopause practitioner and an associate professor of obstetrics and gynecology at New York University, suggested the drug’s safety in the study is encouraging.

”As a medication that treats menopausal symptoms, the study confirmed there are no issues with the endometrium, or lining of the uterus, not that one would expect issues given the mechanism of action,” Dr. Dunham, also codirector of NYU Langone’s Center for Midlife Health and Menopause, said in an interview. Dr. Dunham was not involved in the study.

”Earlier versions of medication in this class have caused liver enzyme elevation.” The trial of this medication showed that there were only transient elevations in liver enzymes, which resolved upon cessation of the medication. Dr. Dunham said. ”If the medicine proves to be safe over long periods of time in different populations, this will be a very significant medication for treating menopausal vasomotor symptoms.”

The research was funded by Astellas Pharma. Dr. Dunham had no disclosures. Dr. Neal-Perry is a scientific advisory board member for Astellas and Ferring Pharmaceuticals, and has received research funding from Merck and Overa.

The drug fezolinetant, a selective neurokinin-3 receptor antagonist under investigation for treatment of menopausal vasomotor symptoms, showed acceptable long-term safety and tolerability during a 1-year phase 3 randomized controlled trial, according to data presented at the annual meeting of the North American Menopause Society. The study, called SKYLIGHT 4, examined fezolinetant treatment, especially in terms of endometrial health.

The findings mean that fezolinetant “may help bridge a gap in the management of vasomotor symptoms,” according to lead author Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

This study was an important step in fezolinetant’s path toward potential approval by the Food and Drug Administration for vasomotor symptoms.

”Moderate and severe vasomotor symptoms can adversely affect quality of life of those affected and result in sleep disruption as well as increased risk for heart disease and other high-risk medical problems,” Dr. Neal-Perry said. “Although menopausal hormone therapy significantly improves vasomotor symptoms, it may not be desired or it may not be safe for some women,” resulting in gaps in care and a need for targeted, nonhormonal therapies for hot flashes. A planned study will also assess the safety of the drug in patients with a diagnosis of hormone-sensitive cancer and disorders that increase the risk for blood clots.

”Fezolinetant has a low side effect profile, it is a nonhormonal option, and it is selective for the neurons that trigger and mediate hot flashes,” Dr. Neal-Perry said.

Hot flashes are caused by kisspeptin, neurokinin B, and dynorphin neurons located in the hypothalamus. Fezolinetant works by selectively blocking the neurokinin 3 receptor (NK3R), which regulates a person’s sense of temperature, Dr. Neal-Perry explained. Overactivation of NK3R, resulting from low estrogen levels, plays a role in the hot flashes and cold sweats women experience during menopause.

Drug development for hot flashes ”has been hampered by a lack of knowledge regarding the biological cause,” Dr. Neal-Perry said. “Now that we have a robust understanding of the basic biology of hot flashes, we can develop novel, highly effective, and targeted therapy.”

This safety study involved 1,830 women, ages 40-65, who were experiencing menopausal vasomotor symptoms and were randomly assigned to one of three arms for 52 weeks: 45 mg of fezolinetant, 30 mg of fezolinetant, or a placebo once daily.

The primary endpoints included the percentage of women with endometrial hyperplasia, the percentage of women with endometrial cancer, and the frequency and severity of treatment-emergent adverse events (TEAEs). To meet the primary safety endpoint, no more than 1% of participants could have hyperplasia or malignancy, with an upper confidence interval boundary not greater than 4%. Women who met prespecified criteria for their endometrial health to be assessed, underwent endometrial biopsies at baseline and at the end of the study. Three independent pathologists analyzed the tissue without knowledge of which study arm each sample came from. Among the 599 endometrial biopsy samples, 0.5% of the 203 participants taking 45 mg fezolinetant had hyperplasia while none of the women in the other two arms did. Among the 210 women taking 30 mg of fezolinetant, 0.5% had a malignancy; no malignancies occurred in the other two arms.

Overall adverse events were similar across all three arms, including rates of adverse events leading to discontinuation. The most common adverse events were headache and COVID-19. TEAEs related to the drug were 18.1% in the 45-mg arm, 15.4% in the 30-mg arm, and 17.4% in the placebo arm. Serious adverse events were similar across all three arms, and only 0.5% of participants in the 45-mg arm experienced drug-related serious adverse events, compared with none of the women in the 30-mg arm and 0.2% of women in the placebo group.

”The frequency of transaminase elevations was low, and these TEAEs were generally isolated, transient, and resolved on treatment or with discontinuation,” the authors reported.

The next steps for fezolinetant will be to assess its effect on mood and quality of life measures related to vasomotor symptoms, Dr. Neal-Perry said.

Samantha Dunham, MD, a NAMS-certified menopause practitioner and an associate professor of obstetrics and gynecology at New York University, suggested the drug’s safety in the study is encouraging.

”As a medication that treats menopausal symptoms, the study confirmed there are no issues with the endometrium, or lining of the uterus, not that one would expect issues given the mechanism of action,” Dr. Dunham, also codirector of NYU Langone’s Center for Midlife Health and Menopause, said in an interview. Dr. Dunham was not involved in the study.

”Earlier versions of medication in this class have caused liver enzyme elevation.” The trial of this medication showed that there were only transient elevations in liver enzymes, which resolved upon cessation of the medication. Dr. Dunham said. ”If the medicine proves to be safe over long periods of time in different populations, this will be a very significant medication for treating menopausal vasomotor symptoms.”

The research was funded by Astellas Pharma. Dr. Dunham had no disclosures. Dr. Neal-Perry is a scientific advisory board member for Astellas and Ferring Pharmaceuticals, and has received research funding from Merck and Overa.

A majority of hospitalized patients at low risk for venous thromboembolism were unnecessarily treated with medication, based on data from more than 400 individuals.

Prevention of venous thromboembolism (VTE) is important, and current guidelines from the American College of Chest Physicians suggest that patients with high or moderate risk for VTE be treated with mechanical prophylaxis, and that pharmacological prophylaxis is not recommended for patients at high risk for bleeding, said Hui Chong Lau, MD, in a presentation at the annual meeting of the American College of Chest Physicians (CHEST).

However, the nature of VTE prophylaxis using a risk assessment score has not been explored, said Dr. Lau, a third-year resident in internal medicine at Crozer-Chester Medical Center, Upland, Penn.

Low-molecular-weight heparin (LWMH) and intermittent pneumatic compression are often used to reduce VTE risk during hospitalization, but for patients with low VTE risk, prophylaxis is not necessarily recommended, he said. In fact, overuse of chemical prophylaxis in low-risk patients can increase bleeding risk and contribute to patient discomfort in the form of additional needle sticks while hospitalized, Dr. Lau said in the presentation.

“We wanted to see how well physicians in the hospital used a risk assessment model to stratify patients,” and how well the patients were assigned to the correct prophylaxis, he explained.

Dr. Lau and colleagues reviewed data from 469 adult patients hospitalized at a single medical center who were hospitalized between January 2021 and June 2021. The researchers retrospectively performed risk assessment using the Padua prediction score. A score of less than 4 was considered low risk for VTE, and a score of 4 or higher was considered high risk.

In the study population, 180 patients were identified as low risk and 289 were considered high risk.

Based on the Padua score, 95% of the patients at high risk were on the correct prophylaxis, Dr. Lau said.

A total of 193 high-risk patients were on heparin. However, many of these patients had good kidney function, and could have been treated with enoxaparin instead; “this would have spared them two needle sticks per day,” Dr. Lau noted.

Of the 180 low-risk patients, 168 (93.3%) were on chemical prophylaxis, and should have been on mechanical prophylaxis, he said. Only 10 patients (5%) who were considered low risk were placed on mechanical prophylaxis.

Overall, 3.6% of all patients who received chemical VTE prophylaxis developed bleeding.

The results were limited by the retrospective design and use of data from a single center. However, the findings emphasize the need for better attention to VTE risk when considering prophylaxis, said Dr. Lau. “We have to have risk assessment every day,” during a hospital stay, and adjust treatment accordingly, he said.

“We are likely overusing chemical VTE prophylaxis in low-risk patients,” he concluded.

Additional research is needed to better understand the potential consequences of overusing chemical VTE, including not only bleeding risk, but also financial costs and patient discomfort, he said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

A majority of hospitalized patients at low risk for venous thromboembolism were unnecessarily treated with medication, based on data from more than 400 individuals.

Prevention of venous thromboembolism (VTE) is important, and current guidelines from the American College of Chest Physicians suggest that patients with high or moderate risk for VTE be treated with mechanical prophylaxis, and that pharmacological prophylaxis is not recommended for patients at high risk for bleeding, said Hui Chong Lau, MD, in a presentation at the annual meeting of the American College of Chest Physicians (CHEST).

However, the nature of VTE prophylaxis using a risk assessment score has not been explored, said Dr. Lau, a third-year resident in internal medicine at Crozer-Chester Medical Center, Upland, Penn.

Low-molecular-weight heparin (LWMH) and intermittent pneumatic compression are often used to reduce VTE risk during hospitalization, but for patients with low VTE risk, prophylaxis is not necessarily recommended, he said. In fact, overuse of chemical prophylaxis in low-risk patients can increase bleeding risk and contribute to patient discomfort in the form of additional needle sticks while hospitalized, Dr. Lau said in the presentation.

“We wanted to see how well physicians in the hospital used a risk assessment model to stratify patients,” and how well the patients were assigned to the correct prophylaxis, he explained.

Dr. Lau and colleagues reviewed data from 469 adult patients hospitalized at a single medical center who were hospitalized between January 2021 and June 2021. The researchers retrospectively performed risk assessment using the Padua prediction score. A score of less than 4 was considered low risk for VTE, and a score of 4 or higher was considered high risk.

In the study population, 180 patients were identified as low risk and 289 were considered high risk.

Based on the Padua score, 95% of the patients at high risk were on the correct prophylaxis, Dr. Lau said.

A total of 193 high-risk patients were on heparin. However, many of these patients had good kidney function, and could have been treated with enoxaparin instead; “this would have spared them two needle sticks per day,” Dr. Lau noted.

Of the 180 low-risk patients, 168 (93.3%) were on chemical prophylaxis, and should have been on mechanical prophylaxis, he said. Only 10 patients (5%) who were considered low risk were placed on mechanical prophylaxis.

Overall, 3.6% of all patients who received chemical VTE prophylaxis developed bleeding.

The results were limited by the retrospective design and use of data from a single center. However, the findings emphasize the need for better attention to VTE risk when considering prophylaxis, said Dr. Lau. “We have to have risk assessment every day,” during a hospital stay, and adjust treatment accordingly, he said.

“We are likely overusing chemical VTE prophylaxis in low-risk patients,” he concluded.

Additional research is needed to better understand the potential consequences of overusing chemical VTE, including not only bleeding risk, but also financial costs and patient discomfort, he said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

A majority of hospitalized patients at low risk for venous thromboembolism were unnecessarily treated with medication, based on data from more than 400 individuals.

Prevention of venous thromboembolism (VTE) is important, and current guidelines from the American College of Chest Physicians suggest that patients with high or moderate risk for VTE be treated with mechanical prophylaxis, and that pharmacological prophylaxis is not recommended for patients at high risk for bleeding, said Hui Chong Lau, MD, in a presentation at the annual meeting of the American College of Chest Physicians (CHEST).

However, the nature of VTE prophylaxis using a risk assessment score has not been explored, said Dr. Lau, a third-year resident in internal medicine at Crozer-Chester Medical Center, Upland, Penn.

Low-molecular-weight heparin (LWMH) and intermittent pneumatic compression are often used to reduce VTE risk during hospitalization, but for patients with low VTE risk, prophylaxis is not necessarily recommended, he said. In fact, overuse of chemical prophylaxis in low-risk patients can increase bleeding risk and contribute to patient discomfort in the form of additional needle sticks while hospitalized, Dr. Lau said in the presentation.

“We wanted to see how well physicians in the hospital used a risk assessment model to stratify patients,” and how well the patients were assigned to the correct prophylaxis, he explained.

Dr. Lau and colleagues reviewed data from 469 adult patients hospitalized at a single medical center who were hospitalized between January 2021 and June 2021. The researchers retrospectively performed risk assessment using the Padua prediction score. A score of less than 4 was considered low risk for VTE, and a score of 4 or higher was considered high risk.

In the study population, 180 patients were identified as low risk and 289 were considered high risk.

Based on the Padua score, 95% of the patients at high risk were on the correct prophylaxis, Dr. Lau said.

A total of 193 high-risk patients were on heparin. However, many of these patients had good kidney function, and could have been treated with enoxaparin instead; “this would have spared them two needle sticks per day,” Dr. Lau noted.

Of the 180 low-risk patients, 168 (93.3%) were on chemical prophylaxis, and should have been on mechanical prophylaxis, he said. Only 10 patients (5%) who were considered low risk were placed on mechanical prophylaxis.

Overall, 3.6% of all patients who received chemical VTE prophylaxis developed bleeding.

The results were limited by the retrospective design and use of data from a single center. However, the findings emphasize the need for better attention to VTE risk when considering prophylaxis, said Dr. Lau. “We have to have risk assessment every day,” during a hospital stay, and adjust treatment accordingly, he said.

“We are likely overusing chemical VTE prophylaxis in low-risk patients,” he concluded.

Additional research is needed to better understand the potential consequences of overusing chemical VTE, including not only bleeding risk, but also financial costs and patient discomfort, he said.

The study received no outside funding. The researchers had no financial conflicts to disclose.