Federal Practitioner

Many labels on fish oil supplements make unsubstantiated health claims, and products contain variable daily doses of EPA plus DHA, a cross-sectional study suggests.

Overall, about 74% of more than 2,800 supplements that were examined had labels that made at least one health claim, and only 19% included a U.S. Food and Drug Administration–reviewed qualified health claim (QHC).

©Clayton Hansen/iStockphoto

‘Vague statements’

To evaluate health claims made on fish oil supplement labels in the United States and to examine doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in commonly available formulations, the investigators analyzed labels on supplements obtained from the National Institutes of Health Dietary Supplement Label Database.

The main outcomes were the frequency and types of health claims made on the labels, including use of an FDA-reviewed QHC versus a structure/function claim and the organ system referenced, as well as the total daily doses in combined EPA and DHA supplements from leading manufacturers and retailers.

QHCs are statements regarding a supplement’s or food’s potential to treatment or prevent disease. Such claims undergo evidence review by the FDA and include qualifying language that reflects lack of scientific consensus or uncertainty.

An example: “Consuming EPA and DHA combined may reduce the risk of CHD [coronary heart disease] by lowering blood pressure. However, FDA has concluded that the evidence is inconsistent and inconclusive. One serving of [name of the food or dietary supplement] provides [ ] gram(s) of EPA and DHA.”

By contrast, structure/function claims “describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans” but do not state that the supplement prevents, treats, or cures any disease. Such a claim “does not require any mitigating language regarding potential scientific uncertainty of the statement.”

Structure/function claims commonly state that the supplement “maintains,” “supports,” or “promotes” the function of certain organs. Examples are “promotes heart health” and “supports heart, mind and mood.”

Among 2,819 fish oil supplements, 2,082 (73.9%) made at least one health claim. Of these, only 399 (19.2%) used a QHC; the rest made only structure/function claims. In addition to heart-health claims, many fish oil supplements also have labels that make claims implying benefit to other organ systems, such as brain/mental health, joint health, and eye health – despite a lack of data from randomized clinical trials that support benefit.

The dose analysis of 255 fish oil supplements across 16 major brands found “substantial variability” in the daily dose of EPA (median interquartile range, 340 [135-647] mg/d), DHA (median IQR, 270 [140-500] mg/d), and total EPA+DHA (median IQR, 600 [300-1,100] mg/d).

Twenty-four (9.4%) of the supplements contained a daily dose of 2 g or more EPA+DHA.

“Significant heterogeneity exists in the daily dose of EPA+DHA in available supplements, leading to potential variability in safety and efficacy between supplements,” the authors conclude. “Increasing regulation of dietary supplement labeling may be needed to prevent consumer misinformation.”

Dr. Navar added, “We now need to understand what consumers are taking away from vague statements like ‘promotes brain health’ or ‘supports joint function’ – and test what language we can use to accurately describe the state of the science around fish oil and heart health.”
 

Enthusiasm vs. evidence

“I agree with these concerns and think that the enthusiasm for these supplements outpaces the evidence from rigorous randomized clinical trials,” JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said in an interview. “Results of the observational studies have tended to be much more favorable than the randomized clinical trials.

“The labels can be very misleading to the general public,” she noted. “People are confronted with a dizzying array of dietary supplements, many of which include structure/function claims that require minimal, if any, evidence of efficacy. Clinicians should emphasize with patients that a dietary supplement will never be a substitute for a heart-healthy diet and that many supplements are not helpful for people who already follow a healthy diet,” she said.

The VITAL trial, for which Dr. Manson was principal investigator, showed that supplementation with n-3 fatty acids did not lead to a lower incidence of major cardiovascular events or cancer, compared with placebo.

A subgroup analysis showed that 1 g/d conferred a 20% reduction in major events only for participants who ate less than 1.5 servings of fish per week, Dr. Manson said.

Regarding supplement labels, clinicians should recommend that patients look for a U.S. Pharmacopoeia seal or a seal from the National Science Foundation or ConsumerLab, she advised. These seals ensure that the product has been audited for purity and consistency of content and that the dose in the capsule is consistent with what is on the label.

Dr. Manson also would like to see labels explain that most of the products have not been reviewed by the FDA. “Many members of the general public are misled by these labels into thinking that they’re going to receive health benefits. They’re spending a lot of money on supplements that likely provide no benefit and may even be associated with increased risks.”

No funding for the study was reported. Dr. Navar has received grants from BMS, Esperion, Amgen, and Janssen and personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Esperion, Janssen, Eli Lilly, Merck, Silence Therapeutics, Novo Nordisk, Novartis, New Amsterdam, and Pfizer outside the submitted work and serves as deputy editor for equity, diversity, and inclusion at JAMA Cardiology.

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

Many labels on fish oil supplements make unsubstantiated health claims, and products contain variable daily doses of EPA plus DHA, a cross-sectional study suggests.

Overall, about 74% of more than 2,800 supplements that were examined had labels that made at least one health claim, and only 19% included a U.S. Food and Drug Administration–reviewed qualified health claim (QHC).

©Clayton Hansen/iStockphoto

‘Vague statements’

To evaluate health claims made on fish oil supplement labels in the United States and to examine doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in commonly available formulations, the investigators analyzed labels on supplements obtained from the National Institutes of Health Dietary Supplement Label Database.

The main outcomes were the frequency and types of health claims made on the labels, including use of an FDA-reviewed QHC versus a structure/function claim and the organ system referenced, as well as the total daily doses in combined EPA and DHA supplements from leading manufacturers and retailers.

QHCs are statements regarding a supplement’s or food’s potential to treatment or prevent disease. Such claims undergo evidence review by the FDA and include qualifying language that reflects lack of scientific consensus or uncertainty.

An example: “Consuming EPA and DHA combined may reduce the risk of CHD [coronary heart disease] by lowering blood pressure. However, FDA has concluded that the evidence is inconsistent and inconclusive. One serving of [name of the food or dietary supplement] provides [ ] gram(s) of EPA and DHA.”

By contrast, structure/function claims “describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans” but do not state that the supplement prevents, treats, or cures any disease. Such a claim “does not require any mitigating language regarding potential scientific uncertainty of the statement.”

Structure/function claims commonly state that the supplement “maintains,” “supports,” or “promotes” the function of certain organs. Examples are “promotes heart health” and “supports heart, mind and mood.”

Among 2,819 fish oil supplements, 2,082 (73.9%) made at least one health claim. Of these, only 399 (19.2%) used a QHC; the rest made only structure/function claims. In addition to heart-health claims, many fish oil supplements also have labels that make claims implying benefit to other organ systems, such as brain/mental health, joint health, and eye health – despite a lack of data from randomized clinical trials that support benefit.

The dose analysis of 255 fish oil supplements across 16 major brands found “substantial variability” in the daily dose of EPA (median interquartile range, 340 [135-647] mg/d), DHA (median IQR, 270 [140-500] mg/d), and total EPA+DHA (median IQR, 600 [300-1,100] mg/d).

Twenty-four (9.4%) of the supplements contained a daily dose of 2 g or more EPA+DHA.

“Significant heterogeneity exists in the daily dose of EPA+DHA in available supplements, leading to potential variability in safety and efficacy between supplements,” the authors conclude. “Increasing regulation of dietary supplement labeling may be needed to prevent consumer misinformation.”

Dr. Navar added, “We now need to understand what consumers are taking away from vague statements like ‘promotes brain health’ or ‘supports joint function’ – and test what language we can use to accurately describe the state of the science around fish oil and heart health.”
 

Enthusiasm vs. evidence

“I agree with these concerns and think that the enthusiasm for these supplements outpaces the evidence from rigorous randomized clinical trials,” JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said in an interview. “Results of the observational studies have tended to be much more favorable than the randomized clinical trials.

“The labels can be very misleading to the general public,” she noted. “People are confronted with a dizzying array of dietary supplements, many of which include structure/function claims that require minimal, if any, evidence of efficacy. Clinicians should emphasize with patients that a dietary supplement will never be a substitute for a heart-healthy diet and that many supplements are not helpful for people who already follow a healthy diet,” she said.

The VITAL trial, for which Dr. Manson was principal investigator, showed that supplementation with n-3 fatty acids did not lead to a lower incidence of major cardiovascular events or cancer, compared with placebo.

A subgroup analysis showed that 1 g/d conferred a 20% reduction in major events only for participants who ate less than 1.5 servings of fish per week, Dr. Manson said.

Regarding supplement labels, clinicians should recommend that patients look for a U.S. Pharmacopoeia seal or a seal from the National Science Foundation or ConsumerLab, she advised. These seals ensure that the product has been audited for purity and consistency of content and that the dose in the capsule is consistent with what is on the label.

Dr. Manson also would like to see labels explain that most of the products have not been reviewed by the FDA. “Many members of the general public are misled by these labels into thinking that they’re going to receive health benefits. They’re spending a lot of money on supplements that likely provide no benefit and may even be associated with increased risks.”

No funding for the study was reported. Dr. Navar has received grants from BMS, Esperion, Amgen, and Janssen and personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Esperion, Janssen, Eli Lilly, Merck, Silence Therapeutics, Novo Nordisk, Novartis, New Amsterdam, and Pfizer outside the submitted work and serves as deputy editor for equity, diversity, and inclusion at JAMA Cardiology.

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

Many labels on fish oil supplements make unsubstantiated health claims, and products contain variable daily doses of EPA plus DHA, a cross-sectional study suggests.

Overall, about 74% of more than 2,800 supplements that were examined had labels that made at least one health claim, and only 19% included a U.S. Food and Drug Administration–reviewed qualified health claim (QHC).

©Clayton Hansen/iStockphoto

‘Vague statements’

To evaluate health claims made on fish oil supplement labels in the United States and to examine doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in commonly available formulations, the investigators analyzed labels on supplements obtained from the National Institutes of Health Dietary Supplement Label Database.

The main outcomes were the frequency and types of health claims made on the labels, including use of an FDA-reviewed QHC versus a structure/function claim and the organ system referenced, as well as the total daily doses in combined EPA and DHA supplements from leading manufacturers and retailers.

QHCs are statements regarding a supplement’s or food’s potential to treatment or prevent disease. Such claims undergo evidence review by the FDA and include qualifying language that reflects lack of scientific consensus or uncertainty.

An example: “Consuming EPA and DHA combined may reduce the risk of CHD [coronary heart disease] by lowering blood pressure. However, FDA has concluded that the evidence is inconsistent and inconclusive. One serving of [name of the food or dietary supplement] provides [ ] gram(s) of EPA and DHA.”

By contrast, structure/function claims “describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans” but do not state that the supplement prevents, treats, or cures any disease. Such a claim “does not require any mitigating language regarding potential scientific uncertainty of the statement.”

Structure/function claims commonly state that the supplement “maintains,” “supports,” or “promotes” the function of certain organs. Examples are “promotes heart health” and “supports heart, mind and mood.”

Among 2,819 fish oil supplements, 2,082 (73.9%) made at least one health claim. Of these, only 399 (19.2%) used a QHC; the rest made only structure/function claims. In addition to heart-health claims, many fish oil supplements also have labels that make claims implying benefit to other organ systems, such as brain/mental health, joint health, and eye health – despite a lack of data from randomized clinical trials that support benefit.

The dose analysis of 255 fish oil supplements across 16 major brands found “substantial variability” in the daily dose of EPA (median interquartile range, 340 [135-647] mg/d), DHA (median IQR, 270 [140-500] mg/d), and total EPA+DHA (median IQR, 600 [300-1,100] mg/d).

Twenty-four (9.4%) of the supplements contained a daily dose of 2 g or more EPA+DHA.

“Significant heterogeneity exists in the daily dose of EPA+DHA in available supplements, leading to potential variability in safety and efficacy between supplements,” the authors conclude. “Increasing regulation of dietary supplement labeling may be needed to prevent consumer misinformation.”

Dr. Navar added, “We now need to understand what consumers are taking away from vague statements like ‘promotes brain health’ or ‘supports joint function’ – and test what language we can use to accurately describe the state of the science around fish oil and heart health.”
 

Enthusiasm vs. evidence

“I agree with these concerns and think that the enthusiasm for these supplements outpaces the evidence from rigorous randomized clinical trials,” JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said in an interview. “Results of the observational studies have tended to be much more favorable than the randomized clinical trials.

“The labels can be very misleading to the general public,” she noted. “People are confronted with a dizzying array of dietary supplements, many of which include structure/function claims that require minimal, if any, evidence of efficacy. Clinicians should emphasize with patients that a dietary supplement will never be a substitute for a heart-healthy diet and that many supplements are not helpful for people who already follow a healthy diet,” she said.

The VITAL trial, for which Dr. Manson was principal investigator, showed that supplementation with n-3 fatty acids did not lead to a lower incidence of major cardiovascular events or cancer, compared with placebo.

A subgroup analysis showed that 1 g/d conferred a 20% reduction in major events only for participants who ate less than 1.5 servings of fish per week, Dr. Manson said.

Regarding supplement labels, clinicians should recommend that patients look for a U.S. Pharmacopoeia seal or a seal from the National Science Foundation or ConsumerLab, she advised. These seals ensure that the product has been audited for purity and consistency of content and that the dose in the capsule is consistent with what is on the label.

Dr. Manson also would like to see labels explain that most of the products have not been reviewed by the FDA. “Many members of the general public are misled by these labels into thinking that they’re going to receive health benefits. They’re spending a lot of money on supplements that likely provide no benefit and may even be associated with increased risks.”

No funding for the study was reported. Dr. Navar has received grants from BMS, Esperion, Amgen, and Janssen and personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Esperion, Janssen, Eli Lilly, Merck, Silence Therapeutics, Novo Nordisk, Novartis, New Amsterdam, and Pfizer outside the submitted work and serves as deputy editor for equity, diversity, and inclusion at JAMA Cardiology.

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

Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.

This drug, isolated from bacteria that haven’t previously been studied, seems to be capable of combating multidrug-resistant “superbugs” thanks to unusual mechanisms of action.

The drug was discovered and has been studied by scientists from Utrecht University in the Netherlands, the University of Bonn in Germany, the German Center for Infection Research, Northeastern University in Boston, and NovoBiotic Pharmaceuticals in Cambridge, Mass.

Their research was published in Cell.

“Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance,” Markus Weingarth, MD, PhD, a researcher in Utrecht University’s chemistry department, said in a press release.
 

Microbial “dark matter”

Researchers isolated clovibactin from sandy soil from North Carolina and studied it using the iChip device, which was developed in 2015. This technique allowed them to grow “bacterial dark matter,” so-called unculturable bacteria, which compose a group to which 99% of bacteria belong.

This device also paved the way for the discovery of the antibiotic teixobactin in 2020. Teixobactin is effective against gram-positive bacteria and is one of the first truly new antibiotics in decades. Its mechanism of action is like that of clovibactin.
 

Combats resistant bacteria

In the Cell article, the researchers showed that clovibactin acts via several mechanisms and that it successfully treated mice infected with the superbug Staphylococcus aureus.

Clovibactin exhibited antibacterial activity against a broad range of gram-positive pathogens, including methicillin-resistant S. aureus, daptomycin-resistant and vancomycin-resistant S. aureus strains, and difficult-to-treat vancomycin-resistant Enterococcus faecalis and E faecium (vancomycin-resistant enterococci). Escherichia coli was only marginally affected “compared with an outer membrane deficient E. coli WO153 strain, probably reflecting insufficient penetration of the compound,” the authors wrote.
 

Original mechanism of action

Clovibactin acts not on one but three molecules, all of which are essential to the construction of bacterial walls: C55PP, lipid II, and lipid IIIWTA, which are from different cell wall biosynthetic pathways. Clovibactin binds to the pyrophosphate portion of these precursors.

“Clovibactin wraps around the pyrophosphate like [a] tight glove, like a cage that encloses its target,” said Dr. Weingarth. This is what gives clovibactin its name, which is derived from Greek word klouvi, meaning cage.

The remarkable aspect of clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it also ignores the variable sugar-peptide part of the targets. The bacteria therefore have a much harder time developing resistance against it. “In fact, we did not observe any resistance to clovibactin in our studies,” Dr. Weingarth confirmed.

Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.
 

Few side effects

Because of the mechanism of action of the antibiotic, few side effects are predicted. Indeed, clovibactin targets bacteria cells but not human cells.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” said Dr. Weingarth.

Other studies – in particular, studies in humans – are needed before the antibiotic can be considered a potential treatment. In the meantime, regulations regarding the proper use of antibiotics must continue to be applied to limit antibiotic resistance.

In 2019, 4.95 million deaths worldwide were associated with bacterial antimicrobial resistance, including 1.27 million deaths directly attributable to bacterial antimicrobial resistance. If this trend continues without new medicines becoming available to treat bacterial infections, it is estimated that by 2050, 10 million people will die every year from antimicrobial drug resistance.
 

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.

This drug, isolated from bacteria that haven’t previously been studied, seems to be capable of combating multidrug-resistant “superbugs” thanks to unusual mechanisms of action.

The drug was discovered and has been studied by scientists from Utrecht University in the Netherlands, the University of Bonn in Germany, the German Center for Infection Research, Northeastern University in Boston, and NovoBiotic Pharmaceuticals in Cambridge, Mass.

Their research was published in Cell.

“Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance,” Markus Weingarth, MD, PhD, a researcher in Utrecht University’s chemistry department, said in a press release.
 

Microbial “dark matter”

Researchers isolated clovibactin from sandy soil from North Carolina and studied it using the iChip device, which was developed in 2015. This technique allowed them to grow “bacterial dark matter,” so-called unculturable bacteria, which compose a group to which 99% of bacteria belong.

This device also paved the way for the discovery of the antibiotic teixobactin in 2020. Teixobactin is effective against gram-positive bacteria and is one of the first truly new antibiotics in decades. Its mechanism of action is like that of clovibactin.
 

Combats resistant bacteria

In the Cell article, the researchers showed that clovibactin acts via several mechanisms and that it successfully treated mice infected with the superbug Staphylococcus aureus.

Clovibactin exhibited antibacterial activity against a broad range of gram-positive pathogens, including methicillin-resistant S. aureus, daptomycin-resistant and vancomycin-resistant S. aureus strains, and difficult-to-treat vancomycin-resistant Enterococcus faecalis and E faecium (vancomycin-resistant enterococci). Escherichia coli was only marginally affected “compared with an outer membrane deficient E. coli WO153 strain, probably reflecting insufficient penetration of the compound,” the authors wrote.
 

Original mechanism of action

Clovibactin acts not on one but three molecules, all of which are essential to the construction of bacterial walls: C55PP, lipid II, and lipid IIIWTA, which are from different cell wall biosynthetic pathways. Clovibactin binds to the pyrophosphate portion of these precursors.

“Clovibactin wraps around the pyrophosphate like [a] tight glove, like a cage that encloses its target,” said Dr. Weingarth. This is what gives clovibactin its name, which is derived from Greek word klouvi, meaning cage.

The remarkable aspect of clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it also ignores the variable sugar-peptide part of the targets. The bacteria therefore have a much harder time developing resistance against it. “In fact, we did not observe any resistance to clovibactin in our studies,” Dr. Weingarth confirmed.

Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.
 

Few side effects

Because of the mechanism of action of the antibiotic, few side effects are predicted. Indeed, clovibactin targets bacteria cells but not human cells.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” said Dr. Weingarth.

Other studies – in particular, studies in humans – are needed before the antibiotic can be considered a potential treatment. In the meantime, regulations regarding the proper use of antibiotics must continue to be applied to limit antibiotic resistance.

In 2019, 4.95 million deaths worldwide were associated with bacterial antimicrobial resistance, including 1.27 million deaths directly attributable to bacterial antimicrobial resistance. If this trend continues without new medicines becoming available to treat bacterial infections, it is estimated that by 2050, 10 million people will die every year from antimicrobial drug resistance.
 

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.

This drug, isolated from bacteria that haven’t previously been studied, seems to be capable of combating multidrug-resistant “superbugs” thanks to unusual mechanisms of action.

The drug was discovered and has been studied by scientists from Utrecht University in the Netherlands, the University of Bonn in Germany, the German Center for Infection Research, Northeastern University in Boston, and NovoBiotic Pharmaceuticals in Cambridge, Mass.

Their research was published in Cell.

“Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance,” Markus Weingarth, MD, PhD, a researcher in Utrecht University’s chemistry department, said in a press release.
 

Microbial “dark matter”

Researchers isolated clovibactin from sandy soil from North Carolina and studied it using the iChip device, which was developed in 2015. This technique allowed them to grow “bacterial dark matter,” so-called unculturable bacteria, which compose a group to which 99% of bacteria belong.

This device also paved the way for the discovery of the antibiotic teixobactin in 2020. Teixobactin is effective against gram-positive bacteria and is one of the first truly new antibiotics in decades. Its mechanism of action is like that of clovibactin.
 

Combats resistant bacteria

In the Cell article, the researchers showed that clovibactin acts via several mechanisms and that it successfully treated mice infected with the superbug Staphylococcus aureus.

Clovibactin exhibited antibacterial activity against a broad range of gram-positive pathogens, including methicillin-resistant S. aureus, daptomycin-resistant and vancomycin-resistant S. aureus strains, and difficult-to-treat vancomycin-resistant Enterococcus faecalis and E faecium (vancomycin-resistant enterococci). Escherichia coli was only marginally affected “compared with an outer membrane deficient E. coli WO153 strain, probably reflecting insufficient penetration of the compound,” the authors wrote.
 

Original mechanism of action

Clovibactin acts not on one but three molecules, all of which are essential to the construction of bacterial walls: C55PP, lipid II, and lipid IIIWTA, which are from different cell wall biosynthetic pathways. Clovibactin binds to the pyrophosphate portion of these precursors.

“Clovibactin wraps around the pyrophosphate like [a] tight glove, like a cage that encloses its target,” said Dr. Weingarth. This is what gives clovibactin its name, which is derived from Greek word klouvi, meaning cage.

The remarkable aspect of clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it also ignores the variable sugar-peptide part of the targets. The bacteria therefore have a much harder time developing resistance against it. “In fact, we did not observe any resistance to clovibactin in our studies,” Dr. Weingarth confirmed.

Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.
 

Few side effects

Because of the mechanism of action of the antibiotic, few side effects are predicted. Indeed, clovibactin targets bacteria cells but not human cells.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” said Dr. Weingarth.

Other studies – in particular, studies in humans – are needed before the antibiotic can be considered a potential treatment. In the meantime, regulations regarding the proper use of antibiotics must continue to be applied to limit antibiotic resistance.

In 2019, 4.95 million deaths worldwide were associated with bacterial antimicrobial resistance, including 1.27 million deaths directly attributable to bacterial antimicrobial resistance. If this trend continues without new medicines becoming available to treat bacterial infections, it is estimated that by 2050, 10 million people will die every year from antimicrobial drug resistance.
 

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.
 

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”
 

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.
 

Innovative, plausible, but still preliminary

In a comment, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, called the investigation “innovative,” with ideas that are “certainly plausible.” However, “at this time, the work is preliminary and not conclusive.”

The hypothesized mechanisms for why amyloid (lecanemab’s target) is toxic to the brain “does incorporate important AD-related brain changes that have been observed in other studies, including inflammatory/immune changes and vascular-related changes,” said Dr. Snyder, who was not involved with the current study.

However, “additional studies that look both in model systems and in humans are needed to further illuminate these relationships,” Dr. Snyder said.

The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Dr. Norris, Dr. Strickland, and Dr. Snyder declared no relevant financial relationships.

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

Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.
 

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”
 

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.
 

Innovative, plausible, but still preliminary

In a comment, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, called the investigation “innovative,” with ideas that are “certainly plausible.” However, “at this time, the work is preliminary and not conclusive.”

The hypothesized mechanisms for why amyloid (lecanemab’s target) is toxic to the brain “does incorporate important AD-related brain changes that have been observed in other studies, including inflammatory/immune changes and vascular-related changes,” said Dr. Snyder, who was not involved with the current study.

However, “additional studies that look both in model systems and in humans are needed to further illuminate these relationships,” Dr. Snyder said.

The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Dr. Norris, Dr. Strickland, and Dr. Snyder declared no relevant financial relationships.

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

Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.
 

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”
 

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.
 

Innovative, plausible, but still preliminary

In a comment, Heather M. Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, called the investigation “innovative,” with ideas that are “certainly plausible.” However, “at this time, the work is preliminary and not conclusive.”

The hypothesized mechanisms for why amyloid (lecanemab’s target) is toxic to the brain “does incorporate important AD-related brain changes that have been observed in other studies, including inflammatory/immune changes and vascular-related changes,” said Dr. Snyder, who was not involved with the current study.

However, “additional studies that look both in model systems and in humans are needed to further illuminate these relationships,” Dr. Snyder said.

The study was supported by grants from the National Institutes of Health as well as the Robertson Therapeutic Development Fund, Samuel Newhouse Foundation, John A. Herrmann, and the May and Samuel Rudin Family Foundation. Dr. Norris, Dr. Strickland, and Dr. Snyder declared no relevant financial relationships.

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

The frequency of medication errors among children who take drugs to treat attention-deficit/hyperactivity disorder reported to U.S. poison control centers increased by nearly 300% over a 22-year period, according to results of a study published in the journal Pediatrics.

The dramatic jump is likely attributable to an increase in the prescribing of ADHD medications for children. According to the study authors, in 2019, nearly 10% of children in the United States had been diagnosed with ADHD, and some 3.3 million – or about 5% of all children in the country – had received a prescription for an ADHD medication.

“Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems,” the authors commented.

The investigators analyzed data from the National Poison Data System from 2000 through 2021 for therapeutic errors associated with ADHD medication among patients younger than 20 years.

“As medicine changes, it’s nice to look back at some of these things and see how some of these problems have changed,” said Natalie I. Rine, PharmD, a coauthor of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital in Columbus.

The researchers identified 124,383 such errors reported to U.S. poison centers during the study period. The frequency increased by 299%.

Two-thirds (66.6%) of the exposures involved children aged 6-12 years, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were linked to exposure to a single substance. Nearly 83% of patients did not receive treatment at a health care facility; however, 2.3% were admitted to the hospital, and 4.2% had a “serious medical outcome,” the researchers found.

The most common scenarios were “inadvertently took or given medication twice” (53.9%), followed by “inadvertently took or given someone else’s medication” (13.4%) and “wrong medication taken or given” (12.9%), according to the researchers. Two percent involved mistakes by a pharmacist or nurse.
 

Easily preventable

Dr. Rine attributed the errors to simple mistakes and said they were likely the product of busy households and distracted caregivers. She added that the errors are easily avoided by storing the medication properly, keeping a sheet with the medication to document what was taken and when, and using a pillbox or one of many apps that can assist in documenting the dispensing of medications.

“I think the biggest thing is that a lot of these errors are preventable, more than anything else,” Dr. Rine said.

The increase in ADHD diagnoses among children and the subsequent prescribing of medications are reasons for the nearly 300% increase in poison control calls. A 2018 study showed that the estimated prevalence of ADHD diagnoses among U.S. children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016. The Centers for Disease Control and Prevention states that 6 million children and adolescents aged 3-17 years have been diagnosed with ADHD, and 62% have received ADHD medication.

Colleen Kraft, MD, a pediatrician at Children’s Hospital Los Angeles, said she was not surprised by the reported increase in errors. In addition to the simple uptick in ADHD diagnoses and prescriptions in the past 2 decades, Dr. Kraft said the growing variety of ADHD medication is a cause for more errors.

“Because we have so many more different types of these medications, it’s easy to confuse them, and it’s easy to make an error when you give this to a child,” she said in an interview.

Dr. Kraft also hypothesized that because ADHD can have a genetic component, some parents with undiagnosed and untreated ADHD are responsible for their child’s medication, a scenario ripe for mistakes.
 

Potential dangers

Not all ADHD medicinal overdosing is created equal, Dr. Kraft pointed out. Doubling up on a stimulant such as methylphenidate (Ritalin) or the combination of amphetamine and dextroamphetamine (Adderall) may cause headaches, suppress appetite, and cause an upset stomach, although those symptoms usually clear up in a few hours.

However, she noted, the use of alpha-1 adrenergic blockers is more concerning. Also used to treat high blood pressure, medications such as guanfacine and clonidine cause sedation. A double dose can cause blood pressure to decrease to dangerous levels.

The study’s primary limitation was bias in self-reporting, which may have led to underreporting of incidences, according to the researchers. Not every case in which an error occurs that involves a child’s taking ADHD medication gets reported to poison control, because some will take a wait-and-see approach and may not call if their child is asymptomatic.

“Our data is only as good as what the callers report to us,” Dr. Rine said.

A version of this article appeared on Medscape.com.

The frequency of medication errors among children who take drugs to treat attention-deficit/hyperactivity disorder reported to U.S. poison control centers increased by nearly 300% over a 22-year period, according to results of a study published in the journal Pediatrics.

The dramatic jump is likely attributable to an increase in the prescribing of ADHD medications for children. According to the study authors, in 2019, nearly 10% of children in the United States had been diagnosed with ADHD, and some 3.3 million – or about 5% of all children in the country – had received a prescription for an ADHD medication.

“Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems,” the authors commented.

The investigators analyzed data from the National Poison Data System from 2000 through 2021 for therapeutic errors associated with ADHD medication among patients younger than 20 years.

“As medicine changes, it’s nice to look back at some of these things and see how some of these problems have changed,” said Natalie I. Rine, PharmD, a coauthor of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital in Columbus.

The researchers identified 124,383 such errors reported to U.S. poison centers during the study period. The frequency increased by 299%.

Two-thirds (66.6%) of the exposures involved children aged 6-12 years, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were linked to exposure to a single substance. Nearly 83% of patients did not receive treatment at a health care facility; however, 2.3% were admitted to the hospital, and 4.2% had a “serious medical outcome,” the researchers found.

The most common scenarios were “inadvertently took or given medication twice” (53.9%), followed by “inadvertently took or given someone else’s medication” (13.4%) and “wrong medication taken or given” (12.9%), according to the researchers. Two percent involved mistakes by a pharmacist or nurse.
 

Easily preventable

Dr. Rine attributed the errors to simple mistakes and said they were likely the product of busy households and distracted caregivers. She added that the errors are easily avoided by storing the medication properly, keeping a sheet with the medication to document what was taken and when, and using a pillbox or one of many apps that can assist in documenting the dispensing of medications.

“I think the biggest thing is that a lot of these errors are preventable, more than anything else,” Dr. Rine said.

The increase in ADHD diagnoses among children and the subsequent prescribing of medications are reasons for the nearly 300% increase in poison control calls. A 2018 study showed that the estimated prevalence of ADHD diagnoses among U.S. children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016. The Centers for Disease Control and Prevention states that 6 million children and adolescents aged 3-17 years have been diagnosed with ADHD, and 62% have received ADHD medication.

Colleen Kraft, MD, a pediatrician at Children’s Hospital Los Angeles, said she was not surprised by the reported increase in errors. In addition to the simple uptick in ADHD diagnoses and prescriptions in the past 2 decades, Dr. Kraft said the growing variety of ADHD medication is a cause for more errors.

“Because we have so many more different types of these medications, it’s easy to confuse them, and it’s easy to make an error when you give this to a child,” she said in an interview.

Dr. Kraft also hypothesized that because ADHD can have a genetic component, some parents with undiagnosed and untreated ADHD are responsible for their child’s medication, a scenario ripe for mistakes.
 

Potential dangers

Not all ADHD medicinal overdosing is created equal, Dr. Kraft pointed out. Doubling up on a stimulant such as methylphenidate (Ritalin) or the combination of amphetamine and dextroamphetamine (Adderall) may cause headaches, suppress appetite, and cause an upset stomach, although those symptoms usually clear up in a few hours.

However, she noted, the use of alpha-1 adrenergic blockers is more concerning. Also used to treat high blood pressure, medications such as guanfacine and clonidine cause sedation. A double dose can cause blood pressure to decrease to dangerous levels.

The study’s primary limitation was bias in self-reporting, which may have led to underreporting of incidences, according to the researchers. Not every case in which an error occurs that involves a child’s taking ADHD medication gets reported to poison control, because some will take a wait-and-see approach and may not call if their child is asymptomatic.

“Our data is only as good as what the callers report to us,” Dr. Rine said.

A version of this article appeared on Medscape.com.

The frequency of medication errors among children who take drugs to treat attention-deficit/hyperactivity disorder reported to U.S. poison control centers increased by nearly 300% over a 22-year period, according to results of a study published in the journal Pediatrics.

The dramatic jump is likely attributable to an increase in the prescribing of ADHD medications for children. According to the study authors, in 2019, nearly 10% of children in the United States had been diagnosed with ADHD, and some 3.3 million – or about 5% of all children in the country – had received a prescription for an ADHD medication.

“Because therapeutic errors are preventable, more attention should be given to patient and caregiver education and development of improved child-resistant medication dispensing and tracking systems,” the authors commented.

The investigators analyzed data from the National Poison Data System from 2000 through 2021 for therapeutic errors associated with ADHD medication among patients younger than 20 years.

“As medicine changes, it’s nice to look back at some of these things and see how some of these problems have changed,” said Natalie I. Rine, PharmD, a coauthor of the study and director of the Central Ohio Poison Center at Nationwide Children’s Hospital in Columbus.

The researchers identified 124,383 such errors reported to U.S. poison centers during the study period. The frequency increased by 299%.

Two-thirds (66.6%) of the exposures involved children aged 6-12 years, three-fourths (76.4%) were among males, and half (50.5%) involved amphetamines and related compounds. Most (79.7%) therapeutic errors were linked to exposure to a single substance. Nearly 83% of patients did not receive treatment at a health care facility; however, 2.3% were admitted to the hospital, and 4.2% had a “serious medical outcome,” the researchers found.

The most common scenarios were “inadvertently took or given medication twice” (53.9%), followed by “inadvertently took or given someone else’s medication” (13.4%) and “wrong medication taken or given” (12.9%), according to the researchers. Two percent involved mistakes by a pharmacist or nurse.
 

Easily preventable

Dr. Rine attributed the errors to simple mistakes and said they were likely the product of busy households and distracted caregivers. She added that the errors are easily avoided by storing the medication properly, keeping a sheet with the medication to document what was taken and when, and using a pillbox or one of many apps that can assist in documenting the dispensing of medications.

“I think the biggest thing is that a lot of these errors are preventable, more than anything else,” Dr. Rine said.

The increase in ADHD diagnoses among children and the subsequent prescribing of medications are reasons for the nearly 300% increase in poison control calls. A 2018 study showed that the estimated prevalence of ADHD diagnoses among U.S. children and adolescents increased from 6.1% in 1997-1998 to 10.2% in 2015-2016. The Centers for Disease Control and Prevention states that 6 million children and adolescents aged 3-17 years have been diagnosed with ADHD, and 62% have received ADHD medication.

Colleen Kraft, MD, a pediatrician at Children’s Hospital Los Angeles, said she was not surprised by the reported increase in errors. In addition to the simple uptick in ADHD diagnoses and prescriptions in the past 2 decades, Dr. Kraft said the growing variety of ADHD medication is a cause for more errors.

“Because we have so many more different types of these medications, it’s easy to confuse them, and it’s easy to make an error when you give this to a child,” she said in an interview.

Dr. Kraft also hypothesized that because ADHD can have a genetic component, some parents with undiagnosed and untreated ADHD are responsible for their child’s medication, a scenario ripe for mistakes.
 

Potential dangers

Not all ADHD medicinal overdosing is created equal, Dr. Kraft pointed out. Doubling up on a stimulant such as methylphenidate (Ritalin) or the combination of amphetamine and dextroamphetamine (Adderall) may cause headaches, suppress appetite, and cause an upset stomach, although those symptoms usually clear up in a few hours.

However, she noted, the use of alpha-1 adrenergic blockers is more concerning. Also used to treat high blood pressure, medications such as guanfacine and clonidine cause sedation. A double dose can cause blood pressure to decrease to dangerous levels.

The study’s primary limitation was bias in self-reporting, which may have led to underreporting of incidences, according to the researchers. Not every case in which an error occurs that involves a child’s taking ADHD medication gets reported to poison control, because some will take a wait-and-see approach and may not call if their child is asymptomatic.

“Our data is only as good as what the callers report to us,” Dr. Rine said.

A version of this article appeared on Medscape.com.

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

Long-term follow-up from the CheckMate 227 study has revealed lasting benefit from the combination of the CTLA-4 inhibitor ipilimumab (IPI) and the PD-1 inhibitor nivolumab (NIVO) in non-small cell lung cancer. After 6 years, previous tumor response, tumor burden reduction, and baseline health-related quality of life all correlated with overall survival, according to the latest analysis from the study.

“Patients treated with NIVO-IPI versus chemotherapy continue to derive long term durable efficacy benefit in CheckMate 227, regardless of PD-L1 expression. This represents the longest ever reported follow-up across phase three studies of frontline immunotherapy in patients with metastatic non–small cell lung cancer, and this further highlights the clinical benefit of frontline NIVO-IPI as a treatment in these patients with metastatic non–small cell lung cancer, regardless of the PD-L1 expression,” said Solange Peters, MD, PhD, during a presentation of the latest analysis at the annual World Conference on Lung Cancer. Dr. Peters is a professor of oncology at Lausanne (Switzerland) University Hospital.

The combination of nivolumab and ipilimumab has shown long-term survival benefit in other cancer types, including advanced melanoma, advanced renal cell carcinoma, and unresectable pleural mesothelioma.

The same session featured other studies demonstrating positive outcomes of immunotherapy in NSCLC. Serving as a discussant, Ferdinandos Skoulidis MD, PhD, commented, “I would argue that we are now at an inflection point where we can claim that we are altering the natural history of the disease for a subset of patients.” Dr. Skoulidis is an associate professor of thoracic oncology at the University of Texas MD Anderson Cancer Center.
 

Updated results

CheckMate 227 enrolled patients with metastatic or recurrent NSCLC, excluding those with EGFR/ALK alterations. Patients with PD-L1 expression greater than or equal to 1% (PD-L1 positive, n = 1,189) were randomized to NIVO-IPI, NIVO, or chemotherapy. Patients with PD-L1 expression less than 1% (n = 550, PD-L1 negative) were randomized to NIVO-IPI, NIVO plus chemotherapy, or chemotherapy alone. The 5-year landmark analysis, which was published by the National Center for Biotechnology Information, showed overall survival rate of 24% among PD-L1 greater than or equal to 1% patients (PD-L1 positive) and 19% in PD-L1 less than 1% (PD-L1 negative) patients who received IPI-NIVO therapy, compared with 14% and 7%, respectively, in the chemotherapy only groups.

At WCLC, Dr. Peters presented data extending to 6 years of follow-up, as well as exploratory analyses. At 6 years of follow-up, in PD-L1 positive patients, 22% of the NIVO-IPI group remained alive, versus 13% of the chemotherapy group (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91), while there was no significant improvement in OS for nivolumab alone, compared with chemotherapy. In the PD-L1 negative group, 16% were alive at 6 years in the IPI-NIVO group (HR, 0.65; 95% CI, 0.52-0.81), as were 10% in NIVO plus chemotherapy (HR, 0.79; 95% CI, 0.64-0.98) group, versus 5% in the chemotherapy group. The benefit of NIVO-IPI was significant in both squamous and non-squamous tumors for both PDL1-positive and PD-L1 negative patients.

At 6 years follow-up, 27% of PD-L1 positive patients who responded to NIVO-IPI remained in response, versus 22% in the NIVO group and 4% in the chemotherapy only group. Among PD-L1 negative patients, 25% of combination therapy responders remained in response at 6 years, while there were 10% still in response among the NIVO group, and none in the chemotherapy only group.
 

Exploratory analyses

Dr. Peters presented a slide showing tumor burden reductions occurring in responders. “What has to be concluded from this very interesting graph is that there are more, deeper responses in the NIVO-IPI versus chemotherapy. Very importantly, too, this is strongly correlated with survival. In both treatment arms, a high magnitude of tumor burden reduction is correlated with an improved survival,” said Dr. Peters. Specifically, among PD-L1 positive patients with more than 80% tumor reduction, survival was 59% at 6 years (95% CI, 44-71%). The figure was 68% in the NIVO only arm (95% CI, 47-82%), and 42% in the chemotherapy only arm (95% CI, 15-66%).

Among PD-L1 negative patients, “there are more, deeper responses in NIVO-IPI versus chemotherapy. That is very clear. And probably differently from the positive PD-L1 arm, the tumor burden reduction is correlated with survival but really only strongly observed in the NIVO-IPI arm,” said Dr. Peters. The figure was 20% in the nivolumab arm (95% CI, 3-48%) and 0% in the chemotherapy only arm (95% CI, not available). “So really something is correlating the tumor burden reduction with the outcome and specifically correlating it in the negative PD-L1 with the treatment of NIVO-IPI,” said Dr. Peters.

The researchers also noted longer progression-free survival and overall response rate in the NIVO-IPI group than the chemotherapy group in both PD-L1 positive and PD-L1 negative patients.

With respect to health-related quality of life, the researchers found a correlation between higher scores at baseline on the EQ-5D-3L scale and overall survival in the chemotherapy group (HR, 0.61; 95% CI, 0.51-0.74) and a trend in the NIVO-IPI group (HR, 0.83; 95% CI, 0.69-1.01). “So this baseline history, the quality of life, is correlated with the outcome regardless of the treatment you deliver,” said Dr. Peters.
 

Personalizing immunotherapy in NSCLC

In his comments, Dr. Skoulidis highlighted the length of responses. “Most importantly, approximately 50% of these patients that are alive at six years are also disease free, suggesting that we are indeed making a dent on the natural history of the disease for these patients,” he said.

He also made a case for personalizing immunotherapy and suggested that CheckMate 227 could provide some guidance. “Ipilimumab/nivolumab – the CheckMate 227 regimen – appears to be particularly active in terms of inducing long-term, long-lasting responses and overall survival in patients harboring tumors that are negative for PD-L1,” he said.

Dr. Skoulidis also highlighted the 16% six-year overall survival among PD-L1 negative patients who received NIVO-IPI, calling it “impressive.” Of those who responded, 25% continued to respond at 6 years. “This is particularly notable in the subset of patients with squamous histology and lack of PD-L1 expression, where the six year overall survival rate with NIVO-IPI versus chemo was 18% versus 4%. So perhaps in patients with squamous histology and lack of PD-L1 expression, NIVO-IPI might represent a favorable regimen to improve long term outcomes,” said Dr. Skoulidis.

CheckMate 227 was funded by Bristol Myers Sqiubb. Dr. Peters has financial relationships with a wide range of pharmaceutical companies, including Bristol Myers Squibb. Dr. Skoulidis has financial relationships with Moderna, BioNTech, Amgen, Intellisphere, Navire, BeiGene, Medscape, Calithera Biosciences, Tango Therapeutics, Guardant Health, Novartis, AIMM Therapeutics, Mirati Therapeutics, Boehringer Ingelheim, Merck, and Pfizer.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

The Food and Drug Administration on Sept. 15 approved the Janus kinase (JAK) inhibitor momelotinib (Ojjaara) for myelofibrosis patients with anemia, according to a press release from maker GSK.

Momelotinib is the fourth JAK inhibitor to be approved by the agency for myelofibrosis but the only one indicated for patients with hemoglobin levels below 10 g/dL.

It’s an important development because, while JAK inhibitors are standard treatment for myelofibrosis, those previously approved for the uncommon blood cancer can cause cytopenia, particularly anemia, which, ironically, is also a hallmark of myelofibrosis itself.

This issue makes using JAK inhibitors for myelofibrosis challenging, according to Anthony Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta, who spoke on the topic recently at the annual meeting of the Society of Hematologic Oncology in Houston. “Momelotinib is an important emerging agent for these more anemic patients.” Momelotinib has a spleen response comparable with ruxolitinib – the first JAK inhibitor approved for myelofibrosis in the United States – and significantly higher rates of transfusion independence, although lower rates of symptom control, he said.

In GSK’s press release, hematologist/oncologist Ruben Mesa, MD, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, N.C., said that, “with momelotinib, we have the potential to establish a new standard of care for myelofibrosis patients with anemia.”

Momelotinib’s specific indication is for “the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), in adults with anemia.”

The once-daily oral medication was approved based on two trials. One trial, MOMENTUM, showed statistically significant response with respect to constitutional symptoms, splenic response, and transfusion independence in anemic patients treated with momelotinib versus danazol.

An anemic subset of the SIMPLIFY-1 trial showed comparable spleen volume reduction versus ruxolitinib but a numerically lower symptom response rate.

The most common momelotinib adverse reactions in trials were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

A version of this article appeared on Medscape.com.

Currently, more than 3.8 million breast cancer survivors reside in the United States, reflecting high prevalence as well as cure rates for this common malignancy.

When over-the-counter measures including vaginal lubricants and moisturizers are not adequate, vaginal estrogen may be a highly effective treatment for genitourinary syndrome of menopause (GSM), a common condition associated with hypoestrogenism that impairs sexual function and quality of life.

Use of vaginal formulations does not result in systemic levels of estrogen above the normal postmenopausal range. Nonetheless, the U.S. Food and Drug Administration lists a history of breast cancer as a contraindication to the use of all systemic as well as vaginal estrogens.

In premenopausal women, chemotherapy for breast cancer often results in early menopause. Aromatase inhibitors, although effective in preventing recurrent disease in menopausal women, exacerbate GSM. These factors result in a high prevalence of GSM in breast cancer survivors.

Because the safety of vaginal estrogen in the setting of breast cancer is uncertain, investigators at Johns Hopkins conducted a cohort study using claims-based data from more than 200 million U.S. patients that identified women with GSM who had previously been diagnosed with breast cancer. Among some 42,000 women diagnosed with GSM after breast cancer, 5% had three or more prescriptions and were considered vaginal estrogen users.

No significant differences were noted in recurrence-free survival between the vaginal estrogen group and the no estrogen group. At 5 and 10 years of follow-up, use of vaginal estrogen was not associated with higher all-cause mortality. Among women with estrogen receptor–positive tumors, risk for breast cancer recurrence was similar between estrogen users and nonusers.

However, concomitant use of vaginal estrogen and aromatase inhibitors was associated with a higher risk for breast cancer recurrence than was use of vaginal estrogen alone.

Although this important study’s findings have the limitations characteristic of observational studies, its large size and careful analyses suggest that in selected well-counseled breast cancer survivors, off-label use of vaginal estrogen may safely improve their sexual function and quality of life.

Dr. Kaunitz is associate chairman, department of obstetrics and gynecology, University of Florida College of Medicine, Jacksonville. This transcript has been edited for clarity. A version of this article first appeared on Medscape.com.

Currently, more than 3.8 million breast cancer survivors reside in the United States, reflecting high prevalence as well as cure rates for this common malignancy.

When over-the-counter measures including vaginal lubricants and moisturizers are not adequate, vaginal estrogen may be a highly effective treatment for genitourinary syndrome of menopause (GSM), a common condition associated with hypoestrogenism that impairs sexual function and quality of life.

Use of vaginal formulations does not result in systemic levels of estrogen above the normal postmenopausal range. Nonetheless, the U.S. Food and Drug Administration lists a history of breast cancer as a contraindication to the use of all systemic as well as vaginal estrogens.

In premenopausal women, chemotherapy for breast cancer often results in early menopause. Aromatase inhibitors, although effective in preventing recurrent disease in menopausal women, exacerbate GSM. These factors result in a high prevalence of GSM in breast cancer survivors.

Because the safety of vaginal estrogen in the setting of breast cancer is uncertain, investigators at Johns Hopkins conducted a cohort study using claims-based data from more than 200 million U.S. patients that identified women with GSM who had previously been diagnosed with breast cancer. Among some 42,000 women diagnosed with GSM after breast cancer, 5% had three or more prescriptions and were considered vaginal estrogen users.

No significant differences were noted in recurrence-free survival between the vaginal estrogen group and the no estrogen group. At 5 and 10 years of follow-up, use of vaginal estrogen was not associated with higher all-cause mortality. Among women with estrogen receptor–positive tumors, risk for breast cancer recurrence was similar between estrogen users and nonusers.

However, concomitant use of vaginal estrogen and aromatase inhibitors was associated with a higher risk for breast cancer recurrence than was use of vaginal estrogen alone.

Although this important study’s findings have the limitations characteristic of observational studies, its large size and careful analyses suggest that in selected well-counseled breast cancer survivors, off-label use of vaginal estrogen may safely improve their sexual function and quality of life.

Dr. Kaunitz is associate chairman, department of obstetrics and gynecology, University of Florida College of Medicine, Jacksonville. This transcript has been edited for clarity. A version of this article first appeared on Medscape.com.

Currently, more than 3.8 million breast cancer survivors reside in the United States, reflecting high prevalence as well as cure rates for this common malignancy.

When over-the-counter measures including vaginal lubricants and moisturizers are not adequate, vaginal estrogen may be a highly effective treatment for genitourinary syndrome of menopause (GSM), a common condition associated with hypoestrogenism that impairs sexual function and quality of life.

Use of vaginal formulations does not result in systemic levels of estrogen above the normal postmenopausal range. Nonetheless, the U.S. Food and Drug Administration lists a history of breast cancer as a contraindication to the use of all systemic as well as vaginal estrogens.

In premenopausal women, chemotherapy for breast cancer often results in early menopause. Aromatase inhibitors, although effective in preventing recurrent disease in menopausal women, exacerbate GSM. These factors result in a high prevalence of GSM in breast cancer survivors.

Because the safety of vaginal estrogen in the setting of breast cancer is uncertain, investigators at Johns Hopkins conducted a cohort study using claims-based data from more than 200 million U.S. patients that identified women with GSM who had previously been diagnosed with breast cancer. Among some 42,000 women diagnosed with GSM after breast cancer, 5% had three or more prescriptions and were considered vaginal estrogen users.

No significant differences were noted in recurrence-free survival between the vaginal estrogen group and the no estrogen group. At 5 and 10 years of follow-up, use of vaginal estrogen was not associated with higher all-cause mortality. Among women with estrogen receptor–positive tumors, risk for breast cancer recurrence was similar between estrogen users and nonusers.

However, concomitant use of vaginal estrogen and aromatase inhibitors was associated with a higher risk for breast cancer recurrence than was use of vaginal estrogen alone.

Although this important study’s findings have the limitations characteristic of observational studies, its large size and careful analyses suggest that in selected well-counseled breast cancer survivors, off-label use of vaginal estrogen may safely improve their sexual function and quality of life.

Dr. Kaunitz is associate chairman, department of obstetrics and gynecology, University of Florida College of Medicine, Jacksonville. This transcript has been edited for clarity. A version of this article first appeared on Medscape.com.

A recent study found a significant association between lower sexual frequency and greater all-cause mortality in young and middle-aged people with hypertension. Should primary care physicians be offering a pleasure prescription to the 6 in 10 Americans living with chronic illness? How can we help these patients access their capacity for sexual pleasure, a critical and life-affirming component of the human experience?

Ask, don’t tell

First, we need to ask routinely about sexual well-being and pleasure. Without asking patients their views, we do not know the relevance of sex for their quality of life. Unless we ask, we do not know what specific kinds of sexual play are important for a person’s pleasure, nor can we assume how they prioritize their sexual functioning in the context of their medical care. When I began asking my primary care patients about sexual well-being, many more than I expected were quietly holding on to distressing issues. Now, as a sexual medicine specialist, in each sexual function evaluation, I ask three key questions: What are your goals? What does sex mean to you? What kinds of sexual play are important for your (and your partner’s) pleasure?

Chronic disease – with physical symptoms as well as psychological, relational, and cultural components – affects both general and genital physiology. Any disease process that alters vascular, neuroendocrine, or musculoskeletal function is likely to influence sexual function, either directly through the disease process or indirectly through complications or the effect on identity and well-being. In addition, a host of iatrogenic changes to sexual function may accompany effects of treatments.

Managing the effects of chronic illness on sexuality requires resilience and flexibility. A serious injury may require a massive adjustment to sexuality, but progressive disease may require continuous accommodations to sexual changes. The life stage at which the disease occurs also matters. People facing disease early in life encounter challenges (finding willing sexual partners and limited medical guidance regarding their sexual functioning) as well as benefits (they may integrate their disease as part of their sexual life). Those who experience sexual changes related to their illness later in life may face a loss of “normal” sexual function and well-being.

Meanwhile, the partner who is not ill may have their own sexual needs, fears, and worries. Both patients and partners may experience disenfranchised grief – a sense of loss about something one is not culturally permitted to mourn (“I/my partner is alive in the face of this terrible illness; who am I to worry about our/my sexual pleasure?”).

Positive marital relationships influence health through improved survival, improved medical adherence, better quality of life for the patient, and improved life satisfaction. Sexual satisfaction is an important factor in relational satisfaction. Helping our patients with these changes therefore may improve not only sexual health but overall health.

How, then, should we address sexual pleasure in chronic illness care? Here are a few tips:

Focus on pleasure. “Performance” is foul language when it comes to sex. Full attention to sensation and enjoyment, the only sexual “skill” anyone needs, is impossible while trying to perform.

Encourage flexibility and recognize that sex encompasses a wide and varied menu of experiences that change over a lifetime. Sex is everything from kissing and cuddling to the wildest things a mind can imagine. We can help both patients and partners think about the wide variety of ways to meet sexual needs. Balancing acceptance of sexual changes with motivation for improvement also is part of our role.

Address the effects of illness on the patient’s relationship with their body. Illness may alter not only bodily function but also self-esteem and body image. A reorganization of self-concept may occur (“I am no longer a sexual person; I’m a sexually dysfunctional asthmatic/diabetic/etc. and should avoid sexual intimacy”). Examining these self-constructs allows shifts in thoughts and behaviors, leading to improved psychological and sexual well-being. Encourage patients to explore what feels good in this body now. When possible, we can help with referral for corrective surgeries or direction to resources like stoma covers, wigs, scarves, and tattoos.

We offer suggestions for “sleep hygiene”; how about pleasure hygiene?

• Encourage open communication with partner(s) and offer resources to develop communication skills.
• Consider needs for physical and emotional preparation for sexual play: adequate rest, preparing the environment for body fluids, pillows for comfort or aides for positioning, and plenty of lubricant at hand.
• Allow adequate time for sexual play and encourage the ability to adjust or stop and start over – with humor and self-compassion.
• Use sexual aides to enhance pleasure.
• Seek out sexual medicine and sex therapy colleagues when things become tricky.

All bodies, no matter their health or illness state, are capable of pleasure. Hey, pleasure might even save lives!

Dr. Kranz is an clinical assistant professor of obstetrics/gynecology and family medicine, University of Rochester (N.Y.) Medical Center. She reported no conflicts of interest.

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

A recent study found a significant association between lower sexual frequency and greater all-cause mortality in young and middle-aged people with hypertension. Should primary care physicians be offering a pleasure prescription to the 6 in 10 Americans living with chronic illness? How can we help these patients access their capacity for sexual pleasure, a critical and life-affirming component of the human experience?

Ask, don’t tell

First, we need to ask routinely about sexual well-being and pleasure. Without asking patients their views, we do not know the relevance of sex for their quality of life. Unless we ask, we do not know what specific kinds of sexual play are important for a person’s pleasure, nor can we assume how they prioritize their sexual functioning in the context of their medical care. When I began asking my primary care patients about sexual well-being, many more than I expected were quietly holding on to distressing issues. Now, as a sexual medicine specialist, in each sexual function evaluation, I ask three key questions: What are your goals? What does sex mean to you? What kinds of sexual play are important for your (and your partner’s) pleasure?

Chronic disease – with physical symptoms as well as psychological, relational, and cultural components – affects both general and genital physiology. Any disease process that alters vascular, neuroendocrine, or musculoskeletal function is likely to influence sexual function, either directly through the disease process or indirectly through complications or the effect on identity and well-being. In addition, a host of iatrogenic changes to sexual function may accompany effects of treatments.

Managing the effects of chronic illness on sexuality requires resilience and flexibility. A serious injury may require a massive adjustment to sexuality, but progressive disease may require continuous accommodations to sexual changes. The life stage at which the disease occurs also matters. People facing disease early in life encounter challenges (finding willing sexual partners and limited medical guidance regarding their sexual functioning) as well as benefits (they may integrate their disease as part of their sexual life). Those who experience sexual changes related to their illness later in life may face a loss of “normal” sexual function and well-being.

Meanwhile, the partner who is not ill may have their own sexual needs, fears, and worries. Both patients and partners may experience disenfranchised grief – a sense of loss about something one is not culturally permitted to mourn (“I/my partner is alive in the face of this terrible illness; who am I to worry about our/my sexual pleasure?”).

Positive marital relationships influence health through improved survival, improved medical adherence, better quality of life for the patient, and improved life satisfaction. Sexual satisfaction is an important factor in relational satisfaction. Helping our patients with these changes therefore may improve not only sexual health but overall health.

How, then, should we address sexual pleasure in chronic illness care? Here are a few tips:

Focus on pleasure. “Performance” is foul language when it comes to sex. Full attention to sensation and enjoyment, the only sexual “skill” anyone needs, is impossible while trying to perform.

Encourage flexibility and recognize that sex encompasses a wide and varied menu of experiences that change over a lifetime. Sex is everything from kissing and cuddling to the wildest things a mind can imagine. We can help both patients and partners think about the wide variety of ways to meet sexual needs. Balancing acceptance of sexual changes with motivation for improvement also is part of our role.

Address the effects of illness on the patient’s relationship with their body. Illness may alter not only bodily function but also self-esteem and body image. A reorganization of self-concept may occur (“I am no longer a sexual person; I’m a sexually dysfunctional asthmatic/diabetic/etc. and should avoid sexual intimacy”). Examining these self-constructs allows shifts in thoughts and behaviors, leading to improved psychological and sexual well-being. Encourage patients to explore what feels good in this body now. When possible, we can help with referral for corrective surgeries or direction to resources like stoma covers, wigs, scarves, and tattoos.

We offer suggestions for “sleep hygiene”; how about pleasure hygiene?

• Encourage open communication with partner(s) and offer resources to develop communication skills.
• Consider needs for physical and emotional preparation for sexual play: adequate rest, preparing the environment for body fluids, pillows for comfort or aides for positioning, and plenty of lubricant at hand.
• Allow adequate time for sexual play and encourage the ability to adjust or stop and start over – with humor and self-compassion.
• Use sexual aides to enhance pleasure.
• Seek out sexual medicine and sex therapy colleagues when things become tricky.

All bodies, no matter their health or illness state, are capable of pleasure. Hey, pleasure might even save lives!

Dr. Kranz is an clinical assistant professor of obstetrics/gynecology and family medicine, University of Rochester (N.Y.) Medical Center. She reported no conflicts of interest.

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

A recent study found a significant association between lower sexual frequency and greater all-cause mortality in young and middle-aged people with hypertension. Should primary care physicians be offering a pleasure prescription to the 6 in 10 Americans living with chronic illness? How can we help these patients access their capacity for sexual pleasure, a critical and life-affirming component of the human experience?

Ask, don’t tell

First, we need to ask routinely about sexual well-being and pleasure. Without asking patients their views, we do not know the relevance of sex for their quality of life. Unless we ask, we do not know what specific kinds of sexual play are important for a person’s pleasure, nor can we assume how they prioritize their sexual functioning in the context of their medical care. When I began asking my primary care patients about sexual well-being, many more than I expected were quietly holding on to distressing issues. Now, as a sexual medicine specialist, in each sexual function evaluation, I ask three key questions: What are your goals? What does sex mean to you? What kinds of sexual play are important for your (and your partner’s) pleasure?

Chronic disease – with physical symptoms as well as psychological, relational, and cultural components – affects both general and genital physiology. Any disease process that alters vascular, neuroendocrine, or musculoskeletal function is likely to influence sexual function, either directly through the disease process or indirectly through complications or the effect on identity and well-being. In addition, a host of iatrogenic changes to sexual function may accompany effects of treatments.

Managing the effects of chronic illness on sexuality requires resilience and flexibility. A serious injury may require a massive adjustment to sexuality, but progressive disease may require continuous accommodations to sexual changes. The life stage at which the disease occurs also matters. People facing disease early in life encounter challenges (finding willing sexual partners and limited medical guidance regarding their sexual functioning) as well as benefits (they may integrate their disease as part of their sexual life). Those who experience sexual changes related to their illness later in life may face a loss of “normal” sexual function and well-being.

Meanwhile, the partner who is not ill may have their own sexual needs, fears, and worries. Both patients and partners may experience disenfranchised grief – a sense of loss about something one is not culturally permitted to mourn (“I/my partner is alive in the face of this terrible illness; who am I to worry about our/my sexual pleasure?”).

Positive marital relationships influence health through improved survival, improved medical adherence, better quality of life for the patient, and improved life satisfaction. Sexual satisfaction is an important factor in relational satisfaction. Helping our patients with these changes therefore may improve not only sexual health but overall health.

How, then, should we address sexual pleasure in chronic illness care? Here are a few tips:

Focus on pleasure. “Performance” is foul language when it comes to sex. Full attention to sensation and enjoyment, the only sexual “skill” anyone needs, is impossible while trying to perform.

Encourage flexibility and recognize that sex encompasses a wide and varied menu of experiences that change over a lifetime. Sex is everything from kissing and cuddling to the wildest things a mind can imagine. We can help both patients and partners think about the wide variety of ways to meet sexual needs. Balancing acceptance of sexual changes with motivation for improvement also is part of our role.

Address the effects of illness on the patient’s relationship with their body. Illness may alter not only bodily function but also self-esteem and body image. A reorganization of self-concept may occur (“I am no longer a sexual person; I’m a sexually dysfunctional asthmatic/diabetic/etc. and should avoid sexual intimacy”). Examining these self-constructs allows shifts in thoughts and behaviors, leading to improved psychological and sexual well-being. Encourage patients to explore what feels good in this body now. When possible, we can help with referral for corrective surgeries or direction to resources like stoma covers, wigs, scarves, and tattoos.

We offer suggestions for “sleep hygiene”; how about pleasure hygiene?