Pharmacology

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

Hundreds of Native American tribes have tentatively settled in what one of the lead attorneys describes as “an epic deal”: The top 3 pharmaceutical distributors in the US and Johnson & Johnson have agreed to pay $665 million for deceptive marketing practices and overdistribution of opioids. Native Americans were among those hardest hit by the opioid epidemic. Between 2006 and 2014, Native Americans were nearly 50% more likely than non-Natives to die of an opioid overdose. In 2014, they ranked number 1 for death by opioid overdose.

Overprescribing was rampant. In some areas, such as southwestern Virginia, eastern Kentucky, and Alabama, prescriptions were 5 to 6 times higher than the national average. The overprescribing was largely due to massive and aggressive billion-dollar marketing campaigns, which misrepresented the safety of opioid medications. Purdue Pharma, for instance, trained sales representatives to claim that the risk of addiction was “less than 1 percent.” In an interview with Smithsonian Magazine, Caleb Alexander, MD, codirector of Johns Hopkins’ Center for Drug Safety and Effectiveness, said, “When I was in residency training, we were taught that one needn’t worry about the addictive potential of opioids if a patient had true pain.” He said it was no accident that physicians were cultivated to overestimate the effectiveness for chronic, noncancer pain while underestimating the risks.

Native Americans were not only in the target group for prescriptions, but also apparently singularly targeted. “We were preyed upon,” said Chickasaw Nation Governor Bill Anoatubby in the Washington Post. “It was unconscionable.” A Washington Post analysis found that, between 2006 and 2014, opioid distributors shipped an average of 36 pills per person in the US. States in the so-called opioid belt (mostly Southern states), received an average of 60 to 66 pills per person. The distributors shipped 57 pills per person to Oklahoma, home to nearly 322,000 Native Americans. (The opioid death rate for Native Americans in Oklahoma from 2006 to 2014 was more than triple the nationwide rate for non-Natives.) In South Dakota as recently as 2015, enough opioids were prescribed to medicate every adult around-the-clock for 19 consecutive days. Native Americans comprise 9% of South Dakota’s population; however, almost 30% of the patients are being treated for opioid use disorder.

In the settlement, which is a first for tribes, McKesson, Cardinal Health, and AmerisourceBergen would pay $515 million over 7 years. Johnson & Johnson would contribute $150 million in 2 years to the federally recognized tribes. “This settlement is a real turning point in history,” said Lloyd Miller, one of the attorneys representing one-third of the litigating tribes.

But the money is still small compensation for ravaging millions of lives. “Flooding the Native community with Western medicine—sedating a population rather than seeking to understand its needs and challenges—is not an acceptable means of handling its trauma,” the Lakota People’s Law Project says in an article on its website. Thus, the money dispersal will be overseen by a panel of tribal health experts, to go toward programs that aid drug users and their communities.

The funds will be managed in a way that will consider the long-term damage, Native American leaders vow. Children, for instance, have not been exempt from the sequelae of the overprescribing. Foster care systems are “overrun” with children of addicted parents, the Law Project says, and the children are placed in homes outside the tribe. “In the long run, this has the potential to curtail tribal membership, break down familial lines, and degrade cultural values.”

Dealing with the problem has drained tribal resources—doubly strained by the COVID-19 epidemic. Chairman Douglas Yankton, of the Spirit Lake Nation in North Dakota, said in a statement, “The dollars that will flow to Tribes under this initial settlement will help fund crucial, on-reservation, culturally appropriate opioid treatment services.”

However, Chairman Kristopher Peters, of the Squaxin Island Tribe in Washington State, told the Washington Post, “There is no amount of money that’s going to solve the generational issues that have been created from this. Our hope is that we can use these funds to help revitalize our culture and help heal our people.”

Johnson & Johnson says it no longer sells prescription opioids in the US

Hundreds of Native American tribes have tentatively settled in what one of the lead attorneys describes as “an epic deal”: The top 3 pharmaceutical distributors in the US and Johnson & Johnson have agreed to pay $665 million for deceptive marketing practices and overdistribution of opioids. Native Americans were among those hardest hit by the opioid epidemic. Between 2006 and 2014, Native Americans were nearly 50% more likely than non-Natives to die of an opioid overdose. In 2014, they ranked number 1 for death by opioid overdose.

Overprescribing was rampant. In some areas, such as southwestern Virginia, eastern Kentucky, and Alabama, prescriptions were 5 to 6 times higher than the national average. The overprescribing was largely due to massive and aggressive billion-dollar marketing campaigns, which misrepresented the safety of opioid medications. Purdue Pharma, for instance, trained sales representatives to claim that the risk of addiction was “less than 1 percent.” In an interview with Smithsonian Magazine, Caleb Alexander, MD, codirector of Johns Hopkins’ Center for Drug Safety and Effectiveness, said, “When I was in residency training, we were taught that one needn’t worry about the addictive potential of opioids if a patient had true pain.” He said it was no accident that physicians were cultivated to overestimate the effectiveness for chronic, noncancer pain while underestimating the risks.

Native Americans were not only in the target group for prescriptions, but also apparently singularly targeted. “We were preyed upon,” said Chickasaw Nation Governor Bill Anoatubby in the Washington Post. “It was unconscionable.” A Washington Post analysis found that, between 2006 and 2014, opioid distributors shipped an average of 36 pills per person in the US. States in the so-called opioid belt (mostly Southern states), received an average of 60 to 66 pills per person. The distributors shipped 57 pills per person to Oklahoma, home to nearly 322,000 Native Americans. (The opioid death rate for Native Americans in Oklahoma from 2006 to 2014 was more than triple the nationwide rate for non-Natives.) In South Dakota as recently as 2015, enough opioids were prescribed to medicate every adult around-the-clock for 19 consecutive days. Native Americans comprise 9% of South Dakota’s population; however, almost 30% of the patients are being treated for opioid use disorder.

In the settlement, which is a first for tribes, McKesson, Cardinal Health, and AmerisourceBergen would pay $515 million over 7 years. Johnson & Johnson would contribute $150 million in 2 years to the federally recognized tribes. “This settlement is a real turning point in history,” said Lloyd Miller, one of the attorneys representing one-third of the litigating tribes.

But the money is still small compensation for ravaging millions of lives. “Flooding the Native community with Western medicine—sedating a population rather than seeking to understand its needs and challenges—is not an acceptable means of handling its trauma,” the Lakota People’s Law Project says in an article on its website. Thus, the money dispersal will be overseen by a panel of tribal health experts, to go toward programs that aid drug users and their communities.

The funds will be managed in a way that will consider the long-term damage, Native American leaders vow. Children, for instance, have not been exempt from the sequelae of the overprescribing. Foster care systems are “overrun” with children of addicted parents, the Law Project says, and the children are placed in homes outside the tribe. “In the long run, this has the potential to curtail tribal membership, break down familial lines, and degrade cultural values.”

Dealing with the problem has drained tribal resources—doubly strained by the COVID-19 epidemic. Chairman Douglas Yankton, of the Spirit Lake Nation in North Dakota, said in a statement, “The dollars that will flow to Tribes under this initial settlement will help fund crucial, on-reservation, culturally appropriate opioid treatment services.”

However, Chairman Kristopher Peters, of the Squaxin Island Tribe in Washington State, told the Washington Post, “There is no amount of money that’s going to solve the generational issues that have been created from this. Our hope is that we can use these funds to help revitalize our culture and help heal our people.”

Johnson & Johnson says it no longer sells prescription opioids in the US

Hundreds of Native American tribes have tentatively settled in what one of the lead attorneys describes as “an epic deal”: The top 3 pharmaceutical distributors in the US and Johnson & Johnson have agreed to pay $665 million for deceptive marketing practices and overdistribution of opioids. Native Americans were among those hardest hit by the opioid epidemic. Between 2006 and 2014, Native Americans were nearly 50% more likely than non-Natives to die of an opioid overdose. In 2014, they ranked number 1 for death by opioid overdose.

Overprescribing was rampant. In some areas, such as southwestern Virginia, eastern Kentucky, and Alabama, prescriptions were 5 to 6 times higher than the national average. The overprescribing was largely due to massive and aggressive billion-dollar marketing campaigns, which misrepresented the safety of opioid medications. Purdue Pharma, for instance, trained sales representatives to claim that the risk of addiction was “less than 1 percent.” In an interview with Smithsonian Magazine, Caleb Alexander, MD, codirector of Johns Hopkins’ Center for Drug Safety and Effectiveness, said, “When I was in residency training, we were taught that one needn’t worry about the addictive potential of opioids if a patient had true pain.” He said it was no accident that physicians were cultivated to overestimate the effectiveness for chronic, noncancer pain while underestimating the risks.

Native Americans were not only in the target group for prescriptions, but also apparently singularly targeted. “We were preyed upon,” said Chickasaw Nation Governor Bill Anoatubby in the Washington Post. “It was unconscionable.” A Washington Post analysis found that, between 2006 and 2014, opioid distributors shipped an average of 36 pills per person in the US. States in the so-called opioid belt (mostly Southern states), received an average of 60 to 66 pills per person. The distributors shipped 57 pills per person to Oklahoma, home to nearly 322,000 Native Americans. (The opioid death rate for Native Americans in Oklahoma from 2006 to 2014 was more than triple the nationwide rate for non-Natives.) In South Dakota as recently as 2015, enough opioids were prescribed to medicate every adult around-the-clock for 19 consecutive days. Native Americans comprise 9% of South Dakota’s population; however, almost 30% of the patients are being treated for opioid use disorder.

In the settlement, which is a first for tribes, McKesson, Cardinal Health, and AmerisourceBergen would pay $515 million over 7 years. Johnson & Johnson would contribute $150 million in 2 years to the federally recognized tribes. “This settlement is a real turning point in history,” said Lloyd Miller, one of the attorneys representing one-third of the litigating tribes.

But the money is still small compensation for ravaging millions of lives. “Flooding the Native community with Western medicine—sedating a population rather than seeking to understand its needs and challenges—is not an acceptable means of handling its trauma,” the Lakota People’s Law Project says in an article on its website. Thus, the money dispersal will be overseen by a panel of tribal health experts, to go toward programs that aid drug users and their communities.

The funds will be managed in a way that will consider the long-term damage, Native American leaders vow. Children, for instance, have not been exempt from the sequelae of the overprescribing. Foster care systems are “overrun” with children of addicted parents, the Law Project says, and the children are placed in homes outside the tribe. “In the long run, this has the potential to curtail tribal membership, break down familial lines, and degrade cultural values.”

Dealing with the problem has drained tribal resources—doubly strained by the COVID-19 epidemic. Chairman Douglas Yankton, of the Spirit Lake Nation in North Dakota, said in a statement, “The dollars that will flow to Tribes under this initial settlement will help fund crucial, on-reservation, culturally appropriate opioid treatment services.”

However, Chairman Kristopher Peters, of the Squaxin Island Tribe in Washington State, told the Washington Post, “There is no amount of money that’s going to solve the generational issues that have been created from this. Our hope is that we can use these funds to help revitalize our culture and help heal our people.”

Johnson & Johnson says it no longer sells prescription opioids in the US

Two illicit drugs are contributing to a sharp rise in fentanyl-related deaths, a new study from the Centers for Disease Control and Prevention shows.

Para-fluorofentanyl, a schedule I substance often found in heroin packets and counterfeit pills, is making a comeback on the illicit drug market, Jordan Trecki, PhD, and associates reported in the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (2022 Jan 28;71[4]:153-5). U.S. medical examiner reports and national law enforcement seizure data point to a rise in encounters of this drug along with metonitazene, a benzimidazole-opioid, in combination with fentanyl.

On their own, para-fluorofentanyl and metonitazene can kill the user through respiratory depression. Combinations of these substances and other opioids, including fentanyl-related compounds or adulterants, “pose an even greater potential harm to the patient than previously observed,” reported Dr. Trecki, a pharmacologist affiliated with the Drug Enforcement Administration, and colleagues.

Opioids contribute to about 75% of all U.S. drug overdose deaths, which rose by 28.5% during 2020-2021, according to the National Center for Health Statistics. And fentanyl is replacing heroin as the primary drug of use, said addiction specialist Brian Fuehrlein, MD, PhD, in an interview.

“For patients with stimulant use disorder and even cannabis use disorder, fentanyl is becoming more and more common as an adulterant in those substances, often resulting in inadvertent use. Hence, fentanyl and fentanyl-like drugs and fentanyl analogues are becoming increasingly common and important,” said Dr. Fuehrlein, director of the psychiatric emergency room at the VA Connecticut Healthcare System. He was not involved with the MMWR study.
 

Tennessee data reflect national problem

Recent data from a medical examiner in Knoxville, Tenn., illustrate what might be happening nationwide with those two emerging substances.

Over the last 2 years, the Knox County Regional Forensic Center has identified para-fluorofentanyl in the toxicology results of drug overdose victims, and metonitazene – either on its own or in combination with fentanyl and para-fluorofentanyl. Fentanyl appeared in 562 or 73% of 770 unintentional drug overdose deaths from November 2020 to August 2021. Forty-eight of these cases involved para-fluorofentanyl, and 26 involved metonitazene.

“Although the percentage of law enforcement encounters with these substances in Tennessee decreased relative to the national total percentage within this time frame, the increase in encounters both within Tennessee and nationally reflect an increased distribution of para-fluorofentanyl and metonitazene throughout the United States,” the authors reported.
 

How to identify substances, manage overdoses

The authors encouraged physicians, labs, and medical examiners to be on the lookout for these two substances either in the emergency department or when identifying the cause of drug overdose deaths.

They also advised that stronger opioids, such as fentanyl, para-fluorofentanyl, metonitazene, or other benzimidazoles may warrant additional doses of the opioid-reversal drug naloxone.

While he hasn’t personally seen any of these drugs in his practice, “I would assume that these are on the rise due to inexpensive cost to manufacture and potency of effect,” said Dr. Fuehrlein, also an associate professor of psychiatry at Yale University, New Haven, Conn.

The need for additional naloxone to manage acute overdoses is a key takeaway of the MMWR paper, he added. Clinicians should also educate patients about harm reduction strategies to avoid overdose death when using potentially powerful and unknown drugs. “Things like start low and go slow, buy from the same supplier, do not use opioids with alcohol or benzos, have Narcan available, do not use alone, etc.”

Dr. Fuehrlein had no disclosures.

Two illicit drugs are contributing to a sharp rise in fentanyl-related deaths, a new study from the Centers for Disease Control and Prevention shows.

Para-fluorofentanyl, a schedule I substance often found in heroin packets and counterfeit pills, is making a comeback on the illicit drug market, Jordan Trecki, PhD, and associates reported in the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (2022 Jan 28;71[4]:153-5). U.S. medical examiner reports and national law enforcement seizure data point to a rise in encounters of this drug along with metonitazene, a benzimidazole-opioid, in combination with fentanyl.

On their own, para-fluorofentanyl and metonitazene can kill the user through respiratory depression. Combinations of these substances and other opioids, including fentanyl-related compounds or adulterants, “pose an even greater potential harm to the patient than previously observed,” reported Dr. Trecki, a pharmacologist affiliated with the Drug Enforcement Administration, and colleagues.

Opioids contribute to about 75% of all U.S. drug overdose deaths, which rose by 28.5% during 2020-2021, according to the National Center for Health Statistics. And fentanyl is replacing heroin as the primary drug of use, said addiction specialist Brian Fuehrlein, MD, PhD, in an interview.

“For patients with stimulant use disorder and even cannabis use disorder, fentanyl is becoming more and more common as an adulterant in those substances, often resulting in inadvertent use. Hence, fentanyl and fentanyl-like drugs and fentanyl analogues are becoming increasingly common and important,” said Dr. Fuehrlein, director of the psychiatric emergency room at the VA Connecticut Healthcare System. He was not involved with the MMWR study.
 

Tennessee data reflect national problem

Recent data from a medical examiner in Knoxville, Tenn., illustrate what might be happening nationwide with those two emerging substances.

Over the last 2 years, the Knox County Regional Forensic Center has identified para-fluorofentanyl in the toxicology results of drug overdose victims, and metonitazene – either on its own or in combination with fentanyl and para-fluorofentanyl. Fentanyl appeared in 562 or 73% of 770 unintentional drug overdose deaths from November 2020 to August 2021. Forty-eight of these cases involved para-fluorofentanyl, and 26 involved metonitazene.

“Although the percentage of law enforcement encounters with these substances in Tennessee decreased relative to the national total percentage within this time frame, the increase in encounters both within Tennessee and nationally reflect an increased distribution of para-fluorofentanyl and metonitazene throughout the United States,” the authors reported.
 

How to identify substances, manage overdoses

The authors encouraged physicians, labs, and medical examiners to be on the lookout for these two substances either in the emergency department or when identifying the cause of drug overdose deaths.

They also advised that stronger opioids, such as fentanyl, para-fluorofentanyl, metonitazene, or other benzimidazoles may warrant additional doses of the opioid-reversal drug naloxone.

While he hasn’t personally seen any of these drugs in his practice, “I would assume that these are on the rise due to inexpensive cost to manufacture and potency of effect,” said Dr. Fuehrlein, also an associate professor of psychiatry at Yale University, New Haven, Conn.

The need for additional naloxone to manage acute overdoses is a key takeaway of the MMWR paper, he added. Clinicians should also educate patients about harm reduction strategies to avoid overdose death when using potentially powerful and unknown drugs. “Things like start low and go slow, buy from the same supplier, do not use opioids with alcohol or benzos, have Narcan available, do not use alone, etc.”

Dr. Fuehrlein had no disclosures.

Two illicit drugs are contributing to a sharp rise in fentanyl-related deaths, a new study from the Centers for Disease Control and Prevention shows.

Para-fluorofentanyl, a schedule I substance often found in heroin packets and counterfeit pills, is making a comeback on the illicit drug market, Jordan Trecki, PhD, and associates reported in the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (2022 Jan 28;71[4]:153-5). U.S. medical examiner reports and national law enforcement seizure data point to a rise in encounters of this drug along with metonitazene, a benzimidazole-opioid, in combination with fentanyl.

On their own, para-fluorofentanyl and metonitazene can kill the user through respiratory depression. Combinations of these substances and other opioids, including fentanyl-related compounds or adulterants, “pose an even greater potential harm to the patient than previously observed,” reported Dr. Trecki, a pharmacologist affiliated with the Drug Enforcement Administration, and colleagues.

Opioids contribute to about 75% of all U.S. drug overdose deaths, which rose by 28.5% during 2020-2021, according to the National Center for Health Statistics. And fentanyl is replacing heroin as the primary drug of use, said addiction specialist Brian Fuehrlein, MD, PhD, in an interview.

“For patients with stimulant use disorder and even cannabis use disorder, fentanyl is becoming more and more common as an adulterant in those substances, often resulting in inadvertent use. Hence, fentanyl and fentanyl-like drugs and fentanyl analogues are becoming increasingly common and important,” said Dr. Fuehrlein, director of the psychiatric emergency room at the VA Connecticut Healthcare System. He was not involved with the MMWR study.
 

Tennessee data reflect national problem

Recent data from a medical examiner in Knoxville, Tenn., illustrate what might be happening nationwide with those two emerging substances.

Over the last 2 years, the Knox County Regional Forensic Center has identified para-fluorofentanyl in the toxicology results of drug overdose victims, and metonitazene – either on its own or in combination with fentanyl and para-fluorofentanyl. Fentanyl appeared in 562 or 73% of 770 unintentional drug overdose deaths from November 2020 to August 2021. Forty-eight of these cases involved para-fluorofentanyl, and 26 involved metonitazene.

“Although the percentage of law enforcement encounters with these substances in Tennessee decreased relative to the national total percentage within this time frame, the increase in encounters both within Tennessee and nationally reflect an increased distribution of para-fluorofentanyl and metonitazene throughout the United States,” the authors reported.
 

How to identify substances, manage overdoses

The authors encouraged physicians, labs, and medical examiners to be on the lookout for these two substances either in the emergency department or when identifying the cause of drug overdose deaths.

They also advised that stronger opioids, such as fentanyl, para-fluorofentanyl, metonitazene, or other benzimidazoles may warrant additional doses of the opioid-reversal drug naloxone.

While he hasn’t personally seen any of these drugs in his practice, “I would assume that these are on the rise due to inexpensive cost to manufacture and potency of effect,” said Dr. Fuehrlein, also an associate professor of psychiatry at Yale University, New Haven, Conn.

The need for additional naloxone to manage acute overdoses is a key takeaway of the MMWR paper, he added. Clinicians should also educate patients about harm reduction strategies to avoid overdose death when using potentially powerful and unknown drugs. “Things like start low and go slow, buy from the same supplier, do not use opioids with alcohol or benzos, have Narcan available, do not use alone, etc.”

Dr. Fuehrlein had no disclosures.

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

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

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

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

Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.

“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.

The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.

Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.

“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”

Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”

With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.

Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.

To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.

They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.

And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.

Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.

“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.

Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
 

Unrecognized genetic strains

Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.

“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.

Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.

“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”

Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”

“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”

Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”

“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”

As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.

“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.

The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.

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

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

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

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

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

A new drug has become the first and only treatment for people with cold agglutinin disease (CAD) that is approved by the U.S. Food and Drug Administration.

CAD is a rare autoimmune hemolytic anemia, affecting about 5,000 people in the United States. It is caused by antibodies binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). This can lead to severe anemia, which is often treated by blood transfusions.

The new product is sutimlimab-jome (Enjaymo), and it works by inhibiting the destruction of red blood cells and so decreases the need for blood transfusions.

“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients,” commented Catherine Broome, MD, associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, in a company press release.

Dr. Broome was the principal investigator in the CARDINAL study, which was the basis for the new approval. In this pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin (Hgb) and bilirubin levels, she commented in the company statement.

The CARDINAL study was a 26-week open-label, single-arm phase 3 study conducted in 24 patients with CAD who had recent history of blood transfusion.

The primary efficacy endpoint was a composite defined as the proportion of patients who achieved normalization of Hgb level greater than or equal to 12 g/dL or demonstrated an increase from baseline in Hgb level greater than or equal to 2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26.

More than half of the patients (13 of 24, 54%) met the composite primary endpoint criteria, with 17 of 24 (71%) patients remaining transfusion-free after week 5. Most patients (22 of 24, 92%) did not use other CAD-related treatments.

For the secondary measures on disease process, patients enrolled in the trial experienced a mean increase in Hgb level of 2.29 g/dL at week 3 and 3.18 g/dL at the 26-week treatment assessment time points (increasing from the mean baseline level of 8.6 g/dL). In addition, there was a mean reduction in bilirubin levels (n = 14) of -2.23 mg/dL from a mean baseline level of 3.23 mg/dL.

The most common adverse reactions occurring in 10% or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 3 of 24 (13%) patients, and these included streptococcal sepsis and staphylococcal wound infection (n = 1), arthralgia (n = 1), and respiratory tract infection (n = 1).

None of the adverse reactions led to discontinuation of the drug, the company noted. Dosage interruptions due to an adverse reaction occurred in 4 of 24 (17%) patients who received the drug.

The recommended dose is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people greater than 75 kg). The drug is administered intravenously weekly for the first 2 weeks with administration every 2 weeks thereafter.

Full prescribing information is available here.

The product is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways, the company noted.

In the U.S., Enjaymo received FDA breakthrough therapy and orphan drug designation, as well as priority review. The product is awaiting approval in Europe and Japan.

Sanofi says the product is expected to be available in the United States in the coming weeks, with a list price, or wholesale acquisition cost, of $1,800 per vial. Actual costs to patients are generally anticipated to be lower, as the list price does not reflect insurance coverage, copay support, or financial assistance from patient support programs. The company offers support for eligible patients on 1-833-223-2428.

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

The U.S. Food and Drug Administration has approved rilpivirine and cabotegravir (Cabenuva) to 2-month dosing for adults living with HIV-1 infection.

Cabenuva was first approved by the FDA in January 2021 to be administered once monthly to treat HIV-1 infection in virologically suppressed adults. The medication was the first injectable complete antiretroviral regimen approved by the FDA.

Cabenuva can replace a current treatment in virologically suppressed adults on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to rilpivirine and cabotegravir, the Janssen Pharmaceutical Companies of Johnson & Johnson said in a press release. Janssen and ViiV Healthcare codeveloped the injectable antiretroviral medication Cabenuva.

The expanded label approval “marks an important step forward in advancing the treatment landscape for people living with HIV,” said Candice Long, the president of infectious diseases and vaccines at Janssen Therapeutics, in a Feb. 1 press release. “With this milestone, adults living with HIV have a treatment option that further reduces the frequency of medication.”

This expanded approval was based on global clinical trial of 1,045 adults with HIV-1, which found Cabenuva administered every 8 weeks (3 mL dose of both cabotegravir and rilpivirine) to be noninferior to the 4-week regimen (2 mL dose of both medicines). At week 48 of the trial, the proportion of participants with viral loads above 50 copies per milliliter was 1.7% in the 2-month arm and 1.0% in the 1-month arm. The study found that rates of virological suppression were similar for both the 1-month and 2-month regimens (93.5% and 94.3%, respectively).

The most common side effects were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Adverse reactions reported in individuals receiving the regimen every 2 months or once monthly were similar. Cabenuva is contraindicated for patients with a hypersensitivity reaction to cabotegravir or rilpivirine or for those receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and more than one dose of systemic dexamethasone.

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

The U.S. Food and Drug Administration has approved rilpivirine and cabotegravir (Cabenuva) to 2-month dosing for adults living with HIV-1 infection.

Cabenuva was first approved by the FDA in January 2021 to be administered once monthly to treat HIV-1 infection in virologically suppressed adults. The medication was the first injectable complete antiretroviral regimen approved by the FDA.

Cabenuva can replace a current treatment in virologically suppressed adults on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to rilpivirine and cabotegravir, the Janssen Pharmaceutical Companies of Johnson & Johnson said in a press release. Janssen and ViiV Healthcare codeveloped the injectable antiretroviral medication Cabenuva.

The expanded label approval “marks an important step forward in advancing the treatment landscape for people living with HIV,” said Candice Long, the president of infectious diseases and vaccines at Janssen Therapeutics, in a Feb. 1 press release. “With this milestone, adults living with HIV have a treatment option that further reduces the frequency of medication.”

This expanded approval was based on global clinical trial of 1,045 adults with HIV-1, which found Cabenuva administered every 8 weeks (3 mL dose of both cabotegravir and rilpivirine) to be noninferior to the 4-week regimen (2 mL dose of both medicines). At week 48 of the trial, the proportion of participants with viral loads above 50 copies per milliliter was 1.7% in the 2-month arm and 1.0% in the 1-month arm. The study found that rates of virological suppression were similar for both the 1-month and 2-month regimens (93.5% and 94.3%, respectively).

The most common side effects were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Adverse reactions reported in individuals receiving the regimen every 2 months or once monthly were similar. Cabenuva is contraindicated for patients with a hypersensitivity reaction to cabotegravir or rilpivirine or for those receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and more than one dose of systemic dexamethasone.

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

The U.S. Food and Drug Administration has approved rilpivirine and cabotegravir (Cabenuva) to 2-month dosing for adults living with HIV-1 infection.

Cabenuva was first approved by the FDA in January 2021 to be administered once monthly to treat HIV-1 infection in virologically suppressed adults. The medication was the first injectable complete antiretroviral regimen approved by the FDA.

Cabenuva can replace a current treatment in virologically suppressed adults on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to rilpivirine and cabotegravir, the Janssen Pharmaceutical Companies of Johnson & Johnson said in a press release. Janssen and ViiV Healthcare codeveloped the injectable antiretroviral medication Cabenuva.

The expanded label approval “marks an important step forward in advancing the treatment landscape for people living with HIV,” said Candice Long, the president of infectious diseases and vaccines at Janssen Therapeutics, in a Feb. 1 press release. “With this milestone, adults living with HIV have a treatment option that further reduces the frequency of medication.”

This expanded approval was based on global clinical trial of 1,045 adults with HIV-1, which found Cabenuva administered every 8 weeks (3 mL dose of both cabotegravir and rilpivirine) to be noninferior to the 4-week regimen (2 mL dose of both medicines). At week 48 of the trial, the proportion of participants with viral loads above 50 copies per milliliter was 1.7% in the 2-month arm and 1.0% in the 1-month arm. The study found that rates of virological suppression were similar for both the 1-month and 2-month regimens (93.5% and 94.3%, respectively).

The most common side effects were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Adverse reactions reported in individuals receiving the regimen every 2 months or once monthly were similar. Cabenuva is contraindicated for patients with a hypersensitivity reaction to cabotegravir or rilpivirine or for those receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and more than one dose of systemic dexamethasone.

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

This transcript has been edited for clarity. The transcript and an accompanying video first appeared on Medscape.com.

This is Mark Kris from chilly New York and Memorial Sloan Kettering. Today I want to talk about a recent article in the Journal of Clinical Oncology that reported a study of a new neurokinin-1 antagonist called fosnetupitant. This was a well-conducted trial that demonstrates the noninferiority of IV fosnetupitant when compared with IV fosaprepitant. By their study criteria, fosnetupitant was not inferior.

But my reason for discussing this is that the paper and the trial miss the point for the field right now. Although the authors talk about the prevention of nausea and vomiting in the introduction, in the paper itself and in the abstract results section, there’s not a single mention about the medication’s ability to control nausea, which is the critical issue for our patients today. You have to go into the supplementary data to find it mentioned, and what you find is that the prevention of nausea is 50% for both the control and this new drug. We control nausea in only half of the patients who receive cisplatin in 2022. That is a huge issue.

When you ask patients what are the effects of cancer treatment that they fear most, that concerns them most, it’s nausea and emesis; indeed, nausea has replaced emesis as the biggest concern. And although this trial used emesis as the main endpoint, and it was useful in defining the drug, it was not useful in coming up with a new treatment that addresses a huge need. Further, the authors talk about an advantage to fosnetupitant based on infusion reactions, but it is a difference of 0.3% vs. 3%. They talk about that sort of thing in the abstract and in the discussion section but don’t include nausea as part of the key endpoint of this trial. Again, you had to dig deeply to find out that, frankly, fosnetupitant was no better than the drugs we already have.

The other concerning point is that we do have another drug that works well. If you go to the American Society of Clinical Oncology or National Comprehensive Cancer Network guidelines for patients receiving high dosages of cisplatin, you find a four-drug regimen, including olanzapine, and that was not used here. Why is olanzapine so critical? It’s an available drug, it’s an inexpensive drug, it’s a safe drug, and it improves nausea by 15%.

So they did this huge trial to show noninferiority, and they neglected to give a drug that could deal with the most serious side effect of cancer therapy – nausea – and improve things by 15%.

A challenge to people in this field: We have to do better. Nausea is a big problem. While noninferiority trials can be helpful for drug development, they’re not really helpful for the field. With a problem of this magnitude, we need better drugs to control nausea. In the meantime, I urge you all to follow the guidelines for high doses of cisplatin. Please use the four-drug regimen that is recommended in the guidelines and widely used in the United States. Going forward, make sure that when we expend huge amounts of energy to develop new agents and report them in our medical journals, that we look for ways to advance care where there are significant gaps in our ability to deliver what we want. Delivering better control of nausea is something we all need to be committed to. It’s a huge unmet need, and I hope future trials will address that need. Our patients will be better for it and we’ll be better in that we’re delivering what patients deserve, what they need, and what they ask for.

Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. He reported serving as a director, officer, partner, employee, adviser, consultant, or trustee for AstraZeneca, Roche/Genentech, and Ariad Pharmaceuticals, and has received research grants from Pfizer, PUMA, and Roche/Genentech.

This transcript has been edited for clarity. The transcript and an accompanying video first appeared on Medscape.com.

This is Mark Kris from chilly New York and Memorial Sloan Kettering. Today I want to talk about a recent article in the Journal of Clinical Oncology that reported a study of a new neurokinin-1 antagonist called fosnetupitant. This was a well-conducted trial that demonstrates the noninferiority of IV fosnetupitant when compared with IV fosaprepitant. By their study criteria, fosnetupitant was not inferior.

But my reason for discussing this is that the paper and the trial miss the point for the field right now. Although the authors talk about the prevention of nausea and vomiting in the introduction, in the paper itself and in the abstract results section, there’s not a single mention about the medication’s ability to control nausea, which is the critical issue for our patients today. You have to go into the supplementary data to find it mentioned, and what you find is that the prevention of nausea is 50% for both the control and this new drug. We control nausea in only half of the patients who receive cisplatin in 2022. That is a huge issue.

When you ask patients what are the effects of cancer treatment that they fear most, that concerns them most, it’s nausea and emesis; indeed, nausea has replaced emesis as the biggest concern. And although this trial used emesis as the main endpoint, and it was useful in defining the drug, it was not useful in coming up with a new treatment that addresses a huge need. Further, the authors talk about an advantage to fosnetupitant based on infusion reactions, but it is a difference of 0.3% vs. 3%. They talk about that sort of thing in the abstract and in the discussion section but don’t include nausea as part of the key endpoint of this trial. Again, you had to dig deeply to find out that, frankly, fosnetupitant was no better than the drugs we already have.

The other concerning point is that we do have another drug that works well. If you go to the American Society of Clinical Oncology or National Comprehensive Cancer Network guidelines for patients receiving high dosages of cisplatin, you find a four-drug regimen, including olanzapine, and that was not used here. Why is olanzapine so critical? It’s an available drug, it’s an inexpensive drug, it’s a safe drug, and it improves nausea by 15%.

So they did this huge trial to show noninferiority, and they neglected to give a drug that could deal with the most serious side effect of cancer therapy – nausea – and improve things by 15%.

A challenge to people in this field: We have to do better. Nausea is a big problem. While noninferiority trials can be helpful for drug development, they’re not really helpful for the field. With a problem of this magnitude, we need better drugs to control nausea. In the meantime, I urge you all to follow the guidelines for high doses of cisplatin. Please use the four-drug regimen that is recommended in the guidelines and widely used in the United States. Going forward, make sure that when we expend huge amounts of energy to develop new agents and report them in our medical journals, that we look for ways to advance care where there are significant gaps in our ability to deliver what we want. Delivering better control of nausea is something we all need to be committed to. It’s a huge unmet need, and I hope future trials will address that need. Our patients will be better for it and we’ll be better in that we’re delivering what patients deserve, what they need, and what they ask for.

Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. He reported serving as a director, officer, partner, employee, adviser, consultant, or trustee for AstraZeneca, Roche/Genentech, and Ariad Pharmaceuticals, and has received research grants from Pfizer, PUMA, and Roche/Genentech.

This transcript has been edited for clarity. The transcript and an accompanying video first appeared on Medscape.com.

This is Mark Kris from chilly New York and Memorial Sloan Kettering. Today I want to talk about a recent article in the Journal of Clinical Oncology that reported a study of a new neurokinin-1 antagonist called fosnetupitant. This was a well-conducted trial that demonstrates the noninferiority of IV fosnetupitant when compared with IV fosaprepitant. By their study criteria, fosnetupitant was not inferior.

But my reason for discussing this is that the paper and the trial miss the point for the field right now. Although the authors talk about the prevention of nausea and vomiting in the introduction, in the paper itself and in the abstract results section, there’s not a single mention about the medication’s ability to control nausea, which is the critical issue for our patients today. You have to go into the supplementary data to find it mentioned, and what you find is that the prevention of nausea is 50% for both the control and this new drug. We control nausea in only half of the patients who receive cisplatin in 2022. That is a huge issue.

When you ask patients what are the effects of cancer treatment that they fear most, that concerns them most, it’s nausea and emesis; indeed, nausea has replaced emesis as the biggest concern. And although this trial used emesis as the main endpoint, and it was useful in defining the drug, it was not useful in coming up with a new treatment that addresses a huge need. Further, the authors talk about an advantage to fosnetupitant based on infusion reactions, but it is a difference of 0.3% vs. 3%. They talk about that sort of thing in the abstract and in the discussion section but don’t include nausea as part of the key endpoint of this trial. Again, you had to dig deeply to find out that, frankly, fosnetupitant was no better than the drugs we already have.

The other concerning point is that we do have another drug that works well. If you go to the American Society of Clinical Oncology or National Comprehensive Cancer Network guidelines for patients receiving high dosages of cisplatin, you find a four-drug regimen, including olanzapine, and that was not used here. Why is olanzapine so critical? It’s an available drug, it’s an inexpensive drug, it’s a safe drug, and it improves nausea by 15%.

So they did this huge trial to show noninferiority, and they neglected to give a drug that could deal with the most serious side effect of cancer therapy – nausea – and improve things by 15%.

A challenge to people in this field: We have to do better. Nausea is a big problem. While noninferiority trials can be helpful for drug development, they’re not really helpful for the field. With a problem of this magnitude, we need better drugs to control nausea. In the meantime, I urge you all to follow the guidelines for high doses of cisplatin. Please use the four-drug regimen that is recommended in the guidelines and widely used in the United States. Going forward, make sure that when we expend huge amounts of energy to develop new agents and report them in our medical journals, that we look for ways to advance care where there are significant gaps in our ability to deliver what we want. Delivering better control of nausea is something we all need to be committed to. It’s a huge unmet need, and I hope future trials will address that need. Our patients will be better for it and we’ll be better in that we’re delivering what patients deserve, what they need, and what they ask for.

Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. He reported serving as a director, officer, partner, employee, adviser, consultant, or trustee for AstraZeneca, Roche/Genentech, and Ariad Pharmaceuticals, and has received research grants from Pfizer, PUMA, and Roche/Genentech.

Two patients with chronic lymphocytic leukemia (CLL) who 10 years ago were among the first to receive groundbreaking chimeric antigen receptor T-cell therapy were still in remission a decade later, and they continued to show detectable levels of CAR T cells.

“We can now conclude that CAR T cells can actually cure patients with leukemia based on these results,” said senior author Carl H. June, MD, in a press briefing on the study published in Nature.

“The major finding from this paper is that, 10 years down the road, you can find these [CAR T] cells,” Dr. June, director of the Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, added. “The cells have evolved, and that was a big surprise ... but they are still able to kill leukemia cells 10 years after infusion.”

CAR T-cell therapy, in which patients’ own T cells are removed, reprogrammed in a lab to recognize and attack cancer cells, and then infused back into the patients, has transformed treatment of various blood cancers and shows often-remarkable results in achieving remissions.

While the treatment has become a routine therapy for certain leukemias, long-term results on the fate and function of the cells over time has been highly anticipated.

In the first published observations of a 10-year follow-up of patients treated with CAR T cells, Dr. June and colleagues described the findings for two patients, both with CLL, who back in 2010 were among the first to be treated with this groundbreaking therapy at the University of Pennsylvania.

A decade later, the CAR T cells are found to have remained detectable in both patients, who achieved complete remission in their first year of treatment, and both have sustained that remission.

Notably, the cells have evolved over the years – from initially being dominated by killer T cells to being dominated primarily by proliferative CD4-positive CAR T cells – with one of the patients exclusively having CD4-positive cells at year 9.3.

“The killer T cells did the initial heavy lifting of eliminating the tumor, “ first author J. Joseph Melenhorst, PhD, said in an interview.

“Once their job was done, those cells went down to very low levels, but the CD4-positive population persisted,” said Dr. Melenhorst, who established the lab at the University of Pennsylvania to follow patients treated with CAR T-cell therapy. “[This] delayed phase of immune response against cancer is a novel insight, and we were surprised to see it.”

Dr. Melenhorst noted that the clonal makeup of the CD4-positive cells importantly stabilized and became dominated by a small number of clones, suggesting further sustainability.

When one of the two patients, Doug Olson, who participated in the press conference, donated his cells back to the center after 9.3 years, the researchers found that his cells were still capable of destroying leukemia cells in the lab.

“Ten years [post infusion], we can’t find any of the leukemia cells and we still have the CAR T cells that are on patrol and on surveillance for residual leukemia,” Dr. June said.

One challenge of the otherwise desirable elimination of leukemia cells is that some aspects of sustaining CAR T-cell activity become problematic.

“The aspect of how the remission is maintained [is] very hard to study in a patient when there is no leukemia at all,” Dr. June explained. “It could be the last cell was gone within 3 weeks [of treatment], or it could be that the [cancer cells] are coming up like whack-a-moles, and they are killed because these CAR T cells are on patrol.”

Sadly, the other CLL patient, Bill Ludwig, who was first to receive the CAR T-cell treatment, died in 2021 from COVID-19.
 

Effects in other blood diseases similar?

CAR T-cell therapy is currently approved in the United States for several blood cancers, and whether similar long-term patterns of the cells may be observed in other patient and cancer types remains to be seen, Dr. Melenhorst said.

“I think in CLL we will see something similar, but in other diseases, we have yet to learn,” he said. “It may depend on issues including which domain has been engineered into the CAR.”

While the prospect of some patients being “cured” is exciting, responses to the therapy have generally been mixed. In CLL, for instance, full remissions have been observed to be maintained in about a quarter of patients, with higher rates observed in some lymphomas and pediatric ALL patients, Dr. Melenhorst explained.

The effects of CAR T-cell therapy in solid cancers have so far been more disappointing, with no research centers reproducing the kinds of results that have been seen with blood cancers.

“There appear to be a number of reasons, including that the [solid] tumor is more complex, and these solid cancers have ways to evade the immune system that need to be overcome,” Dr. June explained.

And despite the more encouraging findings in blood cancers, even with those, “the biggest disappointment is that CAR T-cell therapy doesn’t work all the time. It doesn’t work in every patient,” coauthor David Porter, MD, the University of Pennsylvania oncologist who treated the two patients, said in the press briefing.

“I think the importance of the Nature study is that we are starting to learn the mechanisms of why and how this works, so that we can start to get at how to make it work for more people,” Dr. Porter added. “But what we do see is that, when it works, it really is beyond what we expected 10 or 11 years ago.”

Speaking in the press briefing, Mr. Olson described how several weeks after his treatment in 2010, he became very ill with what has become known as the common, short-term side effect of cytokine release syndrome.

However, after Mr. Olson recovered a few days later, Dr. Porter gave him the remarkable news that “we cannot find a single cancer cell. You appear completely free of CLL.”

Mr. Olson reported that he has since lived a “full life,” kept working, and has even run some half-marathons.

Dr. June confided that the current 10-year results far exceed the team’s early expectations for CAR T-cell therapy. “After Doug [initially] signed his informed consent document for this, we thought that the cells would all be gone within a month or 2. The fact that they have survived for 10 years was a major surprise – and a happy one at that.”

Dr. June, Dr. Melenhorst, and Dr. Porter reported holding patents related to CAR T-cell manufacturing and biomarker discovery.

Two patients with chronic lymphocytic leukemia (CLL) who 10 years ago were among the first to receive groundbreaking chimeric antigen receptor T-cell therapy were still in remission a decade later, and they continued to show detectable levels of CAR T cells.

“We can now conclude that CAR T cells can actually cure patients with leukemia based on these results,” said senior author Carl H. June, MD, in a press briefing on the study published in Nature.

“The major finding from this paper is that, 10 years down the road, you can find these [CAR T] cells,” Dr. June, director of the Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, added. “The cells have evolved, and that was a big surprise ... but they are still able to kill leukemia cells 10 years after infusion.”

CAR T-cell therapy, in which patients’ own T cells are removed, reprogrammed in a lab to recognize and attack cancer cells, and then infused back into the patients, has transformed treatment of various blood cancers and shows often-remarkable results in achieving remissions.

While the treatment has become a routine therapy for certain leukemias, long-term results on the fate and function of the cells over time has been highly anticipated.

In the first published observations of a 10-year follow-up of patients treated with CAR T cells, Dr. June and colleagues described the findings for two patients, both with CLL, who back in 2010 were among the first to be treated with this groundbreaking therapy at the University of Pennsylvania.

A decade later, the CAR T cells are found to have remained detectable in both patients, who achieved complete remission in their first year of treatment, and both have sustained that remission.

Notably, the cells have evolved over the years – from initially being dominated by killer T cells to being dominated primarily by proliferative CD4-positive CAR T cells – with one of the patients exclusively having CD4-positive cells at year 9.3.

“The killer T cells did the initial heavy lifting of eliminating the tumor, “ first author J. Joseph Melenhorst, PhD, said in an interview.

“Once their job was done, those cells went down to very low levels, but the CD4-positive population persisted,” said Dr. Melenhorst, who established the lab at the University of Pennsylvania to follow patients treated with CAR T-cell therapy. “[This] delayed phase of immune response against cancer is a novel insight, and we were surprised to see it.”

Dr. Melenhorst noted that the clonal makeup of the CD4-positive cells importantly stabilized and became dominated by a small number of clones, suggesting further sustainability.

When one of the two patients, Doug Olson, who participated in the press conference, donated his cells back to the center after 9.3 years, the researchers found that his cells were still capable of destroying leukemia cells in the lab.

“Ten years [post infusion], we can’t find any of the leukemia cells and we still have the CAR T cells that are on patrol and on surveillance for residual leukemia,” Dr. June said.

One challenge of the otherwise desirable elimination of leukemia cells is that some aspects of sustaining CAR T-cell activity become problematic.

“The aspect of how the remission is maintained [is] very hard to study in a patient when there is no leukemia at all,” Dr. June explained. “It could be the last cell was gone within 3 weeks [of treatment], or it could be that the [cancer cells] are coming up like whack-a-moles, and they are killed because these CAR T cells are on patrol.”

Sadly, the other CLL patient, Bill Ludwig, who was first to receive the CAR T-cell treatment, died in 2021 from COVID-19.
 

Effects in other blood diseases similar?

CAR T-cell therapy is currently approved in the United States for several blood cancers, and whether similar long-term patterns of the cells may be observed in other patient and cancer types remains to be seen, Dr. Melenhorst said.

“I think in CLL we will see something similar, but in other diseases, we have yet to learn,” he said. “It may depend on issues including which domain has been engineered into the CAR.”

While the prospect of some patients being “cured” is exciting, responses to the therapy have generally been mixed. In CLL, for instance, full remissions have been observed to be maintained in about a quarter of patients, with higher rates observed in some lymphomas and pediatric ALL patients, Dr. Melenhorst explained.

The effects of CAR T-cell therapy in solid cancers have so far been more disappointing, with no research centers reproducing the kinds of results that have been seen with blood cancers.

“There appear to be a number of reasons, including that the [solid] tumor is more complex, and these solid cancers have ways to evade the immune system that need to be overcome,” Dr. June explained.

And despite the more encouraging findings in blood cancers, even with those, “the biggest disappointment is that CAR T-cell therapy doesn’t work all the time. It doesn’t work in every patient,” coauthor David Porter, MD, the University of Pennsylvania oncologist who treated the two patients, said in the press briefing.

“I think the importance of the Nature study is that we are starting to learn the mechanisms of why and how this works, so that we can start to get at how to make it work for more people,” Dr. Porter added. “But what we do see is that, when it works, it really is beyond what we expected 10 or 11 years ago.”

Speaking in the press briefing, Mr. Olson described how several weeks after his treatment in 2010, he became very ill with what has become known as the common, short-term side effect of cytokine release syndrome.

However, after Mr. Olson recovered a few days later, Dr. Porter gave him the remarkable news that “we cannot find a single cancer cell. You appear completely free of CLL.”

Mr. Olson reported that he has since lived a “full life,” kept working, and has even run some half-marathons.

Dr. June confided that the current 10-year results far exceed the team’s early expectations for CAR T-cell therapy. “After Doug [initially] signed his informed consent document for this, we thought that the cells would all be gone within a month or 2. The fact that they have survived for 10 years was a major surprise – and a happy one at that.”

Dr. June, Dr. Melenhorst, and Dr. Porter reported holding patents related to CAR T-cell manufacturing and biomarker discovery.

Two patients with chronic lymphocytic leukemia (CLL) who 10 years ago were among the first to receive groundbreaking chimeric antigen receptor T-cell therapy were still in remission a decade later, and they continued to show detectable levels of CAR T cells.

“We can now conclude that CAR T cells can actually cure patients with leukemia based on these results,” said senior author Carl H. June, MD, in a press briefing on the study published in Nature.

“The major finding from this paper is that, 10 years down the road, you can find these [CAR T] cells,” Dr. June, director of the Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, added. “The cells have evolved, and that was a big surprise ... but they are still able to kill leukemia cells 10 years after infusion.”

CAR T-cell therapy, in which patients’ own T cells are removed, reprogrammed in a lab to recognize and attack cancer cells, and then infused back into the patients, has transformed treatment of various blood cancers and shows often-remarkable results in achieving remissions.

While the treatment has become a routine therapy for certain leukemias, long-term results on the fate and function of the cells over time has been highly anticipated.

In the first published observations of a 10-year follow-up of patients treated with CAR T cells, Dr. June and colleagues described the findings for two patients, both with CLL, who back in 2010 were among the first to be treated with this groundbreaking therapy at the University of Pennsylvania.

A decade later, the CAR T cells are found to have remained detectable in both patients, who achieved complete remission in their first year of treatment, and both have sustained that remission.

Notably, the cells have evolved over the years – from initially being dominated by killer T cells to being dominated primarily by proliferative CD4-positive CAR T cells – with one of the patients exclusively having CD4-positive cells at year 9.3.

“The killer T cells did the initial heavy lifting of eliminating the tumor, “ first author J. Joseph Melenhorst, PhD, said in an interview.

“Once their job was done, those cells went down to very low levels, but the CD4-positive population persisted,” said Dr. Melenhorst, who established the lab at the University of Pennsylvania to follow patients treated with CAR T-cell therapy. “[This] delayed phase of immune response against cancer is a novel insight, and we were surprised to see it.”

Dr. Melenhorst noted that the clonal makeup of the CD4-positive cells importantly stabilized and became dominated by a small number of clones, suggesting further sustainability.

When one of the two patients, Doug Olson, who participated in the press conference, donated his cells back to the center after 9.3 years, the researchers found that his cells were still capable of destroying leukemia cells in the lab.

“Ten years [post infusion], we can’t find any of the leukemia cells and we still have the CAR T cells that are on patrol and on surveillance for residual leukemia,” Dr. June said.

One challenge of the otherwise desirable elimination of leukemia cells is that some aspects of sustaining CAR T-cell activity become problematic.

“The aspect of how the remission is maintained [is] very hard to study in a patient when there is no leukemia at all,” Dr. June explained. “It could be the last cell was gone within 3 weeks [of treatment], or it could be that the [cancer cells] are coming up like whack-a-moles, and they are killed because these CAR T cells are on patrol.”

Sadly, the other CLL patient, Bill Ludwig, who was first to receive the CAR T-cell treatment, died in 2021 from COVID-19.
 

Effects in other blood diseases similar?

CAR T-cell therapy is currently approved in the United States for several blood cancers, and whether similar long-term patterns of the cells may be observed in other patient and cancer types remains to be seen, Dr. Melenhorst said.

“I think in CLL we will see something similar, but in other diseases, we have yet to learn,” he said. “It may depend on issues including which domain has been engineered into the CAR.”

While the prospect of some patients being “cured” is exciting, responses to the therapy have generally been mixed. In CLL, for instance, full remissions have been observed to be maintained in about a quarter of patients, with higher rates observed in some lymphomas and pediatric ALL patients, Dr. Melenhorst explained.

The effects of CAR T-cell therapy in solid cancers have so far been more disappointing, with no research centers reproducing the kinds of results that have been seen with blood cancers.

“There appear to be a number of reasons, including that the [solid] tumor is more complex, and these solid cancers have ways to evade the immune system that need to be overcome,” Dr. June explained.

And despite the more encouraging findings in blood cancers, even with those, “the biggest disappointment is that CAR T-cell therapy doesn’t work all the time. It doesn’t work in every patient,” coauthor David Porter, MD, the University of Pennsylvania oncologist who treated the two patients, said in the press briefing.

“I think the importance of the Nature study is that we are starting to learn the mechanisms of why and how this works, so that we can start to get at how to make it work for more people,” Dr. Porter added. “But what we do see is that, when it works, it really is beyond what we expected 10 or 11 years ago.”

Speaking in the press briefing, Mr. Olson described how several weeks after his treatment in 2010, he became very ill with what has become known as the common, short-term side effect of cytokine release syndrome.

However, after Mr. Olson recovered a few days later, Dr. Porter gave him the remarkable news that “we cannot find a single cancer cell. You appear completely free of CLL.”

Mr. Olson reported that he has since lived a “full life,” kept working, and has even run some half-marathons.

Dr. June confided that the current 10-year results far exceed the team’s early expectations for CAR T-cell therapy. “After Doug [initially] signed his informed consent document for this, we thought that the cells would all be gone within a month or 2. The fact that they have survived for 10 years was a major surprise – and a happy one at that.”

Dr. June, Dr. Melenhorst, and Dr. Porter reported holding patents related to CAR T-cell manufacturing and biomarker discovery.

The use of over-the-counter melatonin supplements grew by fivefold over the past 2 decades in the United States, a new study finds, although only 2% of a recent group of survey respondents said they had taken the sleep aid within the past month.

The findings, reported Feb. 1 in a research letter in the Journal of the American Medical Association, suggest that “millions of U.S. individuals are using melatonin,” study coauthor Naima Covassin, PhD, an associate consultant at Mayo Clinic in Rochester, Minn., told this news organization. “It is important to ask patients who report sleep problems whether they consume melatonin supplements, and these findings should certainly prompt more research in this area.”

The supplements boost the levels of melatonin, a hormone that is linked to the sleep-wake cycle. “Melatonin facilitates our ability to fall asleep at our bedtime by decreasing the natural early evening circadian arousal that helps keep us alert despite our having been awake since the morning,” said David N. Neubauer, MD, a sleep specialist at Johns Hopkins University, Baltimore. “It isn’t so much that melatonin is sedating, but rather that it turns off arousal.”

For the new study, researchers tracked data from the National Health and Nutrition Examination Survey from 1999-2000 to 2017-2018 and focused on respondents aged 20 and older (n = 55,021, mean age, 47.5, 52% women). As the researchers noted, response rates dipped mightily from a high of 84% in 2001-2002 to just 51.9% in 2017-2018.

The study found that the overall reported weighted prevalence of melatonin use grew from 0.4% (95% confidence interval, 0.2%-1.0%) in 1999-2000 to 2.1% (95% CI, 1.5%-2.9%) in 2017-2018 (linear P = .004). In 93.9% of cases of reported melatonin use, the surveyors confirmed it by checking for supplement bottles.

“These trends were similar in men and women and across age groups,” Dr. Covassin said. “We also found that use of more than 5 mg/day melatonin was not reported till 2005-2006, and it has been increasing since.”

Melatonin supplements are now available in tablets, capsules, gummies, powders, liquids, sprays, and other formulations. Users can even buy CBD-melatonin combos.

The survey doesn’t explore why the respondents used melatonin nor whether they thought it actually helped them. “The study was designed to evaluate the breadth of use of melatonin, rather than its effectiveness as a sleep aid,” Dr. Covassin said.

Dr. Neubauer, who wasn’t associated with the study, said the research seems valid. According to him, melatonin use has likely grown because of marketing and a higher number of products. He added that melatonin products are being manufactured at higher doses, although melatonin has a flat dose-response curve. “Higher doses typically do not have a greater effect,” he said.

According to Dr. Covassin, melatonin is generally considered to be safe, although side effects such as fatigue, dizziness, and headaches have been reported in clinical trials. “This is especially evident when high doses are administered,” Dr. Covassin said. “Other potentially more harmful consequences have also been noted. For instance, it has been found that acute administration of melatonin may decrease glucose tolerance, which may be especially problematic in patients with preexisting vulnerabilities such in those with diabetes. There are also very limited data on whether sustained use is safe in the long run.”

Moving forward, Dr. Covassin said, “we are interested in better understanding consumption of melatonin supplements across different populations as well as the impact of chronic use.”

The study authors are supported by grants from the National Natural Science Foundation of China, National Institutes of Health, Sleep Number Corporation (to Mayo Clinic), the Alice Sheets Marriott Professorship, and the Mayo Clinic Marie Ingalls Research Career Development Award.

Dr. Covassin and Dr. Neubauer have disclosed no relevant financial relationships. Study coauthor Virend K. Somers, MD, PhD, reports having served as a consultant for Respicardia, Baker Tilly, Bayer, and Jazz Pharmaceuticals and serving on the Sleep Number Research Advisory Board.

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

The use of over-the-counter melatonin supplements grew by fivefold over the past 2 decades in the United States, a new study finds, although only 2% of a recent group of survey respondents said they had taken the sleep aid within the past month.

The findings, reported Feb. 1 in a research letter in the Journal of the American Medical Association, suggest that “millions of U.S. individuals are using melatonin,” study coauthor Naima Covassin, PhD, an associate consultant at Mayo Clinic in Rochester, Minn., told this news organization. “It is important to ask patients who report sleep problems whether they consume melatonin supplements, and these findings should certainly prompt more research in this area.”

The supplements boost the levels of melatonin, a hormone that is linked to the sleep-wake cycle. “Melatonin facilitates our ability to fall asleep at our bedtime by decreasing the natural early evening circadian arousal that helps keep us alert despite our having been awake since the morning,” said David N. Neubauer, MD, a sleep specialist at Johns Hopkins University, Baltimore. “It isn’t so much that melatonin is sedating, but rather that it turns off arousal.”

For the new study, researchers tracked data from the National Health and Nutrition Examination Survey from 1999-2000 to 2017-2018 and focused on respondents aged 20 and older (n = 55,021, mean age, 47.5, 52% women). As the researchers noted, response rates dipped mightily from a high of 84% in 2001-2002 to just 51.9% in 2017-2018.

The study found that the overall reported weighted prevalence of melatonin use grew from 0.4% (95% confidence interval, 0.2%-1.0%) in 1999-2000 to 2.1% (95% CI, 1.5%-2.9%) in 2017-2018 (linear P = .004). In 93.9% of cases of reported melatonin use, the surveyors confirmed it by checking for supplement bottles.

“These trends were similar in men and women and across age groups,” Dr. Covassin said. “We also found that use of more than 5 mg/day melatonin was not reported till 2005-2006, and it has been increasing since.”

Melatonin supplements are now available in tablets, capsules, gummies, powders, liquids, sprays, and other formulations. Users can even buy CBD-melatonin combos.

The survey doesn’t explore why the respondents used melatonin nor whether they thought it actually helped them. “The study was designed to evaluate the breadth of use of melatonin, rather than its effectiveness as a sleep aid,” Dr. Covassin said.

Dr. Neubauer, who wasn’t associated with the study, said the research seems valid. According to him, melatonin use has likely grown because of marketing and a higher number of products. He added that melatonin products are being manufactured at higher doses, although melatonin has a flat dose-response curve. “Higher doses typically do not have a greater effect,” he said.

According to Dr. Covassin, melatonin is generally considered to be safe, although side effects such as fatigue, dizziness, and headaches have been reported in clinical trials. “This is especially evident when high doses are administered,” Dr. Covassin said. “Other potentially more harmful consequences have also been noted. For instance, it has been found that acute administration of melatonin may decrease glucose tolerance, which may be especially problematic in patients with preexisting vulnerabilities such in those with diabetes. There are also very limited data on whether sustained use is safe in the long run.”

Moving forward, Dr. Covassin said, “we are interested in better understanding consumption of melatonin supplements across different populations as well as the impact of chronic use.”

The study authors are supported by grants from the National Natural Science Foundation of China, National Institutes of Health, Sleep Number Corporation (to Mayo Clinic), the Alice Sheets Marriott Professorship, and the Mayo Clinic Marie Ingalls Research Career Development Award.

Dr. Covassin and Dr. Neubauer have disclosed no relevant financial relationships. Study coauthor Virend K. Somers, MD, PhD, reports having served as a consultant for Respicardia, Baker Tilly, Bayer, and Jazz Pharmaceuticals and serving on the Sleep Number Research Advisory Board.

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

The use of over-the-counter melatonin supplements grew by fivefold over the past 2 decades in the United States, a new study finds, although only 2% of a recent group of survey respondents said they had taken the sleep aid within the past month.

The findings, reported Feb. 1 in a research letter in the Journal of the American Medical Association, suggest that “millions of U.S. individuals are using melatonin,” study coauthor Naima Covassin, PhD, an associate consultant at Mayo Clinic in Rochester, Minn., told this news organization. “It is important to ask patients who report sleep problems whether they consume melatonin supplements, and these findings should certainly prompt more research in this area.”

The supplements boost the levels of melatonin, a hormone that is linked to the sleep-wake cycle. “Melatonin facilitates our ability to fall asleep at our bedtime by decreasing the natural early evening circadian arousal that helps keep us alert despite our having been awake since the morning,” said David N. Neubauer, MD, a sleep specialist at Johns Hopkins University, Baltimore. “It isn’t so much that melatonin is sedating, but rather that it turns off arousal.”

For the new study, researchers tracked data from the National Health and Nutrition Examination Survey from 1999-2000 to 2017-2018 and focused on respondents aged 20 and older (n = 55,021, mean age, 47.5, 52% women). As the researchers noted, response rates dipped mightily from a high of 84% in 2001-2002 to just 51.9% in 2017-2018.

The study found that the overall reported weighted prevalence of melatonin use grew from 0.4% (95% confidence interval, 0.2%-1.0%) in 1999-2000 to 2.1% (95% CI, 1.5%-2.9%) in 2017-2018 (linear P = .004). In 93.9% of cases of reported melatonin use, the surveyors confirmed it by checking for supplement bottles.

“These trends were similar in men and women and across age groups,” Dr. Covassin said. “We also found that use of more than 5 mg/day melatonin was not reported till 2005-2006, and it has been increasing since.”

Melatonin supplements are now available in tablets, capsules, gummies, powders, liquids, sprays, and other formulations. Users can even buy CBD-melatonin combos.

The survey doesn’t explore why the respondents used melatonin nor whether they thought it actually helped them. “The study was designed to evaluate the breadth of use of melatonin, rather than its effectiveness as a sleep aid,” Dr. Covassin said.

Dr. Neubauer, who wasn’t associated with the study, said the research seems valid. According to him, melatonin use has likely grown because of marketing and a higher number of products. He added that melatonin products are being manufactured at higher doses, although melatonin has a flat dose-response curve. “Higher doses typically do not have a greater effect,” he said.

According to Dr. Covassin, melatonin is generally considered to be safe, although side effects such as fatigue, dizziness, and headaches have been reported in clinical trials. “This is especially evident when high doses are administered,” Dr. Covassin said. “Other potentially more harmful consequences have also been noted. For instance, it has been found that acute administration of melatonin may decrease glucose tolerance, which may be especially problematic in patients with preexisting vulnerabilities such in those with diabetes. There are also very limited data on whether sustained use is safe in the long run.”

Moving forward, Dr. Covassin said, “we are interested in better understanding consumption of melatonin supplements across different populations as well as the impact of chronic use.”

The study authors are supported by grants from the National Natural Science Foundation of China, National Institutes of Health, Sleep Number Corporation (to Mayo Clinic), the Alice Sheets Marriott Professorship, and the Mayo Clinic Marie Ingalls Research Career Development Award.

Dr. Covassin and Dr. Neubauer have disclosed no relevant financial relationships. Study coauthor Virend K. Somers, MD, PhD, reports having served as a consultant for Respicardia, Baker Tilly, Bayer, and Jazz Pharmaceuticals and serving on the Sleep Number Research Advisory Board.

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

The newly approved insomnia drug daridorexant (Quviviq) improves sleep onset in adults, new phase 3 data suggest.  In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.

Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.

“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.

The findings were published in the February issue of The Lancet Neurology.
 

Two trials, three doses

Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.

To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.

In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.

During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.

Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.

The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.

The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
 

Dose-dependent effects

At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.

LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.

At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.

In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.

Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
 

Longer studies needed

In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.

However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”

He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.

Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.

Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.

Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.

The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.

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

The newly approved insomnia drug daridorexant (Quviviq) improves sleep onset in adults, new phase 3 data suggest.  In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.

Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.

“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.

The findings were published in the February issue of The Lancet Neurology.
 

Two trials, three doses

Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.

To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.

In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.

During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.

Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.

The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.

The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
 

Dose-dependent effects

At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.

LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.

At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.

In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.

Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
 

Longer studies needed

In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.

However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”

He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.

Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.

Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.

Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.

The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.

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

The newly approved insomnia drug daridorexant (Quviviq) improves sleep onset in adults, new phase 3 data suggest.  In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.

Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.

“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.

The findings were published in the February issue of The Lancet Neurology.
 

Two trials, three doses

Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.

To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.

In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.

During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.

Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.

The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.

The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
 

Dose-dependent effects

At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.

LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.

At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.

In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.

Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
 

Longer studies needed

In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.

However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”

He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.

Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.

Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.

Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.

The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.

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