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LDL lowering to specific targets may offset risk from high Lp(a)
MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.
The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.
Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).
This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”
Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”
The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.
In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.
It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.
“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.
“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”
In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).
Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.
For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.
“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
Handy tool
The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.
“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.
He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.
Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.
During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.
“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.
“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”
However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”
Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.
They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.
The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.
The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.
When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.
For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.
Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.
For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.
This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”
No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.
A version of this article first appeared on Medscape.com.
MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.
The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.
Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).
This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”
Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”
The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.
In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.
It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.
“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.
“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”
In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).
Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.
For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.
“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
Handy tool
The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.
“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.
He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.
Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.
During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.
“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.
“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”
However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”
Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.
They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.
The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.
The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.
When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.
For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.
Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.
For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.
This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”
No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.
A version of this article first appeared on Medscape.com.
MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.
The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.
Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).
This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”
Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”
The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.
In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.
It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.
“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.
“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”
In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).
Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.
For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.
“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
Handy tool
The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.
“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.
He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.
Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.
During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.
“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.
“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”
However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”
Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.
They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.
The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.
The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.
When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.
For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.
Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.
For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.
This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”
No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.
A version of this article first appeared on Medscape.com.
AT EAS 2022
PPIs should be used ‘judiciously’ in patients with cirrhosis
In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.
Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.
Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.
“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”
Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”
In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”
“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”
The research was published online in Gastroenterology.
Looking at the big picture of PPIs in people with cirrhosis
The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.
However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.
To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.
They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.
In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).
Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.
Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.
Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.
However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).
Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).
The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
Large study suggests limited protective PPI indication
Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.
“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.
“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”
“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.
Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”
In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”
Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.
Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.
Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.
“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”
Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”
In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”
“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”
The research was published online in Gastroenterology.
Looking at the big picture of PPIs in people with cirrhosis
The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.
However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.
To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.
They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.
In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).
Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.
Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.
Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.
However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).
Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).
The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
Large study suggests limited protective PPI indication
Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.
“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.
“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”
“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.
Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”
In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”
Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.
Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.
Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.
“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”
Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”
In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”
“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”
The research was published online in Gastroenterology.
Looking at the big picture of PPIs in people with cirrhosis
The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.
However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.
To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.
They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.
In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).
Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.
Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.
Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.
However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).
Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).
The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
Large study suggests limited protective PPI indication
Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.
“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.
“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”
“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.
Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”
In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”
Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM GASTROENTEROLOGY
Misconceptions remain on gene signature use in breast cancer
BERLIN – , a European survey suggests.
The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.
Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.
“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.
Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.
Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.
To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.
The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.
In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.
Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.
Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.
Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.
Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.
In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.
No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.
When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.
When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.
In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.
Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.
The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.
The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.
A version of this article first appeared on Medscape.com.
This article was updated 5/9/22.
BERLIN – , a European survey suggests.
The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.
Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.
“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.
Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.
Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.
To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.
The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.
In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.
Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.
Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.
Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.
Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.
In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.
No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.
When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.
When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.
In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.
Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.
The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.
The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.
A version of this article first appeared on Medscape.com.
This article was updated 5/9/22.
BERLIN – , a European survey suggests.
The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.
Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.
“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.
Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.
Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.
To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.
The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.
In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.
Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.
Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.
Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.
Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.
In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.
No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.
When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.
When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.
In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.
Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.
The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.
The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.
A version of this article first appeared on Medscape.com.
This article was updated 5/9/22.
AT ESMO BCC 2022
High antipsychotic switch rates suggest ‘suboptimal’ prescribing for first-episode psychosis
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
New combination med for severe mental illness tied to less weight gain
, new research suggests. However, at least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the Food and Drug Administration approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder.
Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Dr. Kahn added.
He presented the findings at the annual congress of the Schizophrenia International Research Society.
Potential benefit
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” coinvestigator Christine Graham, PhD, with Alkermes, which manufactures the drug, told this news organization.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Dr. Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the propensity” for clinically significant weight gain, she added.
Dr. Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight gain and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Dr. Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder. The patients were aged 16-39 years and had an initial onset of active phase symptoms less than 4 years previously. They had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less weight gain
Results of the 12-week study showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012).
Dr. Kahn noted this equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Dr. Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed the proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Dr. Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical impact 'questionable'
Commenting on the study, Laura LaChance, MD, a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
On the other hand, Dr. LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes. Dr. Kahn reported having relationships with Alkermes, Angelini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Dr. Graham is an employee of Alkermes.
A version of this article first appeared on Medscape.com.
, new research suggests. However, at least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the Food and Drug Administration approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder.
Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Dr. Kahn added.
He presented the findings at the annual congress of the Schizophrenia International Research Society.
Potential benefit
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” coinvestigator Christine Graham, PhD, with Alkermes, which manufactures the drug, told this news organization.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Dr. Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the propensity” for clinically significant weight gain, she added.
Dr. Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight gain and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Dr. Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder. The patients were aged 16-39 years and had an initial onset of active phase symptoms less than 4 years previously. They had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less weight gain
Results of the 12-week study showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012).
Dr. Kahn noted this equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Dr. Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed the proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Dr. Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical impact 'questionable'
Commenting on the study, Laura LaChance, MD, a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
On the other hand, Dr. LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes. Dr. Kahn reported having relationships with Alkermes, Angelini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Dr. Graham is an employee of Alkermes.
A version of this article first appeared on Medscape.com.
, new research suggests. However, at least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the Food and Drug Administration approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder.
Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Dr. Kahn added.
He presented the findings at the annual congress of the Schizophrenia International Research Society.
Potential benefit
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” coinvestigator Christine Graham, PhD, with Alkermes, which manufactures the drug, told this news organization.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Dr. Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the propensity” for clinically significant weight gain, she added.
Dr. Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight gain and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Dr. Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder. The patients were aged 16-39 years and had an initial onset of active phase symptoms less than 4 years previously. They had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less weight gain
Results of the 12-week study showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012).
Dr. Kahn noted this equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Dr. Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed the proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Dr. Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical impact 'questionable'
Commenting on the study, Laura LaChance, MD, a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
On the other hand, Dr. LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes. Dr. Kahn reported having relationships with Alkermes, Angelini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Dr. Graham is an employee of Alkermes.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
TNF inhibitors prior to surgery safe in patients with IBD: Study
Patients with inflammatory bowel disease (IBD) can safely take tumor necrosis factor inhibitors (TNFi) prior to abdominal surgery, a prospective, multicenter, observational study confirms.
The researchers found that exposure to TNFi in the 12 weeks prior to surgery was not associated with an increased risk of either overall infections or surgical site infections (SSI).
The findings should be “very reassuring” for clinicians, lead author Benjamin L. Cohen, MD, Cleveland Clinic Foundation, told this news organization. “In the past, when clinicians were unsure about the safety of using these drugs in the perioperative period, they may have delayed surgeries or stopped medications unnecessarily.”
“For me, the key take-home point of this study is that we need to plan the timing and management of medications around surgery based on factors other than the use of tumor necrosis factor inhibitors in most patients,” Dr. Cohen continued.
Ultimately, “we will help change practice in how we manage patients with IBD having surgery,” he said.
The research was published online in Gastroenterology.
No increased postop infection risk
The Prospective Cohort of Ulcerative Colitis and Crohn’s Disease Patients Undergoing Surgery to Identify Risk Factors for Post-Operative Infection I (PUCCINI) trial enrolled patients with IBD from 17 sites participating in the Crohn’s and Colitis Foundation Clinical Research Alliance between September 2014 and June 2017.
Patients had Crohn’s disease, ulcerative colitis, or indeterminate colitis, as determined by standard criteria, and planned to undergo intra-abdominal surgery or had undergone intra-abdominal surgery in the preceding 4 days.
Among the 947 patients enrolled, 47.8% were women. All were aged 18 years or older. The median disease duration was 10 years; 34.4% of patients had undergone prior bowel resection, and a further 17.5% had undergone other abdominal surgery.
Systemic corticosteroid use within 2 weeks of surgery was reported by 40.9% of patients, and 42.3% had used antibiotics.
TNFi exposure within the 12 weeks prior to surgery was reported by 40.3% of patients. Adalimumab and infliximab were the most commonly used drugs. Among those who had not used TNFi prior to surgery, 23.7% were TNFi-naive, and 36.0% had used them in the past.
The researchers report that there was no significant difference in the rate of postoperative infections between patients who reported using TNFi in the 12 weeks prior to surgery and those who did not (18.1% vs. 20.2%; P = .469). There was also no difference in SSI, as defined using the Centers for Disease Control and Prevention criteria, between the two groups (12.0% vs 12.6%; P = .889).
Multivariate analysis revealed that current TNFi exposure was not associated with any infection, at an odds ratio versus no exposure of 1.050 (P = .80), or with SSI, at an odds ratio of 1.249 (P = .34).
In contrast, preoperative corticosteroid exposure, prior bowel resection, and current smoking were associated with any infection and with SSI.
Approached for comment, Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, said that the current findings are consistent with those of previous studies and that their relevance extends beyond abdominal surgery.
In the past, when surgeons were “confronted with a patient on a TNF blocker, even if it’s orthopedic or plastic surgery, they recommended against using a TNF blocker or operating at the end of the cycle when the drug levels are low,” he told this news organization.
Dr. Hanauer said such practice gets clinicians into a “bind because you’ve got a patient, for instance, who’s got a blockage with Crohn’s disease ... but the only way you could manage them when the TNFi was out of their system was with steroids, which is worse” in terms of postoperative infection risk, he explained.
Prospective studies important
The researchers note that up to 50% of patients with IBD are exposed to TNFi prior to their first surgery. They also note that there is concern that preoperative treatment with these and other immunosuppressive medications may increase the risk of postoperative infections.
However, the evidence is inconsistent, they write, so whether to continue or stop the drugs prior to surgery remains controversial.
“A lot of the initial studies in the perioperative population were single-center and retrospective for the most part,” Dr. Cohen said, adding that the studies used different modes of assessment and followed different time frames.
“So, there’s a lot of heterogeneity,” he said.
In addition, early studies of TNFi were often conducted with patients who were very ill and who had started receiving the drug right before surgery, and they sometimes had a complication Dr. Cohen said. “But you don’t know if that’s because of the drug itself or because of many other factors associated with them being very sick, such as being on steroids, being very malnourished, or having other complications of disease.”
It is difficult to control for such risk factors in retrospective analyses because the information is not always available from medical records, he said. “That’s why it’s so important to study clinical questions like this in a prospective manner.”
Dr. Cohen added that it is important that studies such as theirs continue to be undertaken as new drugs become available.
“We’re entering an era of rapidly expanding drug discovery, so we’re going to have new medications available for use in our patients with IBD,” he explained. “It’s important that we continue to build prospective cohorts to look at questions such as the safety of medications in the perioperative period, rather than solely relying on retrospective data.”
The study was funded by a Crohn’s & Colitis Foundation Senior Research Award. Dr. Cohen reports relationships with AbbVie, Celgene, Bristol-Myers Squibb, Pfizer, Sublimity Therapeutics, Target RWE, Janssen, Ferring, AlphaSigma, and Takeda. Other authors report numerous financial relationships. Dr. Hanauer reports relationships with Janssen, AbbVie, Pfizer, Amgen, Genentech, and Merck.
A version of this article first appeared on Medscape.com.
Patients with inflammatory bowel disease (IBD) can safely take tumor necrosis factor inhibitors (TNFi) prior to abdominal surgery, a prospective, multicenter, observational study confirms.
The researchers found that exposure to TNFi in the 12 weeks prior to surgery was not associated with an increased risk of either overall infections or surgical site infections (SSI).
The findings should be “very reassuring” for clinicians, lead author Benjamin L. Cohen, MD, Cleveland Clinic Foundation, told this news organization. “In the past, when clinicians were unsure about the safety of using these drugs in the perioperative period, they may have delayed surgeries or stopped medications unnecessarily.”
“For me, the key take-home point of this study is that we need to plan the timing and management of medications around surgery based on factors other than the use of tumor necrosis factor inhibitors in most patients,” Dr. Cohen continued.
Ultimately, “we will help change practice in how we manage patients with IBD having surgery,” he said.
The research was published online in Gastroenterology.
No increased postop infection risk
The Prospective Cohort of Ulcerative Colitis and Crohn’s Disease Patients Undergoing Surgery to Identify Risk Factors for Post-Operative Infection I (PUCCINI) trial enrolled patients with IBD from 17 sites participating in the Crohn’s and Colitis Foundation Clinical Research Alliance between September 2014 and June 2017.
Patients had Crohn’s disease, ulcerative colitis, or indeterminate colitis, as determined by standard criteria, and planned to undergo intra-abdominal surgery or had undergone intra-abdominal surgery in the preceding 4 days.
Among the 947 patients enrolled, 47.8% were women. All were aged 18 years or older. The median disease duration was 10 years; 34.4% of patients had undergone prior bowel resection, and a further 17.5% had undergone other abdominal surgery.
Systemic corticosteroid use within 2 weeks of surgery was reported by 40.9% of patients, and 42.3% had used antibiotics.
TNFi exposure within the 12 weeks prior to surgery was reported by 40.3% of patients. Adalimumab and infliximab were the most commonly used drugs. Among those who had not used TNFi prior to surgery, 23.7% were TNFi-naive, and 36.0% had used them in the past.
The researchers report that there was no significant difference in the rate of postoperative infections between patients who reported using TNFi in the 12 weeks prior to surgery and those who did not (18.1% vs. 20.2%; P = .469). There was also no difference in SSI, as defined using the Centers for Disease Control and Prevention criteria, between the two groups (12.0% vs 12.6%; P = .889).
Multivariate analysis revealed that current TNFi exposure was not associated with any infection, at an odds ratio versus no exposure of 1.050 (P = .80), or with SSI, at an odds ratio of 1.249 (P = .34).
In contrast, preoperative corticosteroid exposure, prior bowel resection, and current smoking were associated with any infection and with SSI.
Approached for comment, Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, said that the current findings are consistent with those of previous studies and that their relevance extends beyond abdominal surgery.
In the past, when surgeons were “confronted with a patient on a TNF blocker, even if it’s orthopedic or plastic surgery, they recommended against using a TNF blocker or operating at the end of the cycle when the drug levels are low,” he told this news organization.
Dr. Hanauer said such practice gets clinicians into a “bind because you’ve got a patient, for instance, who’s got a blockage with Crohn’s disease ... but the only way you could manage them when the TNFi was out of their system was with steroids, which is worse” in terms of postoperative infection risk, he explained.
Prospective studies important
The researchers note that up to 50% of patients with IBD are exposed to TNFi prior to their first surgery. They also note that there is concern that preoperative treatment with these and other immunosuppressive medications may increase the risk of postoperative infections.
However, the evidence is inconsistent, they write, so whether to continue or stop the drugs prior to surgery remains controversial.
“A lot of the initial studies in the perioperative population were single-center and retrospective for the most part,” Dr. Cohen said, adding that the studies used different modes of assessment and followed different time frames.
“So, there’s a lot of heterogeneity,” he said.
In addition, early studies of TNFi were often conducted with patients who were very ill and who had started receiving the drug right before surgery, and they sometimes had a complication Dr. Cohen said. “But you don’t know if that’s because of the drug itself or because of many other factors associated with them being very sick, such as being on steroids, being very malnourished, or having other complications of disease.”
It is difficult to control for such risk factors in retrospective analyses because the information is not always available from medical records, he said. “That’s why it’s so important to study clinical questions like this in a prospective manner.”
Dr. Cohen added that it is important that studies such as theirs continue to be undertaken as new drugs become available.
“We’re entering an era of rapidly expanding drug discovery, so we’re going to have new medications available for use in our patients with IBD,” he explained. “It’s important that we continue to build prospective cohorts to look at questions such as the safety of medications in the perioperative period, rather than solely relying on retrospective data.”
The study was funded by a Crohn’s & Colitis Foundation Senior Research Award. Dr. Cohen reports relationships with AbbVie, Celgene, Bristol-Myers Squibb, Pfizer, Sublimity Therapeutics, Target RWE, Janssen, Ferring, AlphaSigma, and Takeda. Other authors report numerous financial relationships. Dr. Hanauer reports relationships with Janssen, AbbVie, Pfizer, Amgen, Genentech, and Merck.
A version of this article first appeared on Medscape.com.
Patients with inflammatory bowel disease (IBD) can safely take tumor necrosis factor inhibitors (TNFi) prior to abdominal surgery, a prospective, multicenter, observational study confirms.
The researchers found that exposure to TNFi in the 12 weeks prior to surgery was not associated with an increased risk of either overall infections or surgical site infections (SSI).
The findings should be “very reassuring” for clinicians, lead author Benjamin L. Cohen, MD, Cleveland Clinic Foundation, told this news organization. “In the past, when clinicians were unsure about the safety of using these drugs in the perioperative period, they may have delayed surgeries or stopped medications unnecessarily.”
“For me, the key take-home point of this study is that we need to plan the timing and management of medications around surgery based on factors other than the use of tumor necrosis factor inhibitors in most patients,” Dr. Cohen continued.
Ultimately, “we will help change practice in how we manage patients with IBD having surgery,” he said.
The research was published online in Gastroenterology.
No increased postop infection risk
The Prospective Cohort of Ulcerative Colitis and Crohn’s Disease Patients Undergoing Surgery to Identify Risk Factors for Post-Operative Infection I (PUCCINI) trial enrolled patients with IBD from 17 sites participating in the Crohn’s and Colitis Foundation Clinical Research Alliance between September 2014 and June 2017.
Patients had Crohn’s disease, ulcerative colitis, or indeterminate colitis, as determined by standard criteria, and planned to undergo intra-abdominal surgery or had undergone intra-abdominal surgery in the preceding 4 days.
Among the 947 patients enrolled, 47.8% were women. All were aged 18 years or older. The median disease duration was 10 years; 34.4% of patients had undergone prior bowel resection, and a further 17.5% had undergone other abdominal surgery.
Systemic corticosteroid use within 2 weeks of surgery was reported by 40.9% of patients, and 42.3% had used antibiotics.
TNFi exposure within the 12 weeks prior to surgery was reported by 40.3% of patients. Adalimumab and infliximab were the most commonly used drugs. Among those who had not used TNFi prior to surgery, 23.7% were TNFi-naive, and 36.0% had used them in the past.
The researchers report that there was no significant difference in the rate of postoperative infections between patients who reported using TNFi in the 12 weeks prior to surgery and those who did not (18.1% vs. 20.2%; P = .469). There was also no difference in SSI, as defined using the Centers for Disease Control and Prevention criteria, between the two groups (12.0% vs 12.6%; P = .889).
Multivariate analysis revealed that current TNFi exposure was not associated with any infection, at an odds ratio versus no exposure of 1.050 (P = .80), or with SSI, at an odds ratio of 1.249 (P = .34).
In contrast, preoperative corticosteroid exposure, prior bowel resection, and current smoking were associated with any infection and with SSI.
Approached for comment, Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, said that the current findings are consistent with those of previous studies and that their relevance extends beyond abdominal surgery.
In the past, when surgeons were “confronted with a patient on a TNF blocker, even if it’s orthopedic or plastic surgery, they recommended against using a TNF blocker or operating at the end of the cycle when the drug levels are low,” he told this news organization.
Dr. Hanauer said such practice gets clinicians into a “bind because you’ve got a patient, for instance, who’s got a blockage with Crohn’s disease ... but the only way you could manage them when the TNFi was out of their system was with steroids, which is worse” in terms of postoperative infection risk, he explained.
Prospective studies important
The researchers note that up to 50% of patients with IBD are exposed to TNFi prior to their first surgery. They also note that there is concern that preoperative treatment with these and other immunosuppressive medications may increase the risk of postoperative infections.
However, the evidence is inconsistent, they write, so whether to continue or stop the drugs prior to surgery remains controversial.
“A lot of the initial studies in the perioperative population were single-center and retrospective for the most part,” Dr. Cohen said, adding that the studies used different modes of assessment and followed different time frames.
“So, there’s a lot of heterogeneity,” he said.
In addition, early studies of TNFi were often conducted with patients who were very ill and who had started receiving the drug right before surgery, and they sometimes had a complication Dr. Cohen said. “But you don’t know if that’s because of the drug itself or because of many other factors associated with them being very sick, such as being on steroids, being very malnourished, or having other complications of disease.”
It is difficult to control for such risk factors in retrospective analyses because the information is not always available from medical records, he said. “That’s why it’s so important to study clinical questions like this in a prospective manner.”
Dr. Cohen added that it is important that studies such as theirs continue to be undertaken as new drugs become available.
“We’re entering an era of rapidly expanding drug discovery, so we’re going to have new medications available for use in our patients with IBD,” he explained. “It’s important that we continue to build prospective cohorts to look at questions such as the safety of medications in the perioperative period, rather than solely relying on retrospective data.”
The study was funded by a Crohn’s & Colitis Foundation Senior Research Award. Dr. Cohen reports relationships with AbbVie, Celgene, Bristol-Myers Squibb, Pfizer, Sublimity Therapeutics, Target RWE, Janssen, Ferring, AlphaSigma, and Takeda. Other authors report numerous financial relationships. Dr. Hanauer reports relationships with Janssen, AbbVie, Pfizer, Amgen, Genentech, and Merck.
A version of this article first appeared on Medscape.com.
FROM GASTROENTEROLOGY
Zanubrutinib shows worth against standard CLL drugs
MANCHESTER, ENGLAND – A new treatment option may soon be available for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Zanubrutinib (Brukinsa), an irreversible, next-generation Bruton tyrosine kinase (BTK) inhibitor, is designed to minimize the off-target cardiovascular toxicities, such as atrial fibrillation and hypertension, seen with the first-generation ibrutinib (Imbruvica).
Zanubrutinib is already approved for use in mantle cell and marginal zone lymphomas and Waldenström’s macroglobulinemia.
Now it has also shown efficacy in CLL.
However, experts question whether the drug will find its place in an increasingly crowded space for the management of CLL.
Data from two phase 3 trials
The new data from two phase 3 clinical trials were presented recently at the British Society for Haematology 62nd annual scientific meeting, held in Manchester, England.
The ALPINE trial compared zanubrutinib with ibrutinib in 415 patients with CLL/SLL and showed that the novel drug was associated with a significant improvement in overall response rate, at 78% versus 63%.
This first interim analysis also showed that there was an increase in progression-free survival (PFS) with zanubrutinib, and crucially, it was associated with a lower atrial fibrillation/flutter rate than ibrutinib.
“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes,” said lead author Peter Hillmen, MBChB, FRCP, PhD, St. James’s University Hospital, Leeds, England.
The SEQUOIA study looked at zanubrutinib versus bendamustine plus rituximab in patients with untreated CLL/SLL with a 17p deletion and showed that PFS was improved with zanubrutinib by 58%.
Zanubrutinib was also associated with improved overall response rates and was well tolerated.
The results therefore “support the potential utility of zanubrutinib in the frontline management of patients with previously untreated CLL/SLL,” said lead author Talha Munir, MBBS, also of St. James’s University Hospital.
Improvement over ibrutinib
Ibrutinib, the first BTK inhibitor, “truly revolutionized the way we treat CLL,” commented Renata Walewska, MRCP, PhD, consultant hematologist at the Royal Bournemouth (England) Hospital and chair of the UKCLL Forum.
“But it has got quite a lot of, especially cardiac, problems, with atrial fibrillation and hypertension,” she said in an interview. The problem is that it acts not only as an inhibitor of Bruton kinase, but also affects other kinases, she explained.
Zanubrutinib is “much cleaner,” continued Dr. Walewska, who was lead author of the recently published British Society of Haematology guideline for the treatment of CLL.
However, the drug “is not that groundbreaking,” she commented, as acalabrutinib (Calquence), another next-generation BTK inhibitor, is already available for use in the clinic.
“We’re really lucky in CLL,” Dr. Walewska said, “we’ve got so many new drugs available, and it’s getting quite crowded. Trying to find a place for zanubrutinib is going be tricky.”
Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, commented that he “gives a lot of credit” to BeiGene, the company behind zanubrutinib, for “taking on these big studies.”
He said that, with the improvements in PFS and reduced atrial fibrillation with the drug, “there will be many clinicians paying attention to this and zanubrutinib could be preferred over conventional options.”
However, he agreed that it will have to compete with acalabrutinib, adding that, beyond BTK inhibitors, there are “a lot of options” for patients with CLL.
“That makes it very difficult for physicians to figure out what is the best type of therapy” to use in these patients, he added.
Dr. Greenberger told this news organization that further studies will need to demonstrate that zanubrutinib is associated with extended survival, which is “just not possible to show” at the moment with the current follow-up period.
He also noted that, in 10 years, ibrutinib will be off-patent, but zanubrutinib will not, at which point the “substantial” cost of the medication, which is a source of “hardship to patients,” will be increasingly relevant.
Study details
The phase 3 ALPINE study involved 415 adults with CLL/SLL refractory to one or more prior systemic therapies and measurable lymphadenopathy on imaging.
They were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or withdrawal from the study.
Most patients had Binet stage A/B or Ann Arbor stage I/II disease, and 7.3% of patients treated with zanubrutinib and 10.1% of those assigned to ibrutinib had received more than three prior lines of therapy.
Over 60% of patients were aged 65 years or older and around 70% were men, with no significant differences between treatment groups.
Patients were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or study withdrawal.
After a median follow-up of 15 months, the overall response rate was significantly higher with zanubrutinib than ibrutinib, at 78.3% versus 62.5% (P = .0006).
Subgroup analysis confirmed that the effect was seen regardless of age, sex, disease stage, number of prior lines of therapy, mutation status, or bulky disease.
Over a median follow-up of 14 months, the investigator-assessed 12-month PFS was 94.9% for zanubrutinib and 84.0% for ibrutinib (P = .0007). Overall survival at 12 months was 97% versus 92.7%, but the difference was not significant (P = .1081).
Patients treated with zanubrutinib experienced more grade 3 or higher adverse events than those given ibrutinib, at 55.9% versus 51.2%, although they had fewer adverse events leading to treatment discontinuation, at 7.8% versus 13.0%.
More importantly, there were fewer cardiac disorders of any grade with zanubrutinib versus ibrutinib, and any-grade atrial fibrillation was significantly less common, at 2.5% versus 10.1% (P = .0014).
Rates of hypertension and hemorrhage were similar between the two treatments, while rates of neutropenia were higher with zanubrutinib versus ibrutinib, at 28.4% versus 21.7%.
The phase 3 SEQUOIA study looked at an earlier stage of disease and included patients with previously untreated CLL/SLL (without 17p depletion) who were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab.
This trial involved 479 patients randomized to zanubrutinib or bendamustine (days 1 and 2) plus rituximab for six cycles of 28 days each (B+R).
The median age of patients was 70 years, and approximately 80% were at least 65 years old. Just over 60% were men and most (over 70%) were from Europe.
After a median of 26.2 months, independent review committee–assessed PFS was significantly longer with zanubrutinib versus B+R (hazard ratio, 0.42; P < .0001), with an estimated 24-month PFS of 85.5% versus 69.5%.
These results held whether patients were stratified by age, Binet stage, bulky disease, or 11q deletion status, and for patients with an unmutated, but not mutated, immunoglobulin heavy chain gene.
The overall response rate with zanubrutinib was 94.6% versus 85.3% with B+R, and estimated 24-month overall survival was 94.3% versus 94.6%.
Rates of adverse events of any grade were similar between the two treatment groups, although B+R was associated with a higher (grade ≥ 3) adverse event rate, at 79.7%, versus 52.5% for zanubrutinib, and a higher rate of treatment discontinuation because of adverse events, at 13.7% versus 8.3%.
Interestingly, any-grade hypertension was more common with zanubrutinib versus B+R, at 14.2% versus 10.6%, but much lower rates of neutropenia were more common with zanubrutinib, at 15.8% versus 56.8%.
The studies were sponsored by BeiGene. Dr. Hillmen has reported relationships with Janssen, AbbVie, Pharmacyclics, Roche, Gilead, AstraZeneca, SOBI, and BeiGene. Dr. Munir has reported relationships with AbbVie, AstraZeneca, Roche, Alexion, Janssen, MorphoSys, and SOBI. Other authors have also declared numerous relationships.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND – A new treatment option may soon be available for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Zanubrutinib (Brukinsa), an irreversible, next-generation Bruton tyrosine kinase (BTK) inhibitor, is designed to minimize the off-target cardiovascular toxicities, such as atrial fibrillation and hypertension, seen with the first-generation ibrutinib (Imbruvica).
Zanubrutinib is already approved for use in mantle cell and marginal zone lymphomas and Waldenström’s macroglobulinemia.
Now it has also shown efficacy in CLL.
However, experts question whether the drug will find its place in an increasingly crowded space for the management of CLL.
Data from two phase 3 trials
The new data from two phase 3 clinical trials were presented recently at the British Society for Haematology 62nd annual scientific meeting, held in Manchester, England.
The ALPINE trial compared zanubrutinib with ibrutinib in 415 patients with CLL/SLL and showed that the novel drug was associated with a significant improvement in overall response rate, at 78% versus 63%.
This first interim analysis also showed that there was an increase in progression-free survival (PFS) with zanubrutinib, and crucially, it was associated with a lower atrial fibrillation/flutter rate than ibrutinib.
“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes,” said lead author Peter Hillmen, MBChB, FRCP, PhD, St. James’s University Hospital, Leeds, England.
The SEQUOIA study looked at zanubrutinib versus bendamustine plus rituximab in patients with untreated CLL/SLL with a 17p deletion and showed that PFS was improved with zanubrutinib by 58%.
Zanubrutinib was also associated with improved overall response rates and was well tolerated.
The results therefore “support the potential utility of zanubrutinib in the frontline management of patients with previously untreated CLL/SLL,” said lead author Talha Munir, MBBS, also of St. James’s University Hospital.
Improvement over ibrutinib
Ibrutinib, the first BTK inhibitor, “truly revolutionized the way we treat CLL,” commented Renata Walewska, MRCP, PhD, consultant hematologist at the Royal Bournemouth (England) Hospital and chair of the UKCLL Forum.
“But it has got quite a lot of, especially cardiac, problems, with atrial fibrillation and hypertension,” she said in an interview. The problem is that it acts not only as an inhibitor of Bruton kinase, but also affects other kinases, she explained.
Zanubrutinib is “much cleaner,” continued Dr. Walewska, who was lead author of the recently published British Society of Haematology guideline for the treatment of CLL.
However, the drug “is not that groundbreaking,” she commented, as acalabrutinib (Calquence), another next-generation BTK inhibitor, is already available for use in the clinic.
“We’re really lucky in CLL,” Dr. Walewska said, “we’ve got so many new drugs available, and it’s getting quite crowded. Trying to find a place for zanubrutinib is going be tricky.”
Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, commented that he “gives a lot of credit” to BeiGene, the company behind zanubrutinib, for “taking on these big studies.”
He said that, with the improvements in PFS and reduced atrial fibrillation with the drug, “there will be many clinicians paying attention to this and zanubrutinib could be preferred over conventional options.”
However, he agreed that it will have to compete with acalabrutinib, adding that, beyond BTK inhibitors, there are “a lot of options” for patients with CLL.
“That makes it very difficult for physicians to figure out what is the best type of therapy” to use in these patients, he added.
Dr. Greenberger told this news organization that further studies will need to demonstrate that zanubrutinib is associated with extended survival, which is “just not possible to show” at the moment with the current follow-up period.
He also noted that, in 10 years, ibrutinib will be off-patent, but zanubrutinib will not, at which point the “substantial” cost of the medication, which is a source of “hardship to patients,” will be increasingly relevant.
Study details
The phase 3 ALPINE study involved 415 adults with CLL/SLL refractory to one or more prior systemic therapies and measurable lymphadenopathy on imaging.
They were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or withdrawal from the study.
Most patients had Binet stage A/B or Ann Arbor stage I/II disease, and 7.3% of patients treated with zanubrutinib and 10.1% of those assigned to ibrutinib had received more than three prior lines of therapy.
Over 60% of patients were aged 65 years or older and around 70% were men, with no significant differences between treatment groups.
Patients were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or study withdrawal.
After a median follow-up of 15 months, the overall response rate was significantly higher with zanubrutinib than ibrutinib, at 78.3% versus 62.5% (P = .0006).
Subgroup analysis confirmed that the effect was seen regardless of age, sex, disease stage, number of prior lines of therapy, mutation status, or bulky disease.
Over a median follow-up of 14 months, the investigator-assessed 12-month PFS was 94.9% for zanubrutinib and 84.0% for ibrutinib (P = .0007). Overall survival at 12 months was 97% versus 92.7%, but the difference was not significant (P = .1081).
Patients treated with zanubrutinib experienced more grade 3 or higher adverse events than those given ibrutinib, at 55.9% versus 51.2%, although they had fewer adverse events leading to treatment discontinuation, at 7.8% versus 13.0%.
More importantly, there were fewer cardiac disorders of any grade with zanubrutinib versus ibrutinib, and any-grade atrial fibrillation was significantly less common, at 2.5% versus 10.1% (P = .0014).
Rates of hypertension and hemorrhage were similar between the two treatments, while rates of neutropenia were higher with zanubrutinib versus ibrutinib, at 28.4% versus 21.7%.
The phase 3 SEQUOIA study looked at an earlier stage of disease and included patients with previously untreated CLL/SLL (without 17p depletion) who were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab.
This trial involved 479 patients randomized to zanubrutinib or bendamustine (days 1 and 2) plus rituximab for six cycles of 28 days each (B+R).
The median age of patients was 70 years, and approximately 80% were at least 65 years old. Just over 60% were men and most (over 70%) were from Europe.
After a median of 26.2 months, independent review committee–assessed PFS was significantly longer with zanubrutinib versus B+R (hazard ratio, 0.42; P < .0001), with an estimated 24-month PFS of 85.5% versus 69.5%.
These results held whether patients were stratified by age, Binet stage, bulky disease, or 11q deletion status, and for patients with an unmutated, but not mutated, immunoglobulin heavy chain gene.
The overall response rate with zanubrutinib was 94.6% versus 85.3% with B+R, and estimated 24-month overall survival was 94.3% versus 94.6%.
Rates of adverse events of any grade were similar between the two treatment groups, although B+R was associated with a higher (grade ≥ 3) adverse event rate, at 79.7%, versus 52.5% for zanubrutinib, and a higher rate of treatment discontinuation because of adverse events, at 13.7% versus 8.3%.
Interestingly, any-grade hypertension was more common with zanubrutinib versus B+R, at 14.2% versus 10.6%, but much lower rates of neutropenia were more common with zanubrutinib, at 15.8% versus 56.8%.
The studies were sponsored by BeiGene. Dr. Hillmen has reported relationships with Janssen, AbbVie, Pharmacyclics, Roche, Gilead, AstraZeneca, SOBI, and BeiGene. Dr. Munir has reported relationships with AbbVie, AstraZeneca, Roche, Alexion, Janssen, MorphoSys, and SOBI. Other authors have also declared numerous relationships.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND – A new treatment option may soon be available for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Zanubrutinib (Brukinsa), an irreversible, next-generation Bruton tyrosine kinase (BTK) inhibitor, is designed to minimize the off-target cardiovascular toxicities, such as atrial fibrillation and hypertension, seen with the first-generation ibrutinib (Imbruvica).
Zanubrutinib is already approved for use in mantle cell and marginal zone lymphomas and Waldenström’s macroglobulinemia.
Now it has also shown efficacy in CLL.
However, experts question whether the drug will find its place in an increasingly crowded space for the management of CLL.
Data from two phase 3 trials
The new data from two phase 3 clinical trials were presented recently at the British Society for Haematology 62nd annual scientific meeting, held in Manchester, England.
The ALPINE trial compared zanubrutinib with ibrutinib in 415 patients with CLL/SLL and showed that the novel drug was associated with a significant improvement in overall response rate, at 78% versus 63%.
This first interim analysis also showed that there was an increase in progression-free survival (PFS) with zanubrutinib, and crucially, it was associated with a lower atrial fibrillation/flutter rate than ibrutinib.
“These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes,” said lead author Peter Hillmen, MBChB, FRCP, PhD, St. James’s University Hospital, Leeds, England.
The SEQUOIA study looked at zanubrutinib versus bendamustine plus rituximab in patients with untreated CLL/SLL with a 17p deletion and showed that PFS was improved with zanubrutinib by 58%.
Zanubrutinib was also associated with improved overall response rates and was well tolerated.
The results therefore “support the potential utility of zanubrutinib in the frontline management of patients with previously untreated CLL/SLL,” said lead author Talha Munir, MBBS, also of St. James’s University Hospital.
Improvement over ibrutinib
Ibrutinib, the first BTK inhibitor, “truly revolutionized the way we treat CLL,” commented Renata Walewska, MRCP, PhD, consultant hematologist at the Royal Bournemouth (England) Hospital and chair of the UKCLL Forum.
“But it has got quite a lot of, especially cardiac, problems, with atrial fibrillation and hypertension,” she said in an interview. The problem is that it acts not only as an inhibitor of Bruton kinase, but also affects other kinases, she explained.
Zanubrutinib is “much cleaner,” continued Dr. Walewska, who was lead author of the recently published British Society of Haematology guideline for the treatment of CLL.
However, the drug “is not that groundbreaking,” she commented, as acalabrutinib (Calquence), another next-generation BTK inhibitor, is already available for use in the clinic.
“We’re really lucky in CLL,” Dr. Walewska said, “we’ve got so many new drugs available, and it’s getting quite crowded. Trying to find a place for zanubrutinib is going be tricky.”
Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, commented that he “gives a lot of credit” to BeiGene, the company behind zanubrutinib, for “taking on these big studies.”
He said that, with the improvements in PFS and reduced atrial fibrillation with the drug, “there will be many clinicians paying attention to this and zanubrutinib could be preferred over conventional options.”
However, he agreed that it will have to compete with acalabrutinib, adding that, beyond BTK inhibitors, there are “a lot of options” for patients with CLL.
“That makes it very difficult for physicians to figure out what is the best type of therapy” to use in these patients, he added.
Dr. Greenberger told this news organization that further studies will need to demonstrate that zanubrutinib is associated with extended survival, which is “just not possible to show” at the moment with the current follow-up period.
He also noted that, in 10 years, ibrutinib will be off-patent, but zanubrutinib will not, at which point the “substantial” cost of the medication, which is a source of “hardship to patients,” will be increasingly relevant.
Study details
The phase 3 ALPINE study involved 415 adults with CLL/SLL refractory to one or more prior systemic therapies and measurable lymphadenopathy on imaging.
They were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or withdrawal from the study.
Most patients had Binet stage A/B or Ann Arbor stage I/II disease, and 7.3% of patients treated with zanubrutinib and 10.1% of those assigned to ibrutinib had received more than three prior lines of therapy.
Over 60% of patients were aged 65 years or older and around 70% were men, with no significant differences between treatment groups.
Patients were randomized 1:1 to zanubrutinib or ibrutinib until disease progression or study withdrawal.
After a median follow-up of 15 months, the overall response rate was significantly higher with zanubrutinib than ibrutinib, at 78.3% versus 62.5% (P = .0006).
Subgroup analysis confirmed that the effect was seen regardless of age, sex, disease stage, number of prior lines of therapy, mutation status, or bulky disease.
Over a median follow-up of 14 months, the investigator-assessed 12-month PFS was 94.9% for zanubrutinib and 84.0% for ibrutinib (P = .0007). Overall survival at 12 months was 97% versus 92.7%, but the difference was not significant (P = .1081).
Patients treated with zanubrutinib experienced more grade 3 or higher adverse events than those given ibrutinib, at 55.9% versus 51.2%, although they had fewer adverse events leading to treatment discontinuation, at 7.8% versus 13.0%.
More importantly, there were fewer cardiac disorders of any grade with zanubrutinib versus ibrutinib, and any-grade atrial fibrillation was significantly less common, at 2.5% versus 10.1% (P = .0014).
Rates of hypertension and hemorrhage were similar between the two treatments, while rates of neutropenia were higher with zanubrutinib versus ibrutinib, at 28.4% versus 21.7%.
The phase 3 SEQUOIA study looked at an earlier stage of disease and included patients with previously untreated CLL/SLL (without 17p depletion) who were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab.
This trial involved 479 patients randomized to zanubrutinib or bendamustine (days 1 and 2) plus rituximab for six cycles of 28 days each (B+R).
The median age of patients was 70 years, and approximately 80% were at least 65 years old. Just over 60% were men and most (over 70%) were from Europe.
After a median of 26.2 months, independent review committee–assessed PFS was significantly longer with zanubrutinib versus B+R (hazard ratio, 0.42; P < .0001), with an estimated 24-month PFS of 85.5% versus 69.5%.
These results held whether patients were stratified by age, Binet stage, bulky disease, or 11q deletion status, and for patients with an unmutated, but not mutated, immunoglobulin heavy chain gene.
The overall response rate with zanubrutinib was 94.6% versus 85.3% with B+R, and estimated 24-month overall survival was 94.3% versus 94.6%.
Rates of adverse events of any grade were similar between the two treatment groups, although B+R was associated with a higher (grade ≥ 3) adverse event rate, at 79.7%, versus 52.5% for zanubrutinib, and a higher rate of treatment discontinuation because of adverse events, at 13.7% versus 8.3%.
Interestingly, any-grade hypertension was more common with zanubrutinib versus B+R, at 14.2% versus 10.6%, but much lower rates of neutropenia were more common with zanubrutinib, at 15.8% versus 56.8%.
The studies were sponsored by BeiGene. Dr. Hillmen has reported relationships with Janssen, AbbVie, Pharmacyclics, Roche, Gilead, AstraZeneca, SOBI, and BeiGene. Dr. Munir has reported relationships with AbbVie, AstraZeneca, Roche, Alexion, Janssen, MorphoSys, and SOBI. Other authors have also declared numerous relationships.
A version of this article first appeared on Medscape.com.
‘Fragmented’ speech patterns may predict psychosis relapse
In the first study, an algorithm was created to analyze speech patterns and semantic content to create novel “speech networks.” Compared with their healthy peers, patients with FEP had smaller and more fragmented networks. At-risk individuals had fragmented values that were in between those of the FEP and healthy control groups.
“This suggests that semantic speech networks can enable deeper phenotyping of formal thought disorder and psychosis,” said lead author Caroline Nettekoven, PhD, department of psychiatry, University of Cambridge, England.
In the second study, Janna N. de Boer, MD, University of Groningen, the Netherlands, and colleagues examined patients with FEP who did and did not experience relapse after 24 months of follow-up.
An algorithm based on natural language processing (NLP) of speech recordings predicted the relapses with an accuracy of more than 80%.
NLP “is a powerful tool with high potential for clinical application and diagnosis and differentiation, given its ease in acquirement, low cost, and naturally low patient burden,” said de Boer.
The findings for both studies were presented at the annual congress of the Schizophrenia International Research Society.
Fragmented networks
Dr. Nettekoven noted that previous research has shown “mapping the speech of a psychosis patient as a network and analyzing the network using graph theory is useful for understanding formal thought disorder.”
However, these tools ignore the semantic content of speech, which is a “key feature” that is altered in psychotic language, she added.
The researchers therefore proposed a “novel type of network to map the content of speech.”
For example, if someone said, “I see a man,” a semantic speech network developed from this sentence would have the first and last words connected by “the edge” to the word “see,” Dr. Nettekoven explained.
To explore further, the investigators developed an algorithm known as “netts” that automatically creates semantic speech networks from transcribed speech.
They first applied the algorithm to transcribed speech from a general population sample of 436 individuals and then to a clinical sample (n = 53) comprising patients with FEP, those at clinical high risk for psychosis, and a healthy control group.
Comparing the general population sample with randomly generated semantic speech networks, the investigators found that networks from the general population had fewer but larger connected components, which “reflects the nonrandom nature of speech,” said Dr. Nettekoven.
In the clinical sample, networks from the FEP group had a significantly higher number of connected components compared with the healthy control group (P = .05) and a significantly smaller median connected-component size (P < .01).
“So patients’ mental speech networks are more fragmented than those from controls,” said Dr. Nettekoven. She added that the networks from clinically high-risk individuals “showed fragmentation values in between [those of] patients and controls.”
A further clustering analysis suggested the semantic speech networks “capture a novel signal that is not already described” by other NLP measures, Dr. Nettekoven said. In addition, the network features were related to negative symptom scores and scores on the Thought and Language Index.
However, Dr. Nettekoven noted that these relationships “did not survive correcting for multiple comparisons.”
Relapse predictor
During her presentation of the second study, Dr. de Boer said that “predicting relapse remains challenging” in FEP.
However, she noted that recent developments in NLP have proved to be effective in a “range of applications,” including early symptom recognition and differential diagnosis in psychosis.
To determine whether NLP could help predict relapse, the study included 104 patients aged 16-55 years with FEP whose conditions had been in remission for 3-6 months. Speech recordings were made at baseline and after 3 and 6 months and were analyzed via OpenSMILE software.
After a follow-up of 24 months, 24 of the patients remaining in the study had not experienced relapse, while 21 patients had experienced relapse. There were no significant age, education, or gender differences between those who did and those who did not experience relapse.
On the basis of speech analysis, the investigators identified a machine learning classifier, which showed an accuracy of 80.8% in predicting relapse 3 months in advance of the occurrence.
‘Valid and informative’
Commenting on the studies, Eric J. Tan, PhD, Centre for Mental Health, Swinburne University of Technology, Melbourne, said they are “but two of a variety of ways in which speech can be analyzed and are both equally valid and informative.”
The key takeaway “is that both studies are examples of the ways in which speech can be used clinically, such as for predicting relapse and for the potential proxy measure for the assessment of symptom severity,” said Dr. Tan, who was not involved with the research.
The studies also show that “speech is sensitive to different stages of the disorder, as well as its individual symptoms,” he added.
However, Dr. Tan noted that although “speech may be more of a sign of an underlying pathology or dysfunction, given that it waxes and wanes with illness severity, more analyses are needed before drawing definitive conclusions.” This is especially needed “given the relative infancy of quantitative speech analysis,” he said.
“It would also be useful to conduct these analyses across a variety of different languages to look for commonalities and differences that will help shed light on the variables most closely linked to the disorder,” Dr. Tan concluded.
The investigators have reported no relevant financial relationships. Dr. Tan has received an Early Career Research Fellowship from the National Health and Medical Research Council of Australia.
A version of this article first appeared on Medscape.com.
In the first study, an algorithm was created to analyze speech patterns and semantic content to create novel “speech networks.” Compared with their healthy peers, patients with FEP had smaller and more fragmented networks. At-risk individuals had fragmented values that were in between those of the FEP and healthy control groups.
“This suggests that semantic speech networks can enable deeper phenotyping of formal thought disorder and psychosis,” said lead author Caroline Nettekoven, PhD, department of psychiatry, University of Cambridge, England.
In the second study, Janna N. de Boer, MD, University of Groningen, the Netherlands, and colleagues examined patients with FEP who did and did not experience relapse after 24 months of follow-up.
An algorithm based on natural language processing (NLP) of speech recordings predicted the relapses with an accuracy of more than 80%.
NLP “is a powerful tool with high potential for clinical application and diagnosis and differentiation, given its ease in acquirement, low cost, and naturally low patient burden,” said de Boer.
The findings for both studies were presented at the annual congress of the Schizophrenia International Research Society.
Fragmented networks
Dr. Nettekoven noted that previous research has shown “mapping the speech of a psychosis patient as a network and analyzing the network using graph theory is useful for understanding formal thought disorder.”
However, these tools ignore the semantic content of speech, which is a “key feature” that is altered in psychotic language, she added.
The researchers therefore proposed a “novel type of network to map the content of speech.”
For example, if someone said, “I see a man,” a semantic speech network developed from this sentence would have the first and last words connected by “the edge” to the word “see,” Dr. Nettekoven explained.
To explore further, the investigators developed an algorithm known as “netts” that automatically creates semantic speech networks from transcribed speech.
They first applied the algorithm to transcribed speech from a general population sample of 436 individuals and then to a clinical sample (n = 53) comprising patients with FEP, those at clinical high risk for psychosis, and a healthy control group.
Comparing the general population sample with randomly generated semantic speech networks, the investigators found that networks from the general population had fewer but larger connected components, which “reflects the nonrandom nature of speech,” said Dr. Nettekoven.
In the clinical sample, networks from the FEP group had a significantly higher number of connected components compared with the healthy control group (P = .05) and a significantly smaller median connected-component size (P < .01).
“So patients’ mental speech networks are more fragmented than those from controls,” said Dr. Nettekoven. She added that the networks from clinically high-risk individuals “showed fragmentation values in between [those of] patients and controls.”
A further clustering analysis suggested the semantic speech networks “capture a novel signal that is not already described” by other NLP measures, Dr. Nettekoven said. In addition, the network features were related to negative symptom scores and scores on the Thought and Language Index.
However, Dr. Nettekoven noted that these relationships “did not survive correcting for multiple comparisons.”
Relapse predictor
During her presentation of the second study, Dr. de Boer said that “predicting relapse remains challenging” in FEP.
However, she noted that recent developments in NLP have proved to be effective in a “range of applications,” including early symptom recognition and differential diagnosis in psychosis.
To determine whether NLP could help predict relapse, the study included 104 patients aged 16-55 years with FEP whose conditions had been in remission for 3-6 months. Speech recordings were made at baseline and after 3 and 6 months and were analyzed via OpenSMILE software.
After a follow-up of 24 months, 24 of the patients remaining in the study had not experienced relapse, while 21 patients had experienced relapse. There were no significant age, education, or gender differences between those who did and those who did not experience relapse.
On the basis of speech analysis, the investigators identified a machine learning classifier, which showed an accuracy of 80.8% in predicting relapse 3 months in advance of the occurrence.
‘Valid and informative’
Commenting on the studies, Eric J. Tan, PhD, Centre for Mental Health, Swinburne University of Technology, Melbourne, said they are “but two of a variety of ways in which speech can be analyzed and are both equally valid and informative.”
The key takeaway “is that both studies are examples of the ways in which speech can be used clinically, such as for predicting relapse and for the potential proxy measure for the assessment of symptom severity,” said Dr. Tan, who was not involved with the research.
The studies also show that “speech is sensitive to different stages of the disorder, as well as its individual symptoms,” he added.
However, Dr. Tan noted that although “speech may be more of a sign of an underlying pathology or dysfunction, given that it waxes and wanes with illness severity, more analyses are needed before drawing definitive conclusions.” This is especially needed “given the relative infancy of quantitative speech analysis,” he said.
“It would also be useful to conduct these analyses across a variety of different languages to look for commonalities and differences that will help shed light on the variables most closely linked to the disorder,” Dr. Tan concluded.
The investigators have reported no relevant financial relationships. Dr. Tan has received an Early Career Research Fellowship from the National Health and Medical Research Council of Australia.
A version of this article first appeared on Medscape.com.
In the first study, an algorithm was created to analyze speech patterns and semantic content to create novel “speech networks.” Compared with their healthy peers, patients with FEP had smaller and more fragmented networks. At-risk individuals had fragmented values that were in between those of the FEP and healthy control groups.
“This suggests that semantic speech networks can enable deeper phenotyping of formal thought disorder and psychosis,” said lead author Caroline Nettekoven, PhD, department of psychiatry, University of Cambridge, England.
In the second study, Janna N. de Boer, MD, University of Groningen, the Netherlands, and colleagues examined patients with FEP who did and did not experience relapse after 24 months of follow-up.
An algorithm based on natural language processing (NLP) of speech recordings predicted the relapses with an accuracy of more than 80%.
NLP “is a powerful tool with high potential for clinical application and diagnosis and differentiation, given its ease in acquirement, low cost, and naturally low patient burden,” said de Boer.
The findings for both studies were presented at the annual congress of the Schizophrenia International Research Society.
Fragmented networks
Dr. Nettekoven noted that previous research has shown “mapping the speech of a psychosis patient as a network and analyzing the network using graph theory is useful for understanding formal thought disorder.”
However, these tools ignore the semantic content of speech, which is a “key feature” that is altered in psychotic language, she added.
The researchers therefore proposed a “novel type of network to map the content of speech.”
For example, if someone said, “I see a man,” a semantic speech network developed from this sentence would have the first and last words connected by “the edge” to the word “see,” Dr. Nettekoven explained.
To explore further, the investigators developed an algorithm known as “netts” that automatically creates semantic speech networks from transcribed speech.
They first applied the algorithm to transcribed speech from a general population sample of 436 individuals and then to a clinical sample (n = 53) comprising patients with FEP, those at clinical high risk for psychosis, and a healthy control group.
Comparing the general population sample with randomly generated semantic speech networks, the investigators found that networks from the general population had fewer but larger connected components, which “reflects the nonrandom nature of speech,” said Dr. Nettekoven.
In the clinical sample, networks from the FEP group had a significantly higher number of connected components compared with the healthy control group (P = .05) and a significantly smaller median connected-component size (P < .01).
“So patients’ mental speech networks are more fragmented than those from controls,” said Dr. Nettekoven. She added that the networks from clinically high-risk individuals “showed fragmentation values in between [those of] patients and controls.”
A further clustering analysis suggested the semantic speech networks “capture a novel signal that is not already described” by other NLP measures, Dr. Nettekoven said. In addition, the network features were related to negative symptom scores and scores on the Thought and Language Index.
However, Dr. Nettekoven noted that these relationships “did not survive correcting for multiple comparisons.”
Relapse predictor
During her presentation of the second study, Dr. de Boer said that “predicting relapse remains challenging” in FEP.
However, she noted that recent developments in NLP have proved to be effective in a “range of applications,” including early symptom recognition and differential diagnosis in psychosis.
To determine whether NLP could help predict relapse, the study included 104 patients aged 16-55 years with FEP whose conditions had been in remission for 3-6 months. Speech recordings were made at baseline and after 3 and 6 months and were analyzed via OpenSMILE software.
After a follow-up of 24 months, 24 of the patients remaining in the study had not experienced relapse, while 21 patients had experienced relapse. There were no significant age, education, or gender differences between those who did and those who did not experience relapse.
On the basis of speech analysis, the investigators identified a machine learning classifier, which showed an accuracy of 80.8% in predicting relapse 3 months in advance of the occurrence.
‘Valid and informative’
Commenting on the studies, Eric J. Tan, PhD, Centre for Mental Health, Swinburne University of Technology, Melbourne, said they are “but two of a variety of ways in which speech can be analyzed and are both equally valid and informative.”
The key takeaway “is that both studies are examples of the ways in which speech can be used clinically, such as for predicting relapse and for the potential proxy measure for the assessment of symptom severity,” said Dr. Tan, who was not involved with the research.
The studies also show that “speech is sensitive to different stages of the disorder, as well as its individual symptoms,” he added.
However, Dr. Tan noted that although “speech may be more of a sign of an underlying pathology or dysfunction, given that it waxes and wanes with illness severity, more analyses are needed before drawing definitive conclusions.” This is especially needed “given the relative infancy of quantitative speech analysis,” he said.
“It would also be useful to conduct these analyses across a variety of different languages to look for commonalities and differences that will help shed light on the variables most closely linked to the disorder,” Dr. Tan concluded.
The investigators have reported no relevant financial relationships. Dr. Tan has received an Early Career Research Fellowship from the National Health and Medical Research Council of Australia.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
Novel long-acting injection cuts schizophrenia relapse
A long-acting subcutaneous antipsychotic (LASCA) suspension that combines risperidone with a novel copolymer substantially reduces risk for relapse and prolongs time to impending relapse for patients with schizophrenia, new research suggests.
In the phase 3 Risperidone Subcutaneous Extended-Release (RISE) trial, which included more than 500 patients with schizophrenia, those who received the novel combination treatment, known as TV-46000, had relapse reduced by 80% with monthly administration and by 63.5% with the bimonthly dose.
“Long-acting injectable medications are grossly underutilized,” study investigator John M. Kane, MD, Hofstra University, Hempstead, N.Y., told this news organization.
The attributes of TV-46000, which include its subcutaneous delivery rather than intramuscular injections, its being active within 24 hours of first treatment, and its being administered monthly or bimonthly, “might be advantageous for some patients,” Dr. Kane noted.
Because it is also effective in reducing risk for relapse, TV-46000 is “another alternative when people are looking at the possibility of using a long-acting injectable formulation,” he added.
The findings were presented at the annual congress of the Schizophrenia International Research Society.
Time to relapse
To examine the efficacy and safety of monthly and bimonthly doses of the drug, the researchers recruited patients aged 13-65 years who were diagnosed with schizophrenia more than a year previously and who had experienced at least one relapse in the previous 24 months.
After a screening period of up to 4 weeks, participants entered a 12-week pretreatment phase, during which their condition was stabilized on oral risperidone. During this period, the patients’ conditions had to remain stable for at least 4 consecutive weeks.
Patients were then randomly assigned in a 1:1:1 ratio to receive TV-46000 monthly, TV-46000 every 2 months, or matching placebo. All doses were given as subcutaneous injections.
Treatment was continued until participants experienced a relapse event, met at least one criteria for study withdrawal, or the study recorded a total of 90 or more relapse events.
Of 1,267 patients screened, 863 were enrolled in the study, and 544 underwent randomization. The median age of the patients who underwent randomization was 52 years; 61% were male; and the majority (59%) were Black.
In addition, the average length of time with the disease was 20.8 years, and the average time since the most recent relapse was 10.2 months.
The primary endpoint was time to impending relapse, the criteria for which included the following:
- Increases in Positive and Negative Syndrome Scale (PANSS) scores from randomization.
- Hospitalization because of worsening psychotic symptoms.
- Violent behavior resulting in clinically significant injury or damage.
Well tolerated?
In the intent-to-treat population, which comprised all adults who underwent randomization, monthly TV-46000 was associated with a fivefold prolongation of time to impending relapse in comparison with placebo; TV-46000 given every 2 months prolonged the time 2.7-fold.
This translated into a significant benefit vs. placebo for both TV-46000 monthly (hazard ratio for impending relapse, 0.2) and TV-46000 every 2 months (HR, 0.375; P < .0001 for both comparisons).
At the trial’s endpoint, impending relapse rates were 29% in the placebo group vs. 7% in the TV-46000 monthly group and 13% in the group that received TV-46000 every 2 months (P < .0001 for both).
While more patients in the two active-treatment groups met the strict criteria for remission, which included no relapse during the study and PANSS scores of 3 or less for at least 6 months prior to the study endpoint, the differences were not significant.
Treatment-related adverse events (AEs) were experienced by 39%-42% of the TV-46000 groups and by 26% of the placebo group. Serious AEs were experienced by 4%-6% of the TV-46000 groups and by 8% of the placebo group.
The investigators note that TV-46000 was “well tolerated” and that there were no new safety signals in comparison with what is already known about risperidone and “other long-acting risperidone formulations.”
Expanding on the reasons why long-acting antipsychotics are underprescribed, Dr. Kane said that “doctors often overestimate how adherent their patients are.”
He added that doctors may worry they are “insulting” their patient by suggesting they receive injections in order to increase adherence and that doctors are “not very good” at having these types of conversation with their patients.
“We did a study where we trained the clinical staff on how to have those conversations, and the result was the uptake [in patients switching to long-acting antipsychotics] was very high,” Dr. Kane said.
The personnel who received training included all of the medical team, therapists, who spend “much more time” with the patient than does the prescriber, and also social workers, case managers, and rehabilitation counselors, who are typically “not very familiar” with the idea of long-acting medications, he added.
‘Highly desirable’ option
Commenting on the study, Stephen R. Saklad, PharmD, director of the psychiatric pharmacy program, University of Texas Health Science Center at San Antonio, said that to call TV-46000 a LASCA rather than a depot injection is merely a “change in nomenclature.”
However, compared with a once-monthly subcutaneous injection of risperidone (Perseris), which was approved by the U.S. Food and Drug Administration in 2018 for the treatment of schizophrenia, the new drug has fewer injection site reactions, said Dr. Saklad, who was not involved with the current research.
That benefit plus having efficacy similar to that of oral risperidone and having the “more patient- and clinician-desirable administration location” of the upper arm as well as the abdomen means the option to switch a risperidone-stabilized patient directly to TV-46000 monthly or bimonthly is “highly desirable,” he added.
Dr. Saklad also noted the reduction in the likelihood of impending relapse with TV-46000 over placebo is a relatively large effect size “and shows the value toward improving the care of these patients.”
In addition, he agreed with Dr. Kane that the uptake of long-acting antipsychotics is “deplorably low.”
“This is due to a number of factors that include patient reluctance to get a ‘shot’ or ‘jab,’ clinician inexperience with LAIs during training, and the incorrect presentation of LAIs as a punishment paradigm for ‘bad’ patients,” Dr. Saklad said.
He added that “everyone tires of taking their medication or just forgets to take a dose,” and most patients with other disorders will resume their medication the next day.
However, patients with schizophrenia have a “specific cognitive difficulty” in making the connection between stopping their medication and a later relapse. If they miss a dose, they will “incorrectly conclude that they are now ‘well’ and don’t need the medication any longer,” he said.
Dr. Saklad stressed that for a patient with schizophrenia a relapse can mean substantial loss of function and of assets such as housing or support networks, and many “will complete suicide.”
The study was supported by Teva Branded Pharmaceutical Products R&D. Dr. Kane reported relationships with Alkermes, Allergan, Dainioppon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals, Merck, Neurocine, North Shore Therapeutics, Novartis Pharmaceutical, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, Otsuka, Lundbeck, Sunovion, UptoDate, and Vanguard Research Group.
A version of this article first appeared on Medscape.com.
A long-acting subcutaneous antipsychotic (LASCA) suspension that combines risperidone with a novel copolymer substantially reduces risk for relapse and prolongs time to impending relapse for patients with schizophrenia, new research suggests.
In the phase 3 Risperidone Subcutaneous Extended-Release (RISE) trial, which included more than 500 patients with schizophrenia, those who received the novel combination treatment, known as TV-46000, had relapse reduced by 80% with monthly administration and by 63.5% with the bimonthly dose.
“Long-acting injectable medications are grossly underutilized,” study investigator John M. Kane, MD, Hofstra University, Hempstead, N.Y., told this news organization.
The attributes of TV-46000, which include its subcutaneous delivery rather than intramuscular injections, its being active within 24 hours of first treatment, and its being administered monthly or bimonthly, “might be advantageous for some patients,” Dr. Kane noted.
Because it is also effective in reducing risk for relapse, TV-46000 is “another alternative when people are looking at the possibility of using a long-acting injectable formulation,” he added.
The findings were presented at the annual congress of the Schizophrenia International Research Society.
Time to relapse
To examine the efficacy and safety of monthly and bimonthly doses of the drug, the researchers recruited patients aged 13-65 years who were diagnosed with schizophrenia more than a year previously and who had experienced at least one relapse in the previous 24 months.
After a screening period of up to 4 weeks, participants entered a 12-week pretreatment phase, during which their condition was stabilized on oral risperidone. During this period, the patients’ conditions had to remain stable for at least 4 consecutive weeks.
Patients were then randomly assigned in a 1:1:1 ratio to receive TV-46000 monthly, TV-46000 every 2 months, or matching placebo. All doses were given as subcutaneous injections.
Treatment was continued until participants experienced a relapse event, met at least one criteria for study withdrawal, or the study recorded a total of 90 or more relapse events.
Of 1,267 patients screened, 863 were enrolled in the study, and 544 underwent randomization. The median age of the patients who underwent randomization was 52 years; 61% were male; and the majority (59%) were Black.
In addition, the average length of time with the disease was 20.8 years, and the average time since the most recent relapse was 10.2 months.
The primary endpoint was time to impending relapse, the criteria for which included the following:
- Increases in Positive and Negative Syndrome Scale (PANSS) scores from randomization.
- Hospitalization because of worsening psychotic symptoms.
- Violent behavior resulting in clinically significant injury or damage.
Well tolerated?
In the intent-to-treat population, which comprised all adults who underwent randomization, monthly TV-46000 was associated with a fivefold prolongation of time to impending relapse in comparison with placebo; TV-46000 given every 2 months prolonged the time 2.7-fold.
This translated into a significant benefit vs. placebo for both TV-46000 monthly (hazard ratio for impending relapse, 0.2) and TV-46000 every 2 months (HR, 0.375; P < .0001 for both comparisons).
At the trial’s endpoint, impending relapse rates were 29% in the placebo group vs. 7% in the TV-46000 monthly group and 13% in the group that received TV-46000 every 2 months (P < .0001 for both).
While more patients in the two active-treatment groups met the strict criteria for remission, which included no relapse during the study and PANSS scores of 3 or less for at least 6 months prior to the study endpoint, the differences were not significant.
Treatment-related adverse events (AEs) were experienced by 39%-42% of the TV-46000 groups and by 26% of the placebo group. Serious AEs were experienced by 4%-6% of the TV-46000 groups and by 8% of the placebo group.
The investigators note that TV-46000 was “well tolerated” and that there were no new safety signals in comparison with what is already known about risperidone and “other long-acting risperidone formulations.”
Expanding on the reasons why long-acting antipsychotics are underprescribed, Dr. Kane said that “doctors often overestimate how adherent their patients are.”
He added that doctors may worry they are “insulting” their patient by suggesting they receive injections in order to increase adherence and that doctors are “not very good” at having these types of conversation with their patients.
“We did a study where we trained the clinical staff on how to have those conversations, and the result was the uptake [in patients switching to long-acting antipsychotics] was very high,” Dr. Kane said.
The personnel who received training included all of the medical team, therapists, who spend “much more time” with the patient than does the prescriber, and also social workers, case managers, and rehabilitation counselors, who are typically “not very familiar” with the idea of long-acting medications, he added.
‘Highly desirable’ option
Commenting on the study, Stephen R. Saklad, PharmD, director of the psychiatric pharmacy program, University of Texas Health Science Center at San Antonio, said that to call TV-46000 a LASCA rather than a depot injection is merely a “change in nomenclature.”
However, compared with a once-monthly subcutaneous injection of risperidone (Perseris), which was approved by the U.S. Food and Drug Administration in 2018 for the treatment of schizophrenia, the new drug has fewer injection site reactions, said Dr. Saklad, who was not involved with the current research.
That benefit plus having efficacy similar to that of oral risperidone and having the “more patient- and clinician-desirable administration location” of the upper arm as well as the abdomen means the option to switch a risperidone-stabilized patient directly to TV-46000 monthly or bimonthly is “highly desirable,” he added.
Dr. Saklad also noted the reduction in the likelihood of impending relapse with TV-46000 over placebo is a relatively large effect size “and shows the value toward improving the care of these patients.”
In addition, he agreed with Dr. Kane that the uptake of long-acting antipsychotics is “deplorably low.”
“This is due to a number of factors that include patient reluctance to get a ‘shot’ or ‘jab,’ clinician inexperience with LAIs during training, and the incorrect presentation of LAIs as a punishment paradigm for ‘bad’ patients,” Dr. Saklad said.
He added that “everyone tires of taking their medication or just forgets to take a dose,” and most patients with other disorders will resume their medication the next day.
However, patients with schizophrenia have a “specific cognitive difficulty” in making the connection between stopping their medication and a later relapse. If they miss a dose, they will “incorrectly conclude that they are now ‘well’ and don’t need the medication any longer,” he said.
Dr. Saklad stressed that for a patient with schizophrenia a relapse can mean substantial loss of function and of assets such as housing or support networks, and many “will complete suicide.”
The study was supported by Teva Branded Pharmaceutical Products R&D. Dr. Kane reported relationships with Alkermes, Allergan, Dainioppon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals, Merck, Neurocine, North Shore Therapeutics, Novartis Pharmaceutical, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, Otsuka, Lundbeck, Sunovion, UptoDate, and Vanguard Research Group.
A version of this article first appeared on Medscape.com.
A long-acting subcutaneous antipsychotic (LASCA) suspension that combines risperidone with a novel copolymer substantially reduces risk for relapse and prolongs time to impending relapse for patients with schizophrenia, new research suggests.
In the phase 3 Risperidone Subcutaneous Extended-Release (RISE) trial, which included more than 500 patients with schizophrenia, those who received the novel combination treatment, known as TV-46000, had relapse reduced by 80% with monthly administration and by 63.5% with the bimonthly dose.
“Long-acting injectable medications are grossly underutilized,” study investigator John M. Kane, MD, Hofstra University, Hempstead, N.Y., told this news organization.
The attributes of TV-46000, which include its subcutaneous delivery rather than intramuscular injections, its being active within 24 hours of first treatment, and its being administered monthly or bimonthly, “might be advantageous for some patients,” Dr. Kane noted.
Because it is also effective in reducing risk for relapse, TV-46000 is “another alternative when people are looking at the possibility of using a long-acting injectable formulation,” he added.
The findings were presented at the annual congress of the Schizophrenia International Research Society.
Time to relapse
To examine the efficacy and safety of monthly and bimonthly doses of the drug, the researchers recruited patients aged 13-65 years who were diagnosed with schizophrenia more than a year previously and who had experienced at least one relapse in the previous 24 months.
After a screening period of up to 4 weeks, participants entered a 12-week pretreatment phase, during which their condition was stabilized on oral risperidone. During this period, the patients’ conditions had to remain stable for at least 4 consecutive weeks.
Patients were then randomly assigned in a 1:1:1 ratio to receive TV-46000 monthly, TV-46000 every 2 months, or matching placebo. All doses were given as subcutaneous injections.
Treatment was continued until participants experienced a relapse event, met at least one criteria for study withdrawal, or the study recorded a total of 90 or more relapse events.
Of 1,267 patients screened, 863 were enrolled in the study, and 544 underwent randomization. The median age of the patients who underwent randomization was 52 years; 61% were male; and the majority (59%) were Black.
In addition, the average length of time with the disease was 20.8 years, and the average time since the most recent relapse was 10.2 months.
The primary endpoint was time to impending relapse, the criteria for which included the following:
- Increases in Positive and Negative Syndrome Scale (PANSS) scores from randomization.
- Hospitalization because of worsening psychotic symptoms.
- Violent behavior resulting in clinically significant injury or damage.
Well tolerated?
In the intent-to-treat population, which comprised all adults who underwent randomization, monthly TV-46000 was associated with a fivefold prolongation of time to impending relapse in comparison with placebo; TV-46000 given every 2 months prolonged the time 2.7-fold.
This translated into a significant benefit vs. placebo for both TV-46000 monthly (hazard ratio for impending relapse, 0.2) and TV-46000 every 2 months (HR, 0.375; P < .0001 for both comparisons).
At the trial’s endpoint, impending relapse rates were 29% in the placebo group vs. 7% in the TV-46000 monthly group and 13% in the group that received TV-46000 every 2 months (P < .0001 for both).
While more patients in the two active-treatment groups met the strict criteria for remission, which included no relapse during the study and PANSS scores of 3 or less for at least 6 months prior to the study endpoint, the differences were not significant.
Treatment-related adverse events (AEs) were experienced by 39%-42% of the TV-46000 groups and by 26% of the placebo group. Serious AEs were experienced by 4%-6% of the TV-46000 groups and by 8% of the placebo group.
The investigators note that TV-46000 was “well tolerated” and that there were no new safety signals in comparison with what is already known about risperidone and “other long-acting risperidone formulations.”
Expanding on the reasons why long-acting antipsychotics are underprescribed, Dr. Kane said that “doctors often overestimate how adherent their patients are.”
He added that doctors may worry they are “insulting” their patient by suggesting they receive injections in order to increase adherence and that doctors are “not very good” at having these types of conversation with their patients.
“We did a study where we trained the clinical staff on how to have those conversations, and the result was the uptake [in patients switching to long-acting antipsychotics] was very high,” Dr. Kane said.
The personnel who received training included all of the medical team, therapists, who spend “much more time” with the patient than does the prescriber, and also social workers, case managers, and rehabilitation counselors, who are typically “not very familiar” with the idea of long-acting medications, he added.
‘Highly desirable’ option
Commenting on the study, Stephen R. Saklad, PharmD, director of the psychiatric pharmacy program, University of Texas Health Science Center at San Antonio, said that to call TV-46000 a LASCA rather than a depot injection is merely a “change in nomenclature.”
However, compared with a once-monthly subcutaneous injection of risperidone (Perseris), which was approved by the U.S. Food and Drug Administration in 2018 for the treatment of schizophrenia, the new drug has fewer injection site reactions, said Dr. Saklad, who was not involved with the current research.
That benefit plus having efficacy similar to that of oral risperidone and having the “more patient- and clinician-desirable administration location” of the upper arm as well as the abdomen means the option to switch a risperidone-stabilized patient directly to TV-46000 monthly or bimonthly is “highly desirable,” he added.
Dr. Saklad also noted the reduction in the likelihood of impending relapse with TV-46000 over placebo is a relatively large effect size “and shows the value toward improving the care of these patients.”
In addition, he agreed with Dr. Kane that the uptake of long-acting antipsychotics is “deplorably low.”
“This is due to a number of factors that include patient reluctance to get a ‘shot’ or ‘jab,’ clinician inexperience with LAIs during training, and the incorrect presentation of LAIs as a punishment paradigm for ‘bad’ patients,” Dr. Saklad said.
He added that “everyone tires of taking their medication or just forgets to take a dose,” and most patients with other disorders will resume their medication the next day.
However, patients with schizophrenia have a “specific cognitive difficulty” in making the connection between stopping their medication and a later relapse. If they miss a dose, they will “incorrectly conclude that they are now ‘well’ and don’t need the medication any longer,” he said.
Dr. Saklad stressed that for a patient with schizophrenia a relapse can mean substantial loss of function and of assets such as housing or support networks, and many “will complete suicide.”
The study was supported by Teva Branded Pharmaceutical Products R&D. Dr. Kane reported relationships with Alkermes, Allergan, Dainioppon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals, Merck, Neurocine, North Shore Therapeutics, Novartis Pharmaceutical, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, Otsuka, Lundbeck, Sunovion, UptoDate, and Vanguard Research Group.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
A new target in schizophrenia treatment: Brain gamma oscillations
In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206, compared with placebo, increased the power of gamma oscillations, which were in turn associated with positive symptom scores.
The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.
In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told this news organization that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.
Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Dr. Large said.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
‘Opportunity to intervene’
Dr. Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades, “and the pathology of that stage is then different.”
For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Dr. Large.
In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power – and reduced power and “phase locking” to cyclical stimuli – the researchers note.
Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.
Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.
To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18-50 years.
Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2,000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.
At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.
Positive associations
Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli but not in phase locking.
There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).
Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).
While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.
They add that a larger study is now needed to confirm their findings and to “explore efficacy versus clinical symptoms.”
However, Dr. Large noted that participants in their next study will have fragile X syndrome.
He added the reason for this is “not because we’ve given up on schizophrenia – we feel that schizophrenia is a massive opportunity.”
Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Dr. Large said.
In contrast, fragile X is “genetically homogenous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”
Preliminary but worth pursuing?
Commenting on the study, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”
Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said Dr. McNally, who was not involved with the research.
He added that the “idea of targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”
The study was funded by Autifony Therapeutics, of which Dr. Large is an employee.
A version of this article first appeared on Medscape.com.
In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206, compared with placebo, increased the power of gamma oscillations, which were in turn associated with positive symptom scores.
The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.
In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told this news organization that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.
Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Dr. Large said.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
‘Opportunity to intervene’
Dr. Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades, “and the pathology of that stage is then different.”
For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Dr. Large.
In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power – and reduced power and “phase locking” to cyclical stimuli – the researchers note.
Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.
Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.
To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18-50 years.
Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2,000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.
At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.
Positive associations
Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli but not in phase locking.
There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).
Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).
While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.
They add that a larger study is now needed to confirm their findings and to “explore efficacy versus clinical symptoms.”
However, Dr. Large noted that participants in their next study will have fragile X syndrome.
He added the reason for this is “not because we’ve given up on schizophrenia – we feel that schizophrenia is a massive opportunity.”
Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Dr. Large said.
In contrast, fragile X is “genetically homogenous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”
Preliminary but worth pursuing?
Commenting on the study, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”
Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said Dr. McNally, who was not involved with the research.
He added that the “idea of targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”
The study was funded by Autifony Therapeutics, of which Dr. Large is an employee.
A version of this article first appeared on Medscape.com.
In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206, compared with placebo, increased the power of gamma oscillations, which were in turn associated with positive symptom scores.
The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.
In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told this news organization that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.
Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Dr. Large said.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
‘Opportunity to intervene’
Dr. Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades, “and the pathology of that stage is then different.”
For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Dr. Large.
In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power – and reduced power and “phase locking” to cyclical stimuli – the researchers note.
Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.
Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.
To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18-50 years.
Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2,000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.
At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.
Positive associations
Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli but not in phase locking.
There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).
Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).
While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.
They add that a larger study is now needed to confirm their findings and to “explore efficacy versus clinical symptoms.”
However, Dr. Large noted that participants in their next study will have fragile X syndrome.
He added the reason for this is “not because we’ve given up on schizophrenia – we feel that schizophrenia is a massive opportunity.”
Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Dr. Large said.
In contrast, fragile X is “genetically homogenous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”
Preliminary but worth pursuing?
Commenting on the study, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”
Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said Dr. McNally, who was not involved with the research.
He added that the “idea of targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”
The study was funded by Autifony Therapeutics, of which Dr. Large is an employee.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022