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Fish oil labels make health claims, despite lack of data
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).
The authors say “additional regulation” of the claims may be needed to prevent consumer misinformation. Notably, 20% of adults older than 60 years take fish oil supplements for heart health despite the fact that multiple randomized trials show no cardiovascular benefit.
“Based on what I’ve seen personally in the grocery store and pharmacy, I was not surprised to find such high rates of health claims on fish oil supplements,” lead author Joanna Assadourian, BSA, of UT Southwestern Medical Center, Dallas, said in an interview. “What was surprising, though, was just how broad the types of claims being made were – from heart and brain health to joint health, eye health, and immune function.”
Principal author Ann Marie Navar, MD, PhD, also of UT Southwestern, added, “As a preventive cardiologist, I tell my patients that if they are taking fish oil to try to avoid heart disease, then they can stop taking it because it’s not helping them. Their money would be better spent on something that will actually prevent a heart attack, like more fresh vegetables, their blood pressure or cholesterol medication, or a gym membership.”
The study was published online in JAMA Cardiology.
‘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.
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).
The authors say “additional regulation” of the claims may be needed to prevent consumer misinformation. Notably, 20% of adults older than 60 years take fish oil supplements for heart health despite the fact that multiple randomized trials show no cardiovascular benefit.
“Based on what I’ve seen personally in the grocery store and pharmacy, I was not surprised to find such high rates of health claims on fish oil supplements,” lead author Joanna Assadourian, BSA, of UT Southwestern Medical Center, Dallas, said in an interview. “What was surprising, though, was just how broad the types of claims being made were – from heart and brain health to joint health, eye health, and immune function.”
Principal author Ann Marie Navar, MD, PhD, also of UT Southwestern, added, “As a preventive cardiologist, I tell my patients that if they are taking fish oil to try to avoid heart disease, then they can stop taking it because it’s not helping them. Their money would be better spent on something that will actually prevent a heart attack, like more fresh vegetables, their blood pressure or cholesterol medication, or a gym membership.”
The study was published online in JAMA Cardiology.
‘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.
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).
The authors say “additional regulation” of the claims may be needed to prevent consumer misinformation. Notably, 20% of adults older than 60 years take fish oil supplements for heart health despite the fact that multiple randomized trials show no cardiovascular benefit.
“Based on what I’ve seen personally in the grocery store and pharmacy, I was not surprised to find such high rates of health claims on fish oil supplements,” lead author Joanna Assadourian, BSA, of UT Southwestern Medical Center, Dallas, said in an interview. “What was surprising, though, was just how broad the types of claims being made were – from heart and brain health to joint health, eye health, and immune function.”
Principal author Ann Marie Navar, MD, PhD, also of UT Southwestern, added, “As a preventive cardiologist, I tell my patients that if they are taking fish oil to try to avoid heart disease, then they can stop taking it because it’s not helping them. Their money would be better spent on something that will actually prevent a heart attack, like more fresh vegetables, their blood pressure or cholesterol medication, or a gym membership.”
The study was published online in JAMA Cardiology.
‘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.
FROM JAMA CARDIOLOGY
New antibiotic could combat multidrug-resistant superbugs
Antibiotic resistance is a major public health problem. Few new molecules are in development, but a new antibiotic called clovibactin brings hope.
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.
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.
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.
FROM CELL
Should clinic BP be routinely measured lying down?
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.
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.
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.
FROM HYPERTENSION 2023
How does lecanemab work in Alzheimer’s?
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.
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.
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.
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.
FROM PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE
Surge in pediatric ADHD med errors prompts call for prevention
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.
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.
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.
FROM PEDIATRICS
Sotatercept tied to disease modification in pulmonary arterial hypertension
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. ,” 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. ,” 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. ,” 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.
AT ERS 2023
Nivolumab/Ipillimumab combo demonstrates long-term efficacy in NSCLC
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. , 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. , 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. , 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.
FROM WCLC 2023
FDA approves JAK inhibitor momelotinib for myelofibrosis with anemia
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.
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.
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.
Smartphones for children with type 1 diabetes: Cause for concern?
My young patient with type 1 diabetes (T1D) had her cell phone out to provide a share code for her Dexcom clarity app as she was checking into her visit. As my nurse was recording the code, the patient asked him, “Hey, can you add me on Snapchat?”
Her father scrolled through his own Facebook feed in the chair next to her, showing no concern that his daughter was looking to connect with an adult on a social media platform. Meanwhile, we were all grateful that the little girl, who had had a seizure due to hypoglycemia in her preschool and pre–continuous glucose monitoring (CGM) years, had access to the tools harnessed within the sparkly encased phone she held in her small hands. But did anyone in the room fully understand the potential dangers?
We are living in an exhilarating era of diabetes technology, a treatment environment that I couldn’t have dreamed of during my pediatric endocrinology fellowship. T1D is a volatile condition that changes day to day, especially in growing children. A short decade ago, the best CGM available was a bulky device on loan to patients for 3 days at a time. Information was later downloaded in-office to get a better idea of general glucose trends, if insurance would approve its use at all.
Now, we have a variety of very wearable and accurate disposable CGMs accessible to most patients. Every major insulin pump has available closed-loop capabilities. Some patients can dose from apps on their cell phones rather than juggle another device or draw attention to an insulin pump at the cafeteria table.
These developments have been game changers for children and teenagers with diabetes and for their families. When wondering whether an athlete’s dazed appearance on a soccer field was due to hypoglycemia, a parent no longer must demand that a coach pull the player – a quick glance at a smartphone app can verify the blood glucose and change rate. Children can use programs and search engines to quickly verify carbohydrate counts. Life360 and other tracking programs have increased parental feelings of security, especially with young drivers living with a chronic medical condition.
The inevitable outcome of this available technology is that children living with T1D are given cell phones far earlier than are their siblings or peers owing to “necessity.” Parents understandably want a means to stay in close contact with their children in case of a medical emergency. As a physician and mother of young children, I am thankful for the technology that keeps my patients safer and that allows them to fully participate in everything from sports to travel to an uninterrupted night’s sleep.
Smartphone presence in classrooms empowers teachers, students, parents, and school nurses to be aware of glycemic trends and prevent hypoglycemic emergencies. Smartphones have also shown to be a major distraction in that setting, causing many schools to ban their use entirely. Video apps such as YouTube and TikTok can provide a wealth of support and medical information but may also open the door to misinformation and dangerous social contagion, particularly surrounding disordered eating. Informative podcasts such as The Juicebox Podcast and online forums provide incredible support for families, but the constant siren call of a phone in their pockets leads to distracted parents constantly tending to other conversations or responding to ever more demanding employers rather than focusing on face-to-face education sessions.
The Surgeon General recently released a report concerning social media use in children. This eye-opening report revealed that one-third of children admitted to using their cell phones “almost constantly.” Social media use is associated with higher rates of anxiety and depression, especially in teen girls. This is particularly concerning for children with T1D, who are more likely to suffer from these conditions.
Beyond mental health concerns, especially to developing brains, unfettered Internet use increases the risk that children are exposed to predators and harmful content. The online safety monitoring platform Bark shared data from its 2021 surveillance. Bark found that 72% of tweens and 85% of teens were involved in an online bullying situation. Sixty-nine percent of tweens and 91% of teens encountered nudity or sexual content. Ten percent of tweens and 21% of teens encountered predatory behavior.
These alarming finds mirror the prevalence suggested by conversations in my office. I hear reports of my patients sneaking out at night to meet adults they met through social media, having suicidal ideation and attempts after Internet bullying, and sharing earnest belief in bizarre conspiracy theories gleaned from online forums that lead to dangerous health care practices.
Furthermore, time is a finite resource. Teens who are spending an average of 3.5 hours daily on their devices are running out of time to play, study, and grow extracurricular interests. My friend who coaches high school baseball lamented recently the poor athleticism in his recent teams. He theorized that his players had spent their summers on tablets rather than playing catch or climbing trees. The resulting declines in exercise in young people only serve to worsen the childhood obesity epidemic.
What is a concerned parent to do? First, all phones have controls that allow parents to choose which apps are allowed and which are blocked. Caregivers must understand how various social media platforms work. Installing programs such as Bark provides an additional layer of monitoring, though these are no substitute for parental vigilance. Importantly, parents should talk to their children about their concerns regarding social media.
Sadly, I have often noticed that caregivers pity the extra hardships their children endure as the result of T1D and other chronic diseases. Being lax with rules to attempt to compensate for other suffering is far too tempting. The goal is for children and teens living with T1D to have a full and normal childhood, and unrestricted smartphone access and early social media use should not be the goal for any child. For every family, a media use plan is a smart approach. The American Academy of Pediatrics suggests several commonsense steps to use technology wisely, and parents often must address their own relationships with their devices to model healthy engagement.
As health care professionals, we owe it to our patients to discuss the ups and downs of technology with our patients. We can’t ostrich our way through this. We can point our patients and families to supportive groups such as Osprey (Old School Parents Raising Engaged Youth), founded by Ben and Erin Napier from the HGTV show Home Town along with my college friends Taylor and Dr. Catherine Sledge. Wait Until 8th provides information and motivation for parents to make wise choices regarding phone use for their children. The documentary Childhood 2.0 is another compelling resource developed by pediatric emergency physician Dr. Free Hess and her team that summarizes many of these concerns.
In another decade, many of these dangers will be far clearer. As ubiquitous as smartphone misuse is in our society, I remain hopeful that our society will change its behaviors. Just because “everyone else” allows an unhealthy relationship with technology doesn’t mean that we should for our children.
When I was a child, smoking was glamorized in movies and restaurants had dedicated smoking sections. After strong public policy efforts, many geared toward children, smoking is now almost unthinkable. My 8-year-old asked me lately whether a lady smoking a cigarette in the car next to us would have to go to jail. I chose a career in pediatrics because I am an optimist at my very core. We can’t ignore the dangers associated with the wide door opened by mobile devices. We can celebrate the benefits while clearly facing the pitfalls.
Dr. Lilley is director of the pediatric diabetes and lipid program at the Mississippi Center for Advanced Medicine, Madison. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
My young patient with type 1 diabetes (T1D) had her cell phone out to provide a share code for her Dexcom clarity app as she was checking into her visit. As my nurse was recording the code, the patient asked him, “Hey, can you add me on Snapchat?”
Her father scrolled through his own Facebook feed in the chair next to her, showing no concern that his daughter was looking to connect with an adult on a social media platform. Meanwhile, we were all grateful that the little girl, who had had a seizure due to hypoglycemia in her preschool and pre–continuous glucose monitoring (CGM) years, had access to the tools harnessed within the sparkly encased phone she held in her small hands. But did anyone in the room fully understand the potential dangers?
We are living in an exhilarating era of diabetes technology, a treatment environment that I couldn’t have dreamed of during my pediatric endocrinology fellowship. T1D is a volatile condition that changes day to day, especially in growing children. A short decade ago, the best CGM available was a bulky device on loan to patients for 3 days at a time. Information was later downloaded in-office to get a better idea of general glucose trends, if insurance would approve its use at all.
Now, we have a variety of very wearable and accurate disposable CGMs accessible to most patients. Every major insulin pump has available closed-loop capabilities. Some patients can dose from apps on their cell phones rather than juggle another device or draw attention to an insulin pump at the cafeteria table.
These developments have been game changers for children and teenagers with diabetes and for their families. When wondering whether an athlete’s dazed appearance on a soccer field was due to hypoglycemia, a parent no longer must demand that a coach pull the player – a quick glance at a smartphone app can verify the blood glucose and change rate. Children can use programs and search engines to quickly verify carbohydrate counts. Life360 and other tracking programs have increased parental feelings of security, especially with young drivers living with a chronic medical condition.
The inevitable outcome of this available technology is that children living with T1D are given cell phones far earlier than are their siblings or peers owing to “necessity.” Parents understandably want a means to stay in close contact with their children in case of a medical emergency. As a physician and mother of young children, I am thankful for the technology that keeps my patients safer and that allows them to fully participate in everything from sports to travel to an uninterrupted night’s sleep.
Smartphone presence in classrooms empowers teachers, students, parents, and school nurses to be aware of glycemic trends and prevent hypoglycemic emergencies. Smartphones have also shown to be a major distraction in that setting, causing many schools to ban their use entirely. Video apps such as YouTube and TikTok can provide a wealth of support and medical information but may also open the door to misinformation and dangerous social contagion, particularly surrounding disordered eating. Informative podcasts such as The Juicebox Podcast and online forums provide incredible support for families, but the constant siren call of a phone in their pockets leads to distracted parents constantly tending to other conversations or responding to ever more demanding employers rather than focusing on face-to-face education sessions.
The Surgeon General recently released a report concerning social media use in children. This eye-opening report revealed that one-third of children admitted to using their cell phones “almost constantly.” Social media use is associated with higher rates of anxiety and depression, especially in teen girls. This is particularly concerning for children with T1D, who are more likely to suffer from these conditions.
Beyond mental health concerns, especially to developing brains, unfettered Internet use increases the risk that children are exposed to predators and harmful content. The online safety monitoring platform Bark shared data from its 2021 surveillance. Bark found that 72% of tweens and 85% of teens were involved in an online bullying situation. Sixty-nine percent of tweens and 91% of teens encountered nudity or sexual content. Ten percent of tweens and 21% of teens encountered predatory behavior.
These alarming finds mirror the prevalence suggested by conversations in my office. I hear reports of my patients sneaking out at night to meet adults they met through social media, having suicidal ideation and attempts after Internet bullying, and sharing earnest belief in bizarre conspiracy theories gleaned from online forums that lead to dangerous health care practices.
Furthermore, time is a finite resource. Teens who are spending an average of 3.5 hours daily on their devices are running out of time to play, study, and grow extracurricular interests. My friend who coaches high school baseball lamented recently the poor athleticism in his recent teams. He theorized that his players had spent their summers on tablets rather than playing catch or climbing trees. The resulting declines in exercise in young people only serve to worsen the childhood obesity epidemic.
What is a concerned parent to do? First, all phones have controls that allow parents to choose which apps are allowed and which are blocked. Caregivers must understand how various social media platforms work. Installing programs such as Bark provides an additional layer of monitoring, though these are no substitute for parental vigilance. Importantly, parents should talk to their children about their concerns regarding social media.
Sadly, I have often noticed that caregivers pity the extra hardships their children endure as the result of T1D and other chronic diseases. Being lax with rules to attempt to compensate for other suffering is far too tempting. The goal is for children and teens living with T1D to have a full and normal childhood, and unrestricted smartphone access and early social media use should not be the goal for any child. For every family, a media use plan is a smart approach. The American Academy of Pediatrics suggests several commonsense steps to use technology wisely, and parents often must address their own relationships with their devices to model healthy engagement.
As health care professionals, we owe it to our patients to discuss the ups and downs of technology with our patients. We can’t ostrich our way through this. We can point our patients and families to supportive groups such as Osprey (Old School Parents Raising Engaged Youth), founded by Ben and Erin Napier from the HGTV show Home Town along with my college friends Taylor and Dr. Catherine Sledge. Wait Until 8th provides information and motivation for parents to make wise choices regarding phone use for their children. The documentary Childhood 2.0 is another compelling resource developed by pediatric emergency physician Dr. Free Hess and her team that summarizes many of these concerns.
In another decade, many of these dangers will be far clearer. As ubiquitous as smartphone misuse is in our society, I remain hopeful that our society will change its behaviors. Just because “everyone else” allows an unhealthy relationship with technology doesn’t mean that we should for our children.
When I was a child, smoking was glamorized in movies and restaurants had dedicated smoking sections. After strong public policy efforts, many geared toward children, smoking is now almost unthinkable. My 8-year-old asked me lately whether a lady smoking a cigarette in the car next to us would have to go to jail. I chose a career in pediatrics because I am an optimist at my very core. We can’t ignore the dangers associated with the wide door opened by mobile devices. We can celebrate the benefits while clearly facing the pitfalls.
Dr. Lilley is director of the pediatric diabetes and lipid program at the Mississippi Center for Advanced Medicine, Madison. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
My young patient with type 1 diabetes (T1D) had her cell phone out to provide a share code for her Dexcom clarity app as she was checking into her visit. As my nurse was recording the code, the patient asked him, “Hey, can you add me on Snapchat?”
Her father scrolled through his own Facebook feed in the chair next to her, showing no concern that his daughter was looking to connect with an adult on a social media platform. Meanwhile, we were all grateful that the little girl, who had had a seizure due to hypoglycemia in her preschool and pre–continuous glucose monitoring (CGM) years, had access to the tools harnessed within the sparkly encased phone she held in her small hands. But did anyone in the room fully understand the potential dangers?
We are living in an exhilarating era of diabetes technology, a treatment environment that I couldn’t have dreamed of during my pediatric endocrinology fellowship. T1D is a volatile condition that changes day to day, especially in growing children. A short decade ago, the best CGM available was a bulky device on loan to patients for 3 days at a time. Information was later downloaded in-office to get a better idea of general glucose trends, if insurance would approve its use at all.
Now, we have a variety of very wearable and accurate disposable CGMs accessible to most patients. Every major insulin pump has available closed-loop capabilities. Some patients can dose from apps on their cell phones rather than juggle another device or draw attention to an insulin pump at the cafeteria table.
These developments have been game changers for children and teenagers with diabetes and for their families. When wondering whether an athlete’s dazed appearance on a soccer field was due to hypoglycemia, a parent no longer must demand that a coach pull the player – a quick glance at a smartphone app can verify the blood glucose and change rate. Children can use programs and search engines to quickly verify carbohydrate counts. Life360 and other tracking programs have increased parental feelings of security, especially with young drivers living with a chronic medical condition.
The inevitable outcome of this available technology is that children living with T1D are given cell phones far earlier than are their siblings or peers owing to “necessity.” Parents understandably want a means to stay in close contact with their children in case of a medical emergency. As a physician and mother of young children, I am thankful for the technology that keeps my patients safer and that allows them to fully participate in everything from sports to travel to an uninterrupted night’s sleep.
Smartphone presence in classrooms empowers teachers, students, parents, and school nurses to be aware of glycemic trends and prevent hypoglycemic emergencies. Smartphones have also shown to be a major distraction in that setting, causing many schools to ban their use entirely. Video apps such as YouTube and TikTok can provide a wealth of support and medical information but may also open the door to misinformation and dangerous social contagion, particularly surrounding disordered eating. Informative podcasts such as The Juicebox Podcast and online forums provide incredible support for families, but the constant siren call of a phone in their pockets leads to distracted parents constantly tending to other conversations or responding to ever more demanding employers rather than focusing on face-to-face education sessions.
The Surgeon General recently released a report concerning social media use in children. This eye-opening report revealed that one-third of children admitted to using their cell phones “almost constantly.” Social media use is associated with higher rates of anxiety and depression, especially in teen girls. This is particularly concerning for children with T1D, who are more likely to suffer from these conditions.
Beyond mental health concerns, especially to developing brains, unfettered Internet use increases the risk that children are exposed to predators and harmful content. The online safety monitoring platform Bark shared data from its 2021 surveillance. Bark found that 72% of tweens and 85% of teens were involved in an online bullying situation. Sixty-nine percent of tweens and 91% of teens encountered nudity or sexual content. Ten percent of tweens and 21% of teens encountered predatory behavior.
These alarming finds mirror the prevalence suggested by conversations in my office. I hear reports of my patients sneaking out at night to meet adults they met through social media, having suicidal ideation and attempts after Internet bullying, and sharing earnest belief in bizarre conspiracy theories gleaned from online forums that lead to dangerous health care practices.
Furthermore, time is a finite resource. Teens who are spending an average of 3.5 hours daily on their devices are running out of time to play, study, and grow extracurricular interests. My friend who coaches high school baseball lamented recently the poor athleticism in his recent teams. He theorized that his players had spent their summers on tablets rather than playing catch or climbing trees. The resulting declines in exercise in young people only serve to worsen the childhood obesity epidemic.
What is a concerned parent to do? First, all phones have controls that allow parents to choose which apps are allowed and which are blocked. Caregivers must understand how various social media platforms work. Installing programs such as Bark provides an additional layer of monitoring, though these are no substitute for parental vigilance. Importantly, parents should talk to their children about their concerns regarding social media.
Sadly, I have often noticed that caregivers pity the extra hardships their children endure as the result of T1D and other chronic diseases. Being lax with rules to attempt to compensate for other suffering is far too tempting. The goal is for children and teens living with T1D to have a full and normal childhood, and unrestricted smartphone access and early social media use should not be the goal for any child. For every family, a media use plan is a smart approach. The American Academy of Pediatrics suggests several commonsense steps to use technology wisely, and parents often must address their own relationships with their devices to model healthy engagement.
As health care professionals, we owe it to our patients to discuss the ups and downs of technology with our patients. We can’t ostrich our way through this. We can point our patients and families to supportive groups such as Osprey (Old School Parents Raising Engaged Youth), founded by Ben and Erin Napier from the HGTV show Home Town along with my college friends Taylor and Dr. Catherine Sledge. Wait Until 8th provides information and motivation for parents to make wise choices regarding phone use for their children. The documentary Childhood 2.0 is another compelling resource developed by pediatric emergency physician Dr. Free Hess and her team that summarizes many of these concerns.
In another decade, many of these dangers will be far clearer. As ubiquitous as smartphone misuse is in our society, I remain hopeful that our society will change its behaviors. Just because “everyone else” allows an unhealthy relationship with technology doesn’t mean that we should for our children.
When I was a child, smoking was glamorized in movies and restaurants had dedicated smoking sections. After strong public policy efforts, many geared toward children, smoking is now almost unthinkable. My 8-year-old asked me lately whether a lady smoking a cigarette in the car next to us would have to go to jail. I chose a career in pediatrics because I am an optimist at my very core. We can’t ignore the dangers associated with the wide door opened by mobile devices. We can celebrate the benefits while clearly facing the pitfalls.
Dr. Lilley is director of the pediatric diabetes and lipid program at the Mississippi Center for Advanced Medicine, Madison. She reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Antigen tests: After pandemic success, time for bigger role?
Before the pandemic, most of the public probably had a fleeting and limited familiarity with lateral flow tests (LFTs), also known as rapid antigen tests. Perhaps they used, or awaited the results of, a lateral flow home pregnancy test, which detects human chorionic gonadotropin in urine.
Then came COVID-19, and the need for large-scale testing. By late 2022, more than 3 billion tests for SARS-CoV-2 had been done worldwide. Although testing with reverse-transcription polymerase chain reaction (PCR) is the gold standard for diagnosing COVID, LFTs made possible large-scale testing at low cost with rapid results.
As of Sept. 12, the Food and Drug Administration lists 32 rapid antigen tests with emergency use authorizations (EUAs) for home use.
Now, many experts conclude, it’s time to expand the role of LFTs so the technology can help detect a host of other diseases. In a Nature Reviews bioengineering report, global experts from the United States, the United Kingdom, and other countries pointed out that commercial LFTs are currently not available for four of the eight known priority diseases of epidemic potential: Crimean-Congo hemorrhagic fever, Middle East respiratory syndrome coronavirus, Nipah and other henipaviruses, and Rift Valley fever.
Expansion should not only include more tests for more diseases, some experts say, but also make use of existing technology to provide “full-circle” care. After a rapid test, for instance, users could download a mobile phone app, transmit the results to their health care provider, and then set up an appointment if needed or get a prescribed medication at the pharmacy.
Medical community on board
Clinicians support increased availability of LFTs, said Eric J. Topol, MD, professor and executive vice president of Scripps Research, La Jolla, Calif.“Rapid antigen tests are critical, made a big difference in the pandemic, and will be used increasingly for many other applications in the years ahead,” Dr. Topol said in an email.
Physicians welcome their potential, agreed William Schaffner, MD, professor of preventive medicine and infectious disease specialist at Vanderbilt University Medical Center, Nashville, Tenn. At the start of the pandemic, when he was briefed about a lateral flow device in development, he said, “I was blown away by the technology, ease of use, rapidity of getting a result, its reasonable accuracy and its anticipated relatively low price.”
Clinicians would probably see many advantages to having more LFTs for more diseases, Dr. Schaffner said, because they are of use not only at home but also in doctors’ offices and in emergency departments. Their increased use “would help [people] make quick decisions about treatment, especially for flu and COVID.”
How LFTs work
LFTs are capable of targeting antigens, such as for the COVID tests, and antibodies such as IgG or IgM. The tests are also capable of detecting nucleic acids, although the availability of these tests is currently rare.
First, a sample from blood, urine, saliva or other bodily sources is placed onto a sample pad. It travels to a conjugate pad containing antibodies. If the target being looked for is present, the target and antibodies bind and, as the sample moves along to the test line, produces a positive result line along with the control line (to show that the test worked).
Global market outlook
By 2030, the lateral flow assays market is predicted to rise to $14.1 billion, according to a report issued in September by the firm Research and Markets. In 2022, the market was estimated at $9.4 billion, with $3.6 billion of that in the United States.
The report details the performances of 55 major competitors, such as Abbott Laboratories, Siemens, and QuidelOrtho, but smaller companies and start-ups are also involved in LFT development.
LFTs: Pros and cons
Although LFTs give rapid results, their accuracy is lower than that of PCR, especially the sensitivity. For COVID antigen LFTs, the sensitivity ranges from 34.1% to 88.1%, with an overall specificity of 99.6%, according to a Cochrane Review report. The analytical sensitivity performance of PCR testing for COVID is near 100%.
Everyone acknowledges the accuracy challenge of LFTs. The technologies “are generally thought to have limitations of detection that for some applications may present a challenge,” said Douglas C. Bryant, president and CEO of QuidelOrtho, San Diego, which counts the QuickVue rapid test for COVID detection among its products.
However, Mr. Bryant added, “as we saw during the pandemic, there was a place for more sensitive PCR-based technologies that are often run in a lab and there was a place for the use of rapid tests: The key is knowing the strengths and best use cases when applying the different technologies.”
One strength, he said, was that the tests “were shown to be highly effective at detecting active, infectious cases of SARS-CoV-2 and the rapid turnaround time allowed patients to isolate themselves from others quickly to help curb the spread of infection to others.” Another advantage was the ability to screen high-risk populations such as nursing homes to detect positive cases and help prevent outbreaks.
The pandemic familiarized people with the tests, said Jeremy Stackawitz, CEO of Senzo, a start-up in vitro diagnostics company developing an amplified LFT platform for rapid tests for flu, tuberculosis, COVID, and Clostridioides difficile. People liked using them. Physicians generally accepted them. It works great with tele-doc. It works great with personalized medicine.
Now, he said, people used to the COVID self-tests are asking: “Where is my strep test? Where is my sexual health test?”
FDA’s perspective on LFTs
The FDA has no one-size-fits-all standard for evaluating LFTs.
“LFTs are evaluated with respect to their individual indications and the pathway under which they are being reviewed,” said James McKinney, an FDA spokesperson. “A performance recommendation for one type of lateral flow test may not be appropriate for another.”
EUAs, such as those given for the COVID at-home tests, require different levels of evidence than traditional premarket review, he said, whether de novo marketing authorization, 510(k) premarket notification, or premarket approval. The EUAs are evaluated with a risk-benefit analysis to speed up the time it takes to make the devices available.
And, Mr. McKinney said, for some devices, the FDA provides recommendations on the expected performance through guidance documents. For instance, for rapid devices developed to detect influenza A virus antigen, the FDA recommends including enough sample to generate sensitivity of greater than 60% and testing at least 50 samples.
LFTs: The potential, the challenges
Mr. Stackawitz predicted that, as more LFT self-tests become available, more people will seek care, just as they did with the COVID rapid tests. A 22-year-old who thinks he has chlamydia may balk at going to a doctor right away. However, “if he can go buy a soda and a test at CVS, it’s different, it really is. With a little anonymity, people will seek care.”
He has a vision shared by other experts: That testing technology will evolve so that after getting the results at home, people would follow through by sending those results to their health care provider and obtaining needed care or medication. In his opinion, this is superior to the traditional way, which often involves visiting a doctor with symptoms, going for tests, waiting for results, and then beginning treatment.
“It would make more sense if you came in knowing your results,” Mr. Stackawitz said. “It’s a much smarter pathway, gives better outcomes for the patient, is much quicker and at much less cost. And it frees up time for doctors. I think most physicians would embrace that.”
Although rapid testing is gaining well-deserved recognition, funding is an issue, according to the Nature Reviews report. Those experts warned that “a reduction in funding for LFT research post COVID-19 may hamper efforts to capitalize on gains in decentralized testing, especially self-testing, which may be critical to address future pandemic threats.”
A version of this article first appeared on Medscape.com.
Before the pandemic, most of the public probably had a fleeting and limited familiarity with lateral flow tests (LFTs), also known as rapid antigen tests. Perhaps they used, or awaited the results of, a lateral flow home pregnancy test, which detects human chorionic gonadotropin in urine.
Then came COVID-19, and the need for large-scale testing. By late 2022, more than 3 billion tests for SARS-CoV-2 had been done worldwide. Although testing with reverse-transcription polymerase chain reaction (PCR) is the gold standard for diagnosing COVID, LFTs made possible large-scale testing at low cost with rapid results.
As of Sept. 12, the Food and Drug Administration lists 32 rapid antigen tests with emergency use authorizations (EUAs) for home use.
Now, many experts conclude, it’s time to expand the role of LFTs so the technology can help detect a host of other diseases. In a Nature Reviews bioengineering report, global experts from the United States, the United Kingdom, and other countries pointed out that commercial LFTs are currently not available for four of the eight known priority diseases of epidemic potential: Crimean-Congo hemorrhagic fever, Middle East respiratory syndrome coronavirus, Nipah and other henipaviruses, and Rift Valley fever.
Expansion should not only include more tests for more diseases, some experts say, but also make use of existing technology to provide “full-circle” care. After a rapid test, for instance, users could download a mobile phone app, transmit the results to their health care provider, and then set up an appointment if needed or get a prescribed medication at the pharmacy.
Medical community on board
Clinicians support increased availability of LFTs, said Eric J. Topol, MD, professor and executive vice president of Scripps Research, La Jolla, Calif.“Rapid antigen tests are critical, made a big difference in the pandemic, and will be used increasingly for many other applications in the years ahead,” Dr. Topol said in an email.
Physicians welcome their potential, agreed William Schaffner, MD, professor of preventive medicine and infectious disease specialist at Vanderbilt University Medical Center, Nashville, Tenn. At the start of the pandemic, when he was briefed about a lateral flow device in development, he said, “I was blown away by the technology, ease of use, rapidity of getting a result, its reasonable accuracy and its anticipated relatively low price.”
Clinicians would probably see many advantages to having more LFTs for more diseases, Dr. Schaffner said, because they are of use not only at home but also in doctors’ offices and in emergency departments. Their increased use “would help [people] make quick decisions about treatment, especially for flu and COVID.”
How LFTs work
LFTs are capable of targeting antigens, such as for the COVID tests, and antibodies such as IgG or IgM. The tests are also capable of detecting nucleic acids, although the availability of these tests is currently rare.
First, a sample from blood, urine, saliva or other bodily sources is placed onto a sample pad. It travels to a conjugate pad containing antibodies. If the target being looked for is present, the target and antibodies bind and, as the sample moves along to the test line, produces a positive result line along with the control line (to show that the test worked).
Global market outlook
By 2030, the lateral flow assays market is predicted to rise to $14.1 billion, according to a report issued in September by the firm Research and Markets. In 2022, the market was estimated at $9.4 billion, with $3.6 billion of that in the United States.
The report details the performances of 55 major competitors, such as Abbott Laboratories, Siemens, and QuidelOrtho, but smaller companies and start-ups are also involved in LFT development.
LFTs: Pros and cons
Although LFTs give rapid results, their accuracy is lower than that of PCR, especially the sensitivity. For COVID antigen LFTs, the sensitivity ranges from 34.1% to 88.1%, with an overall specificity of 99.6%, according to a Cochrane Review report. The analytical sensitivity performance of PCR testing for COVID is near 100%.
Everyone acknowledges the accuracy challenge of LFTs. The technologies “are generally thought to have limitations of detection that for some applications may present a challenge,” said Douglas C. Bryant, president and CEO of QuidelOrtho, San Diego, which counts the QuickVue rapid test for COVID detection among its products.
However, Mr. Bryant added, “as we saw during the pandemic, there was a place for more sensitive PCR-based technologies that are often run in a lab and there was a place for the use of rapid tests: The key is knowing the strengths and best use cases when applying the different technologies.”
One strength, he said, was that the tests “were shown to be highly effective at detecting active, infectious cases of SARS-CoV-2 and the rapid turnaround time allowed patients to isolate themselves from others quickly to help curb the spread of infection to others.” Another advantage was the ability to screen high-risk populations such as nursing homes to detect positive cases and help prevent outbreaks.
The pandemic familiarized people with the tests, said Jeremy Stackawitz, CEO of Senzo, a start-up in vitro diagnostics company developing an amplified LFT platform for rapid tests for flu, tuberculosis, COVID, and Clostridioides difficile. People liked using them. Physicians generally accepted them. It works great with tele-doc. It works great with personalized medicine.
Now, he said, people used to the COVID self-tests are asking: “Where is my strep test? Where is my sexual health test?”
FDA’s perspective on LFTs
The FDA has no one-size-fits-all standard for evaluating LFTs.
“LFTs are evaluated with respect to their individual indications and the pathway under which they are being reviewed,” said James McKinney, an FDA spokesperson. “A performance recommendation for one type of lateral flow test may not be appropriate for another.”
EUAs, such as those given for the COVID at-home tests, require different levels of evidence than traditional premarket review, he said, whether de novo marketing authorization, 510(k) premarket notification, or premarket approval. The EUAs are evaluated with a risk-benefit analysis to speed up the time it takes to make the devices available.
And, Mr. McKinney said, for some devices, the FDA provides recommendations on the expected performance through guidance documents. For instance, for rapid devices developed to detect influenza A virus antigen, the FDA recommends including enough sample to generate sensitivity of greater than 60% and testing at least 50 samples.
LFTs: The potential, the challenges
Mr. Stackawitz predicted that, as more LFT self-tests become available, more people will seek care, just as they did with the COVID rapid tests. A 22-year-old who thinks he has chlamydia may balk at going to a doctor right away. However, “if he can go buy a soda and a test at CVS, it’s different, it really is. With a little anonymity, people will seek care.”
He has a vision shared by other experts: That testing technology will evolve so that after getting the results at home, people would follow through by sending those results to their health care provider and obtaining needed care or medication. In his opinion, this is superior to the traditional way, which often involves visiting a doctor with symptoms, going for tests, waiting for results, and then beginning treatment.
“It would make more sense if you came in knowing your results,” Mr. Stackawitz said. “It’s a much smarter pathway, gives better outcomes for the patient, is much quicker and at much less cost. And it frees up time for doctors. I think most physicians would embrace that.”
Although rapid testing is gaining well-deserved recognition, funding is an issue, according to the Nature Reviews report. Those experts warned that “a reduction in funding for LFT research post COVID-19 may hamper efforts to capitalize on gains in decentralized testing, especially self-testing, which may be critical to address future pandemic threats.”
A version of this article first appeared on Medscape.com.
Before the pandemic, most of the public probably had a fleeting and limited familiarity with lateral flow tests (LFTs), also known as rapid antigen tests. Perhaps they used, or awaited the results of, a lateral flow home pregnancy test, which detects human chorionic gonadotropin in urine.
Then came COVID-19, and the need for large-scale testing. By late 2022, more than 3 billion tests for SARS-CoV-2 had been done worldwide. Although testing with reverse-transcription polymerase chain reaction (PCR) is the gold standard for diagnosing COVID, LFTs made possible large-scale testing at low cost with rapid results.
As of Sept. 12, the Food and Drug Administration lists 32 rapid antigen tests with emergency use authorizations (EUAs) for home use.
Now, many experts conclude, it’s time to expand the role of LFTs so the technology can help detect a host of other diseases. In a Nature Reviews bioengineering report, global experts from the United States, the United Kingdom, and other countries pointed out that commercial LFTs are currently not available for four of the eight known priority diseases of epidemic potential: Crimean-Congo hemorrhagic fever, Middle East respiratory syndrome coronavirus, Nipah and other henipaviruses, and Rift Valley fever.
Expansion should not only include more tests for more diseases, some experts say, but also make use of existing technology to provide “full-circle” care. After a rapid test, for instance, users could download a mobile phone app, transmit the results to their health care provider, and then set up an appointment if needed or get a prescribed medication at the pharmacy.
Medical community on board
Clinicians support increased availability of LFTs, said Eric J. Topol, MD, professor and executive vice president of Scripps Research, La Jolla, Calif.“Rapid antigen tests are critical, made a big difference in the pandemic, and will be used increasingly for many other applications in the years ahead,” Dr. Topol said in an email.
Physicians welcome their potential, agreed William Schaffner, MD, professor of preventive medicine and infectious disease specialist at Vanderbilt University Medical Center, Nashville, Tenn. At the start of the pandemic, when he was briefed about a lateral flow device in development, he said, “I was blown away by the technology, ease of use, rapidity of getting a result, its reasonable accuracy and its anticipated relatively low price.”
Clinicians would probably see many advantages to having more LFTs for more diseases, Dr. Schaffner said, because they are of use not only at home but also in doctors’ offices and in emergency departments. Their increased use “would help [people] make quick decisions about treatment, especially for flu and COVID.”
How LFTs work
LFTs are capable of targeting antigens, such as for the COVID tests, and antibodies such as IgG or IgM. The tests are also capable of detecting nucleic acids, although the availability of these tests is currently rare.
First, a sample from blood, urine, saliva or other bodily sources is placed onto a sample pad. It travels to a conjugate pad containing antibodies. If the target being looked for is present, the target and antibodies bind and, as the sample moves along to the test line, produces a positive result line along with the control line (to show that the test worked).
Global market outlook
By 2030, the lateral flow assays market is predicted to rise to $14.1 billion, according to a report issued in September by the firm Research and Markets. In 2022, the market was estimated at $9.4 billion, with $3.6 billion of that in the United States.
The report details the performances of 55 major competitors, such as Abbott Laboratories, Siemens, and QuidelOrtho, but smaller companies and start-ups are also involved in LFT development.
LFTs: Pros and cons
Although LFTs give rapid results, their accuracy is lower than that of PCR, especially the sensitivity. For COVID antigen LFTs, the sensitivity ranges from 34.1% to 88.1%, with an overall specificity of 99.6%, according to a Cochrane Review report. The analytical sensitivity performance of PCR testing for COVID is near 100%.
Everyone acknowledges the accuracy challenge of LFTs. The technologies “are generally thought to have limitations of detection that for some applications may present a challenge,” said Douglas C. Bryant, president and CEO of QuidelOrtho, San Diego, which counts the QuickVue rapid test for COVID detection among its products.
However, Mr. Bryant added, “as we saw during the pandemic, there was a place for more sensitive PCR-based technologies that are often run in a lab and there was a place for the use of rapid tests: The key is knowing the strengths and best use cases when applying the different technologies.”
One strength, he said, was that the tests “were shown to be highly effective at detecting active, infectious cases of SARS-CoV-2 and the rapid turnaround time allowed patients to isolate themselves from others quickly to help curb the spread of infection to others.” Another advantage was the ability to screen high-risk populations such as nursing homes to detect positive cases and help prevent outbreaks.
The pandemic familiarized people with the tests, said Jeremy Stackawitz, CEO of Senzo, a start-up in vitro diagnostics company developing an amplified LFT platform for rapid tests for flu, tuberculosis, COVID, and Clostridioides difficile. People liked using them. Physicians generally accepted them. It works great with tele-doc. It works great with personalized medicine.
Now, he said, people used to the COVID self-tests are asking: “Where is my strep test? Where is my sexual health test?”
FDA’s perspective on LFTs
The FDA has no one-size-fits-all standard for evaluating LFTs.
“LFTs are evaluated with respect to their individual indications and the pathway under which they are being reviewed,” said James McKinney, an FDA spokesperson. “A performance recommendation for one type of lateral flow test may not be appropriate for another.”
EUAs, such as those given for the COVID at-home tests, require different levels of evidence than traditional premarket review, he said, whether de novo marketing authorization, 510(k) premarket notification, or premarket approval. The EUAs are evaluated with a risk-benefit analysis to speed up the time it takes to make the devices available.
And, Mr. McKinney said, for some devices, the FDA provides recommendations on the expected performance through guidance documents. For instance, for rapid devices developed to detect influenza A virus antigen, the FDA recommends including enough sample to generate sensitivity of greater than 60% and testing at least 50 samples.
LFTs: The potential, the challenges
Mr. Stackawitz predicted that, as more LFT self-tests become available, more people will seek care, just as they did with the COVID rapid tests. A 22-year-old who thinks he has chlamydia may balk at going to a doctor right away. However, “if he can go buy a soda and a test at CVS, it’s different, it really is. With a little anonymity, people will seek care.”
He has a vision shared by other experts: That testing technology will evolve so that after getting the results at home, people would follow through by sending those results to their health care provider and obtaining needed care or medication. In his opinion, this is superior to the traditional way, which often involves visiting a doctor with symptoms, going for tests, waiting for results, and then beginning treatment.
“It would make more sense if you came in knowing your results,” Mr. Stackawitz said. “It’s a much smarter pathway, gives better outcomes for the patient, is much quicker and at much less cost. And it frees up time for doctors. I think most physicians would embrace that.”
Although rapid testing is gaining well-deserved recognition, funding is an issue, according to the Nature Reviews report. Those experts warned that “a reduction in funding for LFT research post COVID-19 may hamper efforts to capitalize on gains in decentralized testing, especially self-testing, which may be critical to address future pandemic threats.”
A version of this article first appeared on Medscape.com.