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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
Consider switching up treatment regimens for recurrent bacterial vaginosis
Limited data are available to guide treatment of recurrent bacterial vaginosis, but behavioral changes and switching between approved medication regimens may help, according to a presenter at the virtual conference on diseases of the vulva and vagina, hosted by the International Society for the Study of Vulvovaginal Disease.
Investigational treatments – such as a live biotherapeutic product delivered vaginally or vaginal microbiome transplantation – could someday be additional options if they prove safe and effective. said Debra L. Birenbaum, MD, assistant professor of obstetrics and gynecology at Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
As for home remedies, Dr. Birenbaum and another presenter at the conference, Cynthia Rasmussen, MD, urged caution during a panel discussion.
“I think the vagina knows its business, and the more you mess with it, the more you invite trouble,” said Dr. Rasmussen, director emerita of vulvovaginal services at Atrius Health in Burlington, Mass. For instance, tea tree oil, often cited as a home remedy, can be an allergen and very irritating.
“I want to know what women are using, but I try and dissuade them,” said Dr. Birenbaum. “I have to be careful what I say, because you’ll antagonize patients” if you come out strongly against home treatments. “I try to encourage them not to go by things they read on the Internet, because I think that’s where many people are finding their home remedies.”
When counseling patients, an analogy shared during the meeting – the vagina is a self-cleaning oven – may help get the point across. “I love the comment,” Dr. Birenbaum said. “I’ve never used that before. I’m going to start saying that.”
Possible causes and risk factors
Bacterial vaginosis, also known as vaginal dysbiosis, is the most common cause of discharge in women of reproductive age worldwide. Growth of a biofilm may cause the condition, which is characterized by a shift in vaginal flora from a Lactobacilli-dominant environment to one of other bacterial types.
Risk factors include douching, smoking, sex with an uncircumcised partner, and having multiple sexual partners. Bacterial vaginosis may be associated with various complications and infections, including increased risk of preterm delivery, postpartum endometritis, postabortal infection, Trichomonas, chlamydia, and HIV.
Unlike recurrent yeast, which is characterized by four or more episodes per year, recurrent bacterial vaginosis has no official criteria, Dr. Birenbaum said. However, recurrence of bacterial vaginosis “is extremely common,” she said. “Up to 30% of women with [bacterial vaginosis] may recur within 3 months, and up to 50% after 12 months.”
Lifestyle changes and treatments
Recommendations to use condoms, stop smoking, and not douche are important.
In addition, 11 treatment regimens for four drugs – metronidazole, clindamycin, tinidazole, or secnidazole – are available for the treatment of bacterial vaginosis. For recurrent cases, adjusting and switching between the drugs and modes of delivery may help. If a patient started with vaginal gel, they can try an oral medication, or vice versa.
“There’s very little data to guide the optimal therapy for this,” Dr. Birenbaum said. “All of this is worth a try to see if you can beat this before this becomes an ongoing issue.”
As an example of one possible regimen for recurrent bacterial vaginosis, Dr. Birenbaum suggested that a patient could complete a 2- to 4-week course of oral metronidazole instead of the usual 1-week course. The regimen could incorporate boric acid vaginal suppositories 600 mg nightly for 21 days, followed by metronidazole gel 0.75% (one applicator twice per week for 6 months).
New therapies may be on the horizon
In a randomized, double-blind, phase 2b trial published in the New England Journal of Medicine that included more than 220 participants, patients who received an investigational product containing Lactobacillus crispatus CTV-05 (Lactin-V) were less likely to have recurrent bacterial vaginosis at 12 weeks, compared with those who received placebo (30% vs. 45%).
A product in development known as TOL-463, a boric acid–based vaginal anti-infective enhanced with ethylenediaminetetraacetic acid, may be safe and effective, a phase 2 study published in Clinical Infectious Diseases suggests.
Investigators in the United Kingdom designed a trial to compare lactic acid gel and metronidazole, and the findings published in the Trials journal may clarify inconsistent results from prior studies.
Furthermore, preclinical research in Pathogens and Disease has identified cationic amphiphiles that might help fight the biofilm that is formed with Gardnerella vaginalis in patients with bacterial vaginosis, Dr. Birenbaum said.
Finally, an exploratory study in Israel published in Nature Medicine evaluated vaginal microbiome transplants in five patients, three of whom required repeat transplantation. Four patients had long-term remission, and one had a reduction in symptoms
Dr. Birenbaum is a reviewer for UpToDate. Dr. Rasmussen had no relevant disclosures.
Limited data are available to guide treatment of recurrent bacterial vaginosis, but behavioral changes and switching between approved medication regimens may help, according to a presenter at the virtual conference on diseases of the vulva and vagina, hosted by the International Society for the Study of Vulvovaginal Disease.
Investigational treatments – such as a live biotherapeutic product delivered vaginally or vaginal microbiome transplantation – could someday be additional options if they prove safe and effective. said Debra L. Birenbaum, MD, assistant professor of obstetrics and gynecology at Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
As for home remedies, Dr. Birenbaum and another presenter at the conference, Cynthia Rasmussen, MD, urged caution during a panel discussion.
“I think the vagina knows its business, and the more you mess with it, the more you invite trouble,” said Dr. Rasmussen, director emerita of vulvovaginal services at Atrius Health in Burlington, Mass. For instance, tea tree oil, often cited as a home remedy, can be an allergen and very irritating.
“I want to know what women are using, but I try and dissuade them,” said Dr. Birenbaum. “I have to be careful what I say, because you’ll antagonize patients” if you come out strongly against home treatments. “I try to encourage them not to go by things they read on the Internet, because I think that’s where many people are finding their home remedies.”
When counseling patients, an analogy shared during the meeting – the vagina is a self-cleaning oven – may help get the point across. “I love the comment,” Dr. Birenbaum said. “I’ve never used that before. I’m going to start saying that.”
Possible causes and risk factors
Bacterial vaginosis, also known as vaginal dysbiosis, is the most common cause of discharge in women of reproductive age worldwide. Growth of a biofilm may cause the condition, which is characterized by a shift in vaginal flora from a Lactobacilli-dominant environment to one of other bacterial types.
Risk factors include douching, smoking, sex with an uncircumcised partner, and having multiple sexual partners. Bacterial vaginosis may be associated with various complications and infections, including increased risk of preterm delivery, postpartum endometritis, postabortal infection, Trichomonas, chlamydia, and HIV.
Unlike recurrent yeast, which is characterized by four or more episodes per year, recurrent bacterial vaginosis has no official criteria, Dr. Birenbaum said. However, recurrence of bacterial vaginosis “is extremely common,” she said. “Up to 30% of women with [bacterial vaginosis] may recur within 3 months, and up to 50% after 12 months.”
Lifestyle changes and treatments
Recommendations to use condoms, stop smoking, and not douche are important.
In addition, 11 treatment regimens for four drugs – metronidazole, clindamycin, tinidazole, or secnidazole – are available for the treatment of bacterial vaginosis. For recurrent cases, adjusting and switching between the drugs and modes of delivery may help. If a patient started with vaginal gel, they can try an oral medication, or vice versa.
“There’s very little data to guide the optimal therapy for this,” Dr. Birenbaum said. “All of this is worth a try to see if you can beat this before this becomes an ongoing issue.”
As an example of one possible regimen for recurrent bacterial vaginosis, Dr. Birenbaum suggested that a patient could complete a 2- to 4-week course of oral metronidazole instead of the usual 1-week course. The regimen could incorporate boric acid vaginal suppositories 600 mg nightly for 21 days, followed by metronidazole gel 0.75% (one applicator twice per week for 6 months).
New therapies may be on the horizon
In a randomized, double-blind, phase 2b trial published in the New England Journal of Medicine that included more than 220 participants, patients who received an investigational product containing Lactobacillus crispatus CTV-05 (Lactin-V) were less likely to have recurrent bacterial vaginosis at 12 weeks, compared with those who received placebo (30% vs. 45%).
A product in development known as TOL-463, a boric acid–based vaginal anti-infective enhanced with ethylenediaminetetraacetic acid, may be safe and effective, a phase 2 study published in Clinical Infectious Diseases suggests.
Investigators in the United Kingdom designed a trial to compare lactic acid gel and metronidazole, and the findings published in the Trials journal may clarify inconsistent results from prior studies.
Furthermore, preclinical research in Pathogens and Disease has identified cationic amphiphiles that might help fight the biofilm that is formed with Gardnerella vaginalis in patients with bacterial vaginosis, Dr. Birenbaum said.
Finally, an exploratory study in Israel published in Nature Medicine evaluated vaginal microbiome transplants in five patients, three of whom required repeat transplantation. Four patients had long-term remission, and one had a reduction in symptoms
Dr. Birenbaum is a reviewer for UpToDate. Dr. Rasmussen had no relevant disclosures.
Limited data are available to guide treatment of recurrent bacterial vaginosis, but behavioral changes and switching between approved medication regimens may help, according to a presenter at the virtual conference on diseases of the vulva and vagina, hosted by the International Society for the Study of Vulvovaginal Disease.
Investigational treatments – such as a live biotherapeutic product delivered vaginally or vaginal microbiome transplantation – could someday be additional options if they prove safe and effective. said Debra L. Birenbaum, MD, assistant professor of obstetrics and gynecology at Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
As for home remedies, Dr. Birenbaum and another presenter at the conference, Cynthia Rasmussen, MD, urged caution during a panel discussion.
“I think the vagina knows its business, and the more you mess with it, the more you invite trouble,” said Dr. Rasmussen, director emerita of vulvovaginal services at Atrius Health in Burlington, Mass. For instance, tea tree oil, often cited as a home remedy, can be an allergen and very irritating.
“I want to know what women are using, but I try and dissuade them,” said Dr. Birenbaum. “I have to be careful what I say, because you’ll antagonize patients” if you come out strongly against home treatments. “I try to encourage them not to go by things they read on the Internet, because I think that’s where many people are finding their home remedies.”
When counseling patients, an analogy shared during the meeting – the vagina is a self-cleaning oven – may help get the point across. “I love the comment,” Dr. Birenbaum said. “I’ve never used that before. I’m going to start saying that.”
Possible causes and risk factors
Bacterial vaginosis, also known as vaginal dysbiosis, is the most common cause of discharge in women of reproductive age worldwide. Growth of a biofilm may cause the condition, which is characterized by a shift in vaginal flora from a Lactobacilli-dominant environment to one of other bacterial types.
Risk factors include douching, smoking, sex with an uncircumcised partner, and having multiple sexual partners. Bacterial vaginosis may be associated with various complications and infections, including increased risk of preterm delivery, postpartum endometritis, postabortal infection, Trichomonas, chlamydia, and HIV.
Unlike recurrent yeast, which is characterized by four or more episodes per year, recurrent bacterial vaginosis has no official criteria, Dr. Birenbaum said. However, recurrence of bacterial vaginosis “is extremely common,” she said. “Up to 30% of women with [bacterial vaginosis] may recur within 3 months, and up to 50% after 12 months.”
Lifestyle changes and treatments
Recommendations to use condoms, stop smoking, and not douche are important.
In addition, 11 treatment regimens for four drugs – metronidazole, clindamycin, tinidazole, or secnidazole – are available for the treatment of bacterial vaginosis. For recurrent cases, adjusting and switching between the drugs and modes of delivery may help. If a patient started with vaginal gel, they can try an oral medication, or vice versa.
“There’s very little data to guide the optimal therapy for this,” Dr. Birenbaum said. “All of this is worth a try to see if you can beat this before this becomes an ongoing issue.”
As an example of one possible regimen for recurrent bacterial vaginosis, Dr. Birenbaum suggested that a patient could complete a 2- to 4-week course of oral metronidazole instead of the usual 1-week course. The regimen could incorporate boric acid vaginal suppositories 600 mg nightly for 21 days, followed by metronidazole gel 0.75% (one applicator twice per week for 6 months).
New therapies may be on the horizon
In a randomized, double-blind, phase 2b trial published in the New England Journal of Medicine that included more than 220 participants, patients who received an investigational product containing Lactobacillus crispatus CTV-05 (Lactin-V) were less likely to have recurrent bacterial vaginosis at 12 weeks, compared with those who received placebo (30% vs. 45%).
A product in development known as TOL-463, a boric acid–based vaginal anti-infective enhanced with ethylenediaminetetraacetic acid, may be safe and effective, a phase 2 study published in Clinical Infectious Diseases suggests.
Investigators in the United Kingdom designed a trial to compare lactic acid gel and metronidazole, and the findings published in the Trials journal may clarify inconsistent results from prior studies.
Furthermore, preclinical research in Pathogens and Disease has identified cationic amphiphiles that might help fight the biofilm that is formed with Gardnerella vaginalis in patients with bacterial vaginosis, Dr. Birenbaum said.
Finally, an exploratory study in Israel published in Nature Medicine evaluated vaginal microbiome transplants in five patients, three of whom required repeat transplantation. Four patients had long-term remission, and one had a reduction in symptoms
Dr. Birenbaum is a reviewer for UpToDate. Dr. Rasmussen had no relevant disclosures.
FROM THE ISSVD BIENNIAL CONFERENCE
Identifying pancreatitis etiology may help prevent progression
Pancreatitis remains the third most common gastroenterological cause of hospital admission, and staying on top of the latest quality indicators is important for the care and safety of patients, said Jamie S. Barkin, MD, professor of medicine in the division of gastroenterology at the University of Miami, in a virtual presentation at the annual Digestive Diseases: New Advances conference jointly provided by Rutgers and Global Academy for Medical Education.
The basics of treatment have changed, said Dr. Barkin. “A large volume of ringers lactate intravenous fluids given within the first 24 hours of admission, as opposed to normal saline, may decrease the inflammatory response in patients with acute pancreatitis.” The preferred diagnostic method remains clinical evaluation along with use of serum lipase, which is more sensitive than serum amylase (97%) but with similar specificity (99%), and current wisdom does not support the need for an early CT for diagnosis unless there is a diagnostic dilemma.
Early establishment of disease etiology and its therapy is imperative to attempt to prevent recurrent episodes and progression to chronic pancreatitis, Dr. Barkin said. Genetic testing studies suggest that approximately 10% of acute pancreatitis cases are the result of genetic factors, and Dr. Barkin recommended performing genetic testing after a first attack of idiopathic acute pancreatitis, especially in younger patients.
There is an extensive list of medications that may cause acute pancreatitis, according to a recent study published in PLOS One, the most common of which include acetaminophen, amiodarone, azathioprine, and angiotensin-converting enzyme inhibitors, Dr. Barkin said. In addition, acute pancreatitis can be caused by isonicotinic acid hydrazide (INH), cannabis, L-asparaginase, metronidazole, mesalamine, simvastatin, sulindac, sitagliptin, thiazides, tigecycline, trans-retinoic acid, and valproic acid, among others.
Current recommendations for hospital treatment of acute pancreatitis include early large volume fluid replacement and initiation of per-oral nutrition as soon as able to be tolerated, as well as pain control, Dr. Barkin said. In addition, management includes strict glycemic and triglyceride control and performance of cholecystectomy for mild and or moderate biliary pancreatitis or endoscopic retrograde cholangiopancreatography (ERCP) if the patient is not an operative candidate during the same hospital stay.
Current recommendations for the prevention of acute pancreatitis include avoidance of irritants such as alcohol, nicotine, and drugs known to cause acute pancreatitis, including marijuana, said Dr. Barkin. In addition, controlling metabolic factors such as obesity, diabetes, and triglycerides can help reduce risk of recurrent episodes in susceptible patients. Several of these factors are also linked to increased risk for progression of acute pancreatitis to chronic pancreatitis.
For patients with biliary pancreatitis, Dr. Barkin noted that cholecystectomy should be performed prior to discharge during the index hospitalization. “In patients who cannot undergo surgery, endoscopic sphincterotomy should be performed to allow spontaneous passage of any stones still in the gallbladder,” he noted.
In addition, patients who have experienced an attack of acute pancreatitis should be screened long-term for development of pancreatic exocrine insufficiency, which may be present in approximately one-quarter of patients following an acute pancreatitis episode, and diabetes, Dr. Barkin said. He cited a population-based study published in the American Journal of Gastroenterology in 2019 in which individuals with postpancreatitis diabetes had significantly higher rates of all-cause mortality, as well as hospitalization for conditions including chronic pulmonary disease, severe renal disease, and infectious disease.
Finally, at the time of discharge, it is essential to evaluate acute pancreatitis patients for risk of readmission, Dr. Barkin said. In addition to severe disease and systemic inflammatory response syndrome at the time of patient discharge, several factors increase the likelihood of readmission including ongoing abdominal pain requiring use of pain medicine, obesity, and inability to tolerate solid food, he noted.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Barkin had no relevant financial conflicts to disclose.
Pancreatitis remains the third most common gastroenterological cause of hospital admission, and staying on top of the latest quality indicators is important for the care and safety of patients, said Jamie S. Barkin, MD, professor of medicine in the division of gastroenterology at the University of Miami, in a virtual presentation at the annual Digestive Diseases: New Advances conference jointly provided by Rutgers and Global Academy for Medical Education.
The basics of treatment have changed, said Dr. Barkin. “A large volume of ringers lactate intravenous fluids given within the first 24 hours of admission, as opposed to normal saline, may decrease the inflammatory response in patients with acute pancreatitis.” The preferred diagnostic method remains clinical evaluation along with use of serum lipase, which is more sensitive than serum amylase (97%) but with similar specificity (99%), and current wisdom does not support the need for an early CT for diagnosis unless there is a diagnostic dilemma.
Early establishment of disease etiology and its therapy is imperative to attempt to prevent recurrent episodes and progression to chronic pancreatitis, Dr. Barkin said. Genetic testing studies suggest that approximately 10% of acute pancreatitis cases are the result of genetic factors, and Dr. Barkin recommended performing genetic testing after a first attack of idiopathic acute pancreatitis, especially in younger patients.
There is an extensive list of medications that may cause acute pancreatitis, according to a recent study published in PLOS One, the most common of which include acetaminophen, amiodarone, azathioprine, and angiotensin-converting enzyme inhibitors, Dr. Barkin said. In addition, acute pancreatitis can be caused by isonicotinic acid hydrazide (INH), cannabis, L-asparaginase, metronidazole, mesalamine, simvastatin, sulindac, sitagliptin, thiazides, tigecycline, trans-retinoic acid, and valproic acid, among others.
Current recommendations for hospital treatment of acute pancreatitis include early large volume fluid replacement and initiation of per-oral nutrition as soon as able to be tolerated, as well as pain control, Dr. Barkin said. In addition, management includes strict glycemic and triglyceride control and performance of cholecystectomy for mild and or moderate biliary pancreatitis or endoscopic retrograde cholangiopancreatography (ERCP) if the patient is not an operative candidate during the same hospital stay.
Current recommendations for the prevention of acute pancreatitis include avoidance of irritants such as alcohol, nicotine, and drugs known to cause acute pancreatitis, including marijuana, said Dr. Barkin. In addition, controlling metabolic factors such as obesity, diabetes, and triglycerides can help reduce risk of recurrent episodes in susceptible patients. Several of these factors are also linked to increased risk for progression of acute pancreatitis to chronic pancreatitis.
For patients with biliary pancreatitis, Dr. Barkin noted that cholecystectomy should be performed prior to discharge during the index hospitalization. “In patients who cannot undergo surgery, endoscopic sphincterotomy should be performed to allow spontaneous passage of any stones still in the gallbladder,” he noted.
In addition, patients who have experienced an attack of acute pancreatitis should be screened long-term for development of pancreatic exocrine insufficiency, which may be present in approximately one-quarter of patients following an acute pancreatitis episode, and diabetes, Dr. Barkin said. He cited a population-based study published in the American Journal of Gastroenterology in 2019 in which individuals with postpancreatitis diabetes had significantly higher rates of all-cause mortality, as well as hospitalization for conditions including chronic pulmonary disease, severe renal disease, and infectious disease.
Finally, at the time of discharge, it is essential to evaluate acute pancreatitis patients for risk of readmission, Dr. Barkin said. In addition to severe disease and systemic inflammatory response syndrome at the time of patient discharge, several factors increase the likelihood of readmission including ongoing abdominal pain requiring use of pain medicine, obesity, and inability to tolerate solid food, he noted.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Barkin had no relevant financial conflicts to disclose.
Pancreatitis remains the third most common gastroenterological cause of hospital admission, and staying on top of the latest quality indicators is important for the care and safety of patients, said Jamie S. Barkin, MD, professor of medicine in the division of gastroenterology at the University of Miami, in a virtual presentation at the annual Digestive Diseases: New Advances conference jointly provided by Rutgers and Global Academy for Medical Education.
The basics of treatment have changed, said Dr. Barkin. “A large volume of ringers lactate intravenous fluids given within the first 24 hours of admission, as opposed to normal saline, may decrease the inflammatory response in patients with acute pancreatitis.” The preferred diagnostic method remains clinical evaluation along with use of serum lipase, which is more sensitive than serum amylase (97%) but with similar specificity (99%), and current wisdom does not support the need for an early CT for diagnosis unless there is a diagnostic dilemma.
Early establishment of disease etiology and its therapy is imperative to attempt to prevent recurrent episodes and progression to chronic pancreatitis, Dr. Barkin said. Genetic testing studies suggest that approximately 10% of acute pancreatitis cases are the result of genetic factors, and Dr. Barkin recommended performing genetic testing after a first attack of idiopathic acute pancreatitis, especially in younger patients.
There is an extensive list of medications that may cause acute pancreatitis, according to a recent study published in PLOS One, the most common of which include acetaminophen, amiodarone, azathioprine, and angiotensin-converting enzyme inhibitors, Dr. Barkin said. In addition, acute pancreatitis can be caused by isonicotinic acid hydrazide (INH), cannabis, L-asparaginase, metronidazole, mesalamine, simvastatin, sulindac, sitagliptin, thiazides, tigecycline, trans-retinoic acid, and valproic acid, among others.
Current recommendations for hospital treatment of acute pancreatitis include early large volume fluid replacement and initiation of per-oral nutrition as soon as able to be tolerated, as well as pain control, Dr. Barkin said. In addition, management includes strict glycemic and triglyceride control and performance of cholecystectomy for mild and or moderate biliary pancreatitis or endoscopic retrograde cholangiopancreatography (ERCP) if the patient is not an operative candidate during the same hospital stay.
Current recommendations for the prevention of acute pancreatitis include avoidance of irritants such as alcohol, nicotine, and drugs known to cause acute pancreatitis, including marijuana, said Dr. Barkin. In addition, controlling metabolic factors such as obesity, diabetes, and triglycerides can help reduce risk of recurrent episodes in susceptible patients. Several of these factors are also linked to increased risk for progression of acute pancreatitis to chronic pancreatitis.
For patients with biliary pancreatitis, Dr. Barkin noted that cholecystectomy should be performed prior to discharge during the index hospitalization. “In patients who cannot undergo surgery, endoscopic sphincterotomy should be performed to allow spontaneous passage of any stones still in the gallbladder,” he noted.
In addition, patients who have experienced an attack of acute pancreatitis should be screened long-term for development of pancreatic exocrine insufficiency, which may be present in approximately one-quarter of patients following an acute pancreatitis episode, and diabetes, Dr. Barkin said. He cited a population-based study published in the American Journal of Gastroenterology in 2019 in which individuals with postpancreatitis diabetes had significantly higher rates of all-cause mortality, as well as hospitalization for conditions including chronic pulmonary disease, severe renal disease, and infectious disease.
Finally, at the time of discharge, it is essential to evaluate acute pancreatitis patients for risk of readmission, Dr. Barkin said. In addition to severe disease and systemic inflammatory response syndrome at the time of patient discharge, several factors increase the likelihood of readmission including ongoing abdominal pain requiring use of pain medicine, obesity, and inability to tolerate solid food, he noted.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Barkin had no relevant financial conflicts to disclose.
FROM DIGESTIVE DISEASES: NEW ADVANCES
Novel schizophrenia drugs advance through pipeline
Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.
The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.
Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.
And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.
Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.
“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.
Broad agreement exists that current antipsychotics targeting D2 dopamine and serotonin receptors in schizophrenia leave much to be desired. They’re ineffective for two of the three major symptom categories that define schizophrenia: cognitive impairment and negative symptoms, such as apathy and social withdrawal. And even for the current antipsychotics’ forte – treatment of positive symptoms, including hallucinations and delusions – effectiveness is often only modest to moderate and accompanied by limiting side effects.
KarXT
KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.
He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.
The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.
Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.
“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.
An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.
“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.
As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”
The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.
A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.
“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.
BI 425809
BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.
He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.
The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.
“That’s a very nice but also an unusual finding for a trial of this length,” he observed.
The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.
“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”
A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
Pimavanserin
It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.
At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.
A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
LY500307
Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.
“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.
What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).
The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.
This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.
All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.
“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.
He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.
Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
SOURCE: ECNP 2020, Session S.12.
Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.
The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.
Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.
And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.
Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.
“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.
Broad agreement exists that current antipsychotics targeting D2 dopamine and serotonin receptors in schizophrenia leave much to be desired. They’re ineffective for two of the three major symptom categories that define schizophrenia: cognitive impairment and negative symptoms, such as apathy and social withdrawal. And even for the current antipsychotics’ forte – treatment of positive symptoms, including hallucinations and delusions – effectiveness is often only modest to moderate and accompanied by limiting side effects.
KarXT
KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.
He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.
The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.
Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.
“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.
An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.
“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.
As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”
The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.
A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.
“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.
BI 425809
BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.
He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.
The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.
“That’s a very nice but also an unusual finding for a trial of this length,” he observed.
The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.
“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”
A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
Pimavanserin
It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.
At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.
A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
LY500307
Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.
“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.
What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).
The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.
This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.
All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.
“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.
He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.
Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
SOURCE: ECNP 2020, Session S.12.
Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.
The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.
Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.
And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.
Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.
“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.
Broad agreement exists that current antipsychotics targeting D2 dopamine and serotonin receptors in schizophrenia leave much to be desired. They’re ineffective for two of the three major symptom categories that define schizophrenia: cognitive impairment and negative symptoms, such as apathy and social withdrawal. And even for the current antipsychotics’ forte – treatment of positive symptoms, including hallucinations and delusions – effectiveness is often only modest to moderate and accompanied by limiting side effects.
KarXT
KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.
He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.
The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.
Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.
“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.
An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.
“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.
As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”
The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.
A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.
“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.
BI 425809
BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.
He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.
The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.
“That’s a very nice but also an unusual finding for a trial of this length,” he observed.
The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.
“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”
A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
Pimavanserin
It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.
At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.
A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
LY500307
Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.
“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.
What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).
The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.
This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.
All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.
“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.
He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.
Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
SOURCE: ECNP 2020, Session S.12.
FROM ECNP 2020
Binge eating in ADHD may not be impulsivity-related
The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.
She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.
“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).
She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.
A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.
Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.
On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.
The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.
in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”
Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.
“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.
She reported having no financial conflicts regarding the study, which was supported by university funding.
SOURCE: Martin E. ECNP 2020. Abstr. P.041.
The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.
She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.
“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).
She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.
A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.
Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.
On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.
The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.
in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”
Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.
“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.
She reported having no financial conflicts regarding the study, which was supported by university funding.
SOURCE: Martin E. ECNP 2020. Abstr. P.041.
The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.
She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.
“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).
She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.
A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.
Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.
On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.
The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.
in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”
Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.
“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.
She reported having no financial conflicts regarding the study, which was supported by university funding.
SOURCE: Martin E. ECNP 2020. Abstr. P.041.
FROM ECNP 2020
Address root causes to manage NASH
Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.
“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.
“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.
Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.
Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.
A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.
In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.
Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.
Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.
“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.
Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.
Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.
“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.
Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Help your patients understand their risks for NASH by sharing AGA patient education at http://ow.ly/5AAk30rbK5y.
Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.
“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.
“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.
Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.
Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.
A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.
In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.
Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.
Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.
“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.
Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.
Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.
“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.
Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Help your patients understand their risks for NASH by sharing AGA patient education at http://ow.ly/5AAk30rbK5y.
Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.
“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.
“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.
Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.
Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.
A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.
In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.
Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.
Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.
“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.
Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.
Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.
“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.
Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Help your patients understand their risks for NASH by sharing AGA patient education at http://ow.ly/5AAk30rbK5y.
FROM DIGESTIVE DISEASES: NEW ADVANCES
DAPA-CKD resets eGFR floor for safe SGLT2 inhibitor use
The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.
Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m2, an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.
Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m2.
Using SGLT2 inhibitors when eGFR is as low as 25
“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).
While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”
Other experts not associated with the study agreed.
The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m2, and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”
The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.
Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).
“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
Results show many dapagliflozin benefits
While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.
DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.
The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.
Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.
“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”
DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.
SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.
The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.
Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m2, an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.
Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m2.
Using SGLT2 inhibitors when eGFR is as low as 25
“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).
While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”
Other experts not associated with the study agreed.
The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m2, and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”
The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.
Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).
“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
Results show many dapagliflozin benefits
While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.
DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.
The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.
Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.
“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”
DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.
SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.
The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.
Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m2, an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.
Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m2.
Using SGLT2 inhibitors when eGFR is as low as 25
“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).
While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”
Other experts not associated with the study agreed.
The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m2, and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”
The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.
Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).
“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
Results show many dapagliflozin benefits
While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.
DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.
The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.
Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.
“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”
DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.
SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.
FROM EASD 2020
Suicidality jumped in Israel during spring COVID-19 lockdown
Suicidality appears to have increased sharply in Israel during the initial nationwide lockdown implemented in response to the COVID-19 pandemic, Gil Zalsman, MD, MHA, reported at the virtual congress of the European College of Neuropsychopharmacology.
He presented highlights from a soon-to-be-published analysis of the content of online chat sessions fielded by a national crisis hotline (Sahar.org.il) during the first 6 months of 2020, compared with January through June 2019, in the pre-COVID-19 era.
It’s far too early to say whether actual deaths tied to suicide rose significantly during the spring lockdown, since medical examiners often take a long time before ruling suicide as cause of death. But this much is clear: The number of suicide-related chat sessions recorded at the volunteer-staffed national hotline during April 2020 was two-and-a-half times greater than in April 2019, and threefold greater in May 2020 than a year earlier, according to Dr. Zalsman, professor of psychiatry at Tel Aviv University and director of the Geha Mental Health Center in Petach Tikva, Israel, where he also directs an adolescent day unit.
The proportion of chats handled at the crisis hotline, many of them concerned with the standard topics – relationships, stress, fears, anxiety, and other non–suicide-related issues – was 48% greater in the first half of 2020, compared with a year earlier. Indeed, the pandemic is putting an enormous strain on crisis hotlines the world over.
“Everybody who is working hotlines knows that they’re falling apart. There are too many calls, too many chats. They need to multiply their volunteers,” Dr. Zalsman said.
The number of suicide-related online chats jumped the week of March 12, when schools closed across Israel and a partial lockdown began. The peak in suicide-related chats occurred beginning the week of April 17, when the forced total lockdown was declared.
“Everything was closed. You couldn’t go out or the police would arrest you,” Dr. Zalsman recalled.
The suicide-related chat count started to drop off in mid-May, when schools reopened, and continued to decline through the end of June.
Only a small percentage of suicide-related chats were deemed by crisis hotline volunteers and their supervisors to be truly life-threatening situations necessitating a call to the police. But the number of such exchanges was significantly greater in April and May 2020 than in January and February, or in April and May 2019.
Use of the crisis hotline is ordinarily skewed toward tech-savvy young people, or as Dr. Zalsman called them, “kids who live inside their computers.” He note that the psychological impact of the pandemic on children and adolescents is largely unexplored research territory to date.
“ You can kill your grandfather by coughing,” Dr. Zalsman said.
Older people also seek help
A finding that he and his coinvestigators didn’t anticipate was the significantly increased use of the service by individuals aged 65 and older during the pandemic. This underscores the increased vulnerability of older people, which stems in part from their heightened risk for severe infection and consequent need for prolonged physical isolation, he said.
The conventional thinking among suicidologists is that during times of crisis – wars, natural disasters – suicidality plunges, then rises quickly afterward.
“People withhold themselves. When there’s a big danger from outside they ignore the danger from inside. And once the danger from outside is gone, they’re left with emptiness, unemployment, economic crisis, and they start” taking their own lives, Dr. Zalsman explained. He expects suicidality to increase after the pandemic, or as the Israeli crisis hotline data suggest, perhaps even during it, for multiple reasons. Patients with preexisting psychiatric disorders are often going untreated. The prolonged physical isolation causes emotional difficulties for some people, especially when accompanied by social isolation and loneliness. There is grief over the loss of friends and relatives because of COVID-19. And there is an expectation of looming economic hardship, with mounting unemployment and bankruptcies.
Dr. Zalsman reported having no financial conflicts regarding his study, conducted free of commercial support.
SOURCE: Zalsman G. ECNP 2020, Session TP.06.
Suicidality appears to have increased sharply in Israel during the initial nationwide lockdown implemented in response to the COVID-19 pandemic, Gil Zalsman, MD, MHA, reported at the virtual congress of the European College of Neuropsychopharmacology.
He presented highlights from a soon-to-be-published analysis of the content of online chat sessions fielded by a national crisis hotline (Sahar.org.il) during the first 6 months of 2020, compared with January through June 2019, in the pre-COVID-19 era.
It’s far too early to say whether actual deaths tied to suicide rose significantly during the spring lockdown, since medical examiners often take a long time before ruling suicide as cause of death. But this much is clear: The number of suicide-related chat sessions recorded at the volunteer-staffed national hotline during April 2020 was two-and-a-half times greater than in April 2019, and threefold greater in May 2020 than a year earlier, according to Dr. Zalsman, professor of psychiatry at Tel Aviv University and director of the Geha Mental Health Center in Petach Tikva, Israel, where he also directs an adolescent day unit.
The proportion of chats handled at the crisis hotline, many of them concerned with the standard topics – relationships, stress, fears, anxiety, and other non–suicide-related issues – was 48% greater in the first half of 2020, compared with a year earlier. Indeed, the pandemic is putting an enormous strain on crisis hotlines the world over.
“Everybody who is working hotlines knows that they’re falling apart. There are too many calls, too many chats. They need to multiply their volunteers,” Dr. Zalsman said.
The number of suicide-related online chats jumped the week of March 12, when schools closed across Israel and a partial lockdown began. The peak in suicide-related chats occurred beginning the week of April 17, when the forced total lockdown was declared.
“Everything was closed. You couldn’t go out or the police would arrest you,” Dr. Zalsman recalled.
The suicide-related chat count started to drop off in mid-May, when schools reopened, and continued to decline through the end of June.
Only a small percentage of suicide-related chats were deemed by crisis hotline volunteers and their supervisors to be truly life-threatening situations necessitating a call to the police. But the number of such exchanges was significantly greater in April and May 2020 than in January and February, or in April and May 2019.
Use of the crisis hotline is ordinarily skewed toward tech-savvy young people, or as Dr. Zalsman called them, “kids who live inside their computers.” He note that the psychological impact of the pandemic on children and adolescents is largely unexplored research territory to date.
“ You can kill your grandfather by coughing,” Dr. Zalsman said.
Older people also seek help
A finding that he and his coinvestigators didn’t anticipate was the significantly increased use of the service by individuals aged 65 and older during the pandemic. This underscores the increased vulnerability of older people, which stems in part from their heightened risk for severe infection and consequent need for prolonged physical isolation, he said.
The conventional thinking among suicidologists is that during times of crisis – wars, natural disasters – suicidality plunges, then rises quickly afterward.
“People withhold themselves. When there’s a big danger from outside they ignore the danger from inside. And once the danger from outside is gone, they’re left with emptiness, unemployment, economic crisis, and they start” taking their own lives, Dr. Zalsman explained. He expects suicidality to increase after the pandemic, or as the Israeli crisis hotline data suggest, perhaps even during it, for multiple reasons. Patients with preexisting psychiatric disorders are often going untreated. The prolonged physical isolation causes emotional difficulties for some people, especially when accompanied by social isolation and loneliness. There is grief over the loss of friends and relatives because of COVID-19. And there is an expectation of looming economic hardship, with mounting unemployment and bankruptcies.
Dr. Zalsman reported having no financial conflicts regarding his study, conducted free of commercial support.
SOURCE: Zalsman G. ECNP 2020, Session TP.06.
Suicidality appears to have increased sharply in Israel during the initial nationwide lockdown implemented in response to the COVID-19 pandemic, Gil Zalsman, MD, MHA, reported at the virtual congress of the European College of Neuropsychopharmacology.
He presented highlights from a soon-to-be-published analysis of the content of online chat sessions fielded by a national crisis hotline (Sahar.org.il) during the first 6 months of 2020, compared with January through June 2019, in the pre-COVID-19 era.
It’s far too early to say whether actual deaths tied to suicide rose significantly during the spring lockdown, since medical examiners often take a long time before ruling suicide as cause of death. But this much is clear: The number of suicide-related chat sessions recorded at the volunteer-staffed national hotline during April 2020 was two-and-a-half times greater than in April 2019, and threefold greater in May 2020 than a year earlier, according to Dr. Zalsman, professor of psychiatry at Tel Aviv University and director of the Geha Mental Health Center in Petach Tikva, Israel, where he also directs an adolescent day unit.
The proportion of chats handled at the crisis hotline, many of them concerned with the standard topics – relationships, stress, fears, anxiety, and other non–suicide-related issues – was 48% greater in the first half of 2020, compared with a year earlier. Indeed, the pandemic is putting an enormous strain on crisis hotlines the world over.
“Everybody who is working hotlines knows that they’re falling apart. There are too many calls, too many chats. They need to multiply their volunteers,” Dr. Zalsman said.
The number of suicide-related online chats jumped the week of March 12, when schools closed across Israel and a partial lockdown began. The peak in suicide-related chats occurred beginning the week of April 17, when the forced total lockdown was declared.
“Everything was closed. You couldn’t go out or the police would arrest you,” Dr. Zalsman recalled.
The suicide-related chat count started to drop off in mid-May, when schools reopened, and continued to decline through the end of June.
Only a small percentage of suicide-related chats were deemed by crisis hotline volunteers and their supervisors to be truly life-threatening situations necessitating a call to the police. But the number of such exchanges was significantly greater in April and May 2020 than in January and February, or in April and May 2019.
Use of the crisis hotline is ordinarily skewed toward tech-savvy young people, or as Dr. Zalsman called them, “kids who live inside their computers.” He note that the psychological impact of the pandemic on children and adolescents is largely unexplored research territory to date.
“ You can kill your grandfather by coughing,” Dr. Zalsman said.
Older people also seek help
A finding that he and his coinvestigators didn’t anticipate was the significantly increased use of the service by individuals aged 65 and older during the pandemic. This underscores the increased vulnerability of older people, which stems in part from their heightened risk for severe infection and consequent need for prolonged physical isolation, he said.
The conventional thinking among suicidologists is that during times of crisis – wars, natural disasters – suicidality plunges, then rises quickly afterward.
“People withhold themselves. When there’s a big danger from outside they ignore the danger from inside. And once the danger from outside is gone, they’re left with emptiness, unemployment, economic crisis, and they start” taking their own lives, Dr. Zalsman explained. He expects suicidality to increase after the pandemic, or as the Israeli crisis hotline data suggest, perhaps even during it, for multiple reasons. Patients with preexisting psychiatric disorders are often going untreated. The prolonged physical isolation causes emotional difficulties for some people, especially when accompanied by social isolation and loneliness. There is grief over the loss of friends and relatives because of COVID-19. And there is an expectation of looming economic hardship, with mounting unemployment and bankruptcies.
Dr. Zalsman reported having no financial conflicts regarding his study, conducted free of commercial support.
SOURCE: Zalsman G. ECNP 2020, Session TP.06.
FROM ECNP 2020
Lower rituximab doses may be as effective, safer in MS
Further data suggesting that (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”
Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.
“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.
The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.
In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).
Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.
Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.
The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).
Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.
New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.
Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.
Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.
A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.
Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.
“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.
She reported that her hospital has been using rituximab extensively in MS.
“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”
While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”
Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.
“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.
“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”
Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”
Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”
Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
A version of this article originally appeared on Medscape.com.
Further data suggesting that (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”
Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.
“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.
The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.
In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).
Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.
Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.
The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).
Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.
New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.
Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.
Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.
A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.
Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.
“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.
She reported that her hospital has been using rituximab extensively in MS.
“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”
While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”
Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.
“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.
“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”
Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”
Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”
Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
A version of this article originally appeared on Medscape.com.
Further data suggesting that (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”
Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.
“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.
The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.
In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).
Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.
Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.
The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).
Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.
New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.
Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.
Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.
A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.
Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.
“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.
She reported that her hospital has been using rituximab extensively in MS.
“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”
While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”
Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.
“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.
“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”
Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”
Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”
Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
A version of this article originally appeared on Medscape.com.
FROM MSVIRTUAL2020
Prior autoimmunity does not predict adverse events of alemtuzumab
a new study has shown.
These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.
But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.
To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.
Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.
Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.
In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.
In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.
There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.
He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.
“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.
“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.
“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
Risk stratification
Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.
“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.
With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.
“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.
On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”
The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new study has shown.
These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.
But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.
To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.
Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.
Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.
In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.
In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.
There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.
He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.
“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.
“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.
“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
Risk stratification
Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.
“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.
With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.
“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.
On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”
The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new study has shown.
These latest data were reported by Alasdair J. Coles, MD, University of Cambridge (England), at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.
Dr. Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.
But as postmarketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand this better, regulators have suggested that the presence of non–multiple sclerosis (MS) autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.
To investigate if this was the case, Dr. Coles and colleagues analyzed data on 1,216 patients who received alemtuzumab in the clinical development program. Of these, 96 had preexisting non-MS autoimmunity.
Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) preexisting autoimmunity.
Similar percentages of patients with versus without preexisting autoimmunity had two or more new autoimmune events (5.2% vs. 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.
In addition, treatment-emergent thyroid autoimmunity after the first alemtuzumab course was not associated with subsequent nonthyroid autoimmunity after the second course. Similarly, thyroid autoimmunity after the second course did not predict non-thyroid autoimmunity after the third course.
In another analysis of the incidence of serious autoimmune events from postmarketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in 9 patients.
There was “no hint at all” that baseline thyroid disorders or postalemtuzumab thyroid disorders are associated with increased risk of these serious autoimmune adverse events, Dr. Coles said.
He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.
“From two separate data sources – phase 2/3 trials populations combined and postmarketing data – there is no evidence to support the hypothesis that preexisting non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described, nor does thyroid autoimmunity following the use of alemtuzumab,” Dr. Coles stated.
“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.
“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well-understood thyroid autoimmunity and the very unlikely, rare, but serious autoimmune disease,” he concluded.
Risk stratification
Commenting on the presentation, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that, whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.
“We like to identify those at higher risk [and perhaps not use the therapy] and those at lower risk [and perhaps consider more likely the use of that therapy],” he said.
With regard to alemtuzumab, Dr. Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.
“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.
On Dr. Coles’ view of alemtuzumab as a “reasonable” treatment option, Dr. Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”
The current work was supported by Sanofi and Bayer HealthCare. Dr. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Dr. Fox has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM MSVIRTUAL2020
Reassuring rheumatic disease patients on value of bisphosphonates
“When we think about bisphosphonates, we have to think about whether they are good players or bad players,” Marcy B. Bolster, MD, of Harvard Medical School, Boston, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Although bisphosphonates are a first-line treatment for many patients to reduce fracture risk, rheumatology patients have distinct concerns about these medications, said Dr. Bolster, who is director of the Rheumatology Fellowship Training Program at Massachusetts General Hospital, Boston, and medical lead for the Fracture Liaison Service there.
She shared her insights on four questions most often asked by patients in her practice:
How long do I need to take this medication?
When discussing bisphosphonates with a patient for the first time, “I typically start with the benefits, and include the risks,” she said. “Then I outline my plans for treatment, which would include treatment duration.”
Setting expectations with the patient about planned duration of therapy, reviewing risks and benefits, and preparing to be flexible if changes are needed can help relieve patients’ concerns, she said.
For example, in a hypothetical case of a 69-year-old woman with a 17% chance of a major osteoporotic fracture and 3.8% chance of hip fracture in the next 10 years based on FRAX scores, Dr. Bolster said she would treat with alendronate or zoledronic acid.
Duration must be a clinical decision individualized to the patient, she noted. Research studies support that some patients benefit from a longer duration of therapy. In the Fracture Intervention Trial (FIT) Long-Term Extension, which included 1,099 women, the risk of clinical vertebral fractures significantly declined with 10 years of alendronate treatment, compared with 5 years of treatment, she said.
In the HORIZON trial of 1,233 postmenopausal women, the risk of new morphometric vertebral fractures was significantly lower in those treated with IV zoledronic acid for 6 years versus those treated for 3 years. These studies support that patients at particularly high risk for vertebral fractures may benefit from a longer duration of bisphosphonate therapy, she said.
What should I know about infusion side effects?
Infusion side effects remain a concern, and the acute phase reaction of zoledronic acid occurs in about 30% of patients, but most of these are mild and not recurring, Dr. Bolster said. “I tell patients that 90% report mild to moderate infusion side effects, and that it usually occurs only with the first infusion,” she noted.
To potentially prevent an acute-phase reaction, Dr. Bolster has advised patients to take acetaminophen prior to infusion. “I would tend to recommend acetaminophen over NSAIDs to avoid gastric and renal toxicities,” she said.
“Determining the risks of atypical femoral fractures are challenging” but are another potential side effect that worries patients, she said. An atypical femoral fracture (AFF) is a femur fracture in the proximal third of the shaft, she said.
AFF may occur in patients with osteoporosis even in the absence of bisphosphonate use, Dr. Bolster noted. However, AFF “may occur at increased frequency in those patients with osteoporosis and prolonged bisphosphonate use,” she said. AFF is rare overall, and known risk factors include Asian race (in North America), as well as femoral bowing and glucocorticoid use, she said.
A 2019 meta-analysis favored fracture prevention benefits over potential risk associated with bisphosphonate use. Predicting the risk of AFF remains difficult given several factors, including the low incidence of AFF, the unavailability of radiographs in all studies, not accounting for potential confounding by indication in some studies, and lack of adjustment for low bone mineral density or fracture risk, she added.
Osteonecrosis of the jaw has been linked to bisphosphonate use, and some patients ask about it, Dr. Bolster said. Current data show an incidence of 1 in 10,000 to 1 in 100,000 in patients with osteoporosis, while the incidence in the general population is 1 in 100,000, she noted. The highest risk is associated with use of IV bisphosphonates, although it does occur in patients on oral bisphosphonates and denosumab (Prolia), she added. Given the relatively low risk, the American Dental Association states that there is “no need to discontinue bisphosphonates prior to procedures.” Based on current evidence, bisphosphonate treatment outweighs the low risk of medication-related osteonecrosis of the jaw in patients in need of osteoporosis treatment because of the high risk of fragility fractures in the osteoporosis population, she emphasized.
When will I need another dual x-ray absorptiometry scan?
Osteoporosis develops in fewer than 10% of older postmenopausal women using a 15-year screening interval for those with normal bone mineral density or mild osteopenia at an initial scan, with T-scores of –1.49 or higher, she noted. Therefore, the need for repeat dual x-ray absorptiometry (DXA) scans should be individualized, so some patients with normal bone density or osteopenia and few comorbidities and risk factors for osteoporosis may not need frequent DXA scans, she added.
Although little evidence exists to specifically demonstrate the value of monitoring bone mineral density during a 5-year drug treatment period, as is noted by the American College of Physicians 2017 clinical practice guideline published in Annals of Internal Medicine, Dr. Bolster said that a DXA scan showing loss of bone mineral density during treatment could indicate incorrect drug use or noncompliance, or a secondary cause for bone loss that may otherwise go unnoticed. For IV zoledronic acid in particular, a DXA scan at 3-4 years can determine whether a drug holiday is warranted, or for patients with severe osteoporosis, whether another 3 years of treatment is necessary. She suggested considering a DXA scan at 2-3 years with alendronate and at 3-4 years with IV zoledronic acid.
Will I need a new medication if I fracture while on treatment?
For patients who ask whether to change medications following a new fracture, Dr. Bolster said it is important to evaluate the patient’s compliance with the treatment regimen and also consider the presence of secondary causes of bone loss. Consideration can be given to keeping the patient on the same regimen because osteoporosis treatment regimens have demonstrated a 50%-70% fracture-risk reduction so they do not prevent all fractures, she said. “It is therefore reasonable, after confirming compliance and ruling out secondary causes of bone loss, to keep a patient on the same regimen following a fracture. For patients using denosumab, there is an increased risk of rapid bone loss and sustaining multiple vertebral fracture with missed doses or discontinuation,” she said.
It is important to evaluate patients who fracture while on therapy for secondary causes of bone loss, assess compliance, and consider strategies such as modifying the route of administration, seeking a different mechanism of action, or continuing on the same regimen, Dr. Bolster noted.
Dr. Bolster disclosed participation in clinical trials for Corbus, Cumberland, and Genentech, as well as research grants from the Rheumatology Research Foundation. She also disclosed serving on advisory boards for Gilead Sciences and Clinical Learning Designs, serving on the American College of Rheumatology’s Committee on Marketing and Communications, and holding investments in Johnson & Johnson.
Global Academy for Medical Education and this news organization are owned by the same parent company.
“When we think about bisphosphonates, we have to think about whether they are good players or bad players,” Marcy B. Bolster, MD, of Harvard Medical School, Boston, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Although bisphosphonates are a first-line treatment for many patients to reduce fracture risk, rheumatology patients have distinct concerns about these medications, said Dr. Bolster, who is director of the Rheumatology Fellowship Training Program at Massachusetts General Hospital, Boston, and medical lead for the Fracture Liaison Service there.
She shared her insights on four questions most often asked by patients in her practice:
How long do I need to take this medication?
When discussing bisphosphonates with a patient for the first time, “I typically start with the benefits, and include the risks,” she said. “Then I outline my plans for treatment, which would include treatment duration.”
Setting expectations with the patient about planned duration of therapy, reviewing risks and benefits, and preparing to be flexible if changes are needed can help relieve patients’ concerns, she said.
For example, in a hypothetical case of a 69-year-old woman with a 17% chance of a major osteoporotic fracture and 3.8% chance of hip fracture in the next 10 years based on FRAX scores, Dr. Bolster said she would treat with alendronate or zoledronic acid.
Duration must be a clinical decision individualized to the patient, she noted. Research studies support that some patients benefit from a longer duration of therapy. In the Fracture Intervention Trial (FIT) Long-Term Extension, which included 1,099 women, the risk of clinical vertebral fractures significantly declined with 10 years of alendronate treatment, compared with 5 years of treatment, she said.
In the HORIZON trial of 1,233 postmenopausal women, the risk of new morphometric vertebral fractures was significantly lower in those treated with IV zoledronic acid for 6 years versus those treated for 3 years. These studies support that patients at particularly high risk for vertebral fractures may benefit from a longer duration of bisphosphonate therapy, she said.
What should I know about infusion side effects?
Infusion side effects remain a concern, and the acute phase reaction of zoledronic acid occurs in about 30% of patients, but most of these are mild and not recurring, Dr. Bolster said. “I tell patients that 90% report mild to moderate infusion side effects, and that it usually occurs only with the first infusion,” she noted.
To potentially prevent an acute-phase reaction, Dr. Bolster has advised patients to take acetaminophen prior to infusion. “I would tend to recommend acetaminophen over NSAIDs to avoid gastric and renal toxicities,” she said.
“Determining the risks of atypical femoral fractures are challenging” but are another potential side effect that worries patients, she said. An atypical femoral fracture (AFF) is a femur fracture in the proximal third of the shaft, she said.
AFF may occur in patients with osteoporosis even in the absence of bisphosphonate use, Dr. Bolster noted. However, AFF “may occur at increased frequency in those patients with osteoporosis and prolonged bisphosphonate use,” she said. AFF is rare overall, and known risk factors include Asian race (in North America), as well as femoral bowing and glucocorticoid use, she said.
A 2019 meta-analysis favored fracture prevention benefits over potential risk associated with bisphosphonate use. Predicting the risk of AFF remains difficult given several factors, including the low incidence of AFF, the unavailability of radiographs in all studies, not accounting for potential confounding by indication in some studies, and lack of adjustment for low bone mineral density or fracture risk, she added.
Osteonecrosis of the jaw has been linked to bisphosphonate use, and some patients ask about it, Dr. Bolster said. Current data show an incidence of 1 in 10,000 to 1 in 100,000 in patients with osteoporosis, while the incidence in the general population is 1 in 100,000, she noted. The highest risk is associated with use of IV bisphosphonates, although it does occur in patients on oral bisphosphonates and denosumab (Prolia), she added. Given the relatively low risk, the American Dental Association states that there is “no need to discontinue bisphosphonates prior to procedures.” Based on current evidence, bisphosphonate treatment outweighs the low risk of medication-related osteonecrosis of the jaw in patients in need of osteoporosis treatment because of the high risk of fragility fractures in the osteoporosis population, she emphasized.
When will I need another dual x-ray absorptiometry scan?
Osteoporosis develops in fewer than 10% of older postmenopausal women using a 15-year screening interval for those with normal bone mineral density or mild osteopenia at an initial scan, with T-scores of –1.49 or higher, she noted. Therefore, the need for repeat dual x-ray absorptiometry (DXA) scans should be individualized, so some patients with normal bone density or osteopenia and few comorbidities and risk factors for osteoporosis may not need frequent DXA scans, she added.
Although little evidence exists to specifically demonstrate the value of monitoring bone mineral density during a 5-year drug treatment period, as is noted by the American College of Physicians 2017 clinical practice guideline published in Annals of Internal Medicine, Dr. Bolster said that a DXA scan showing loss of bone mineral density during treatment could indicate incorrect drug use or noncompliance, or a secondary cause for bone loss that may otherwise go unnoticed. For IV zoledronic acid in particular, a DXA scan at 3-4 years can determine whether a drug holiday is warranted, or for patients with severe osteoporosis, whether another 3 years of treatment is necessary. She suggested considering a DXA scan at 2-3 years with alendronate and at 3-4 years with IV zoledronic acid.
Will I need a new medication if I fracture while on treatment?
For patients who ask whether to change medications following a new fracture, Dr. Bolster said it is important to evaluate the patient’s compliance with the treatment regimen and also consider the presence of secondary causes of bone loss. Consideration can be given to keeping the patient on the same regimen because osteoporosis treatment regimens have demonstrated a 50%-70% fracture-risk reduction so they do not prevent all fractures, she said. “It is therefore reasonable, after confirming compliance and ruling out secondary causes of bone loss, to keep a patient on the same regimen following a fracture. For patients using denosumab, there is an increased risk of rapid bone loss and sustaining multiple vertebral fracture with missed doses or discontinuation,” she said.
It is important to evaluate patients who fracture while on therapy for secondary causes of bone loss, assess compliance, and consider strategies such as modifying the route of administration, seeking a different mechanism of action, or continuing on the same regimen, Dr. Bolster noted.
Dr. Bolster disclosed participation in clinical trials for Corbus, Cumberland, and Genentech, as well as research grants from the Rheumatology Research Foundation. She also disclosed serving on advisory boards for Gilead Sciences and Clinical Learning Designs, serving on the American College of Rheumatology’s Committee on Marketing and Communications, and holding investments in Johnson & Johnson.
Global Academy for Medical Education and this news organization are owned by the same parent company.
“When we think about bisphosphonates, we have to think about whether they are good players or bad players,” Marcy B. Bolster, MD, of Harvard Medical School, Boston, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Although bisphosphonates are a first-line treatment for many patients to reduce fracture risk, rheumatology patients have distinct concerns about these medications, said Dr. Bolster, who is director of the Rheumatology Fellowship Training Program at Massachusetts General Hospital, Boston, and medical lead for the Fracture Liaison Service there.
She shared her insights on four questions most often asked by patients in her practice:
How long do I need to take this medication?
When discussing bisphosphonates with a patient for the first time, “I typically start with the benefits, and include the risks,” she said. “Then I outline my plans for treatment, which would include treatment duration.”
Setting expectations with the patient about planned duration of therapy, reviewing risks and benefits, and preparing to be flexible if changes are needed can help relieve patients’ concerns, she said.
For example, in a hypothetical case of a 69-year-old woman with a 17% chance of a major osteoporotic fracture and 3.8% chance of hip fracture in the next 10 years based on FRAX scores, Dr. Bolster said she would treat with alendronate or zoledronic acid.
Duration must be a clinical decision individualized to the patient, she noted. Research studies support that some patients benefit from a longer duration of therapy. In the Fracture Intervention Trial (FIT) Long-Term Extension, which included 1,099 women, the risk of clinical vertebral fractures significantly declined with 10 years of alendronate treatment, compared with 5 years of treatment, she said.
In the HORIZON trial of 1,233 postmenopausal women, the risk of new morphometric vertebral fractures was significantly lower in those treated with IV zoledronic acid for 6 years versus those treated for 3 years. These studies support that patients at particularly high risk for vertebral fractures may benefit from a longer duration of bisphosphonate therapy, she said.
What should I know about infusion side effects?
Infusion side effects remain a concern, and the acute phase reaction of zoledronic acid occurs in about 30% of patients, but most of these are mild and not recurring, Dr. Bolster said. “I tell patients that 90% report mild to moderate infusion side effects, and that it usually occurs only with the first infusion,” she noted.
To potentially prevent an acute-phase reaction, Dr. Bolster has advised patients to take acetaminophen prior to infusion. “I would tend to recommend acetaminophen over NSAIDs to avoid gastric and renal toxicities,” she said.
“Determining the risks of atypical femoral fractures are challenging” but are another potential side effect that worries patients, she said. An atypical femoral fracture (AFF) is a femur fracture in the proximal third of the shaft, she said.
AFF may occur in patients with osteoporosis even in the absence of bisphosphonate use, Dr. Bolster noted. However, AFF “may occur at increased frequency in those patients with osteoporosis and prolonged bisphosphonate use,” she said. AFF is rare overall, and known risk factors include Asian race (in North America), as well as femoral bowing and glucocorticoid use, she said.
A 2019 meta-analysis favored fracture prevention benefits over potential risk associated with bisphosphonate use. Predicting the risk of AFF remains difficult given several factors, including the low incidence of AFF, the unavailability of radiographs in all studies, not accounting for potential confounding by indication in some studies, and lack of adjustment for low bone mineral density or fracture risk, she added.
Osteonecrosis of the jaw has been linked to bisphosphonate use, and some patients ask about it, Dr. Bolster said. Current data show an incidence of 1 in 10,000 to 1 in 100,000 in patients with osteoporosis, while the incidence in the general population is 1 in 100,000, she noted. The highest risk is associated with use of IV bisphosphonates, although it does occur in patients on oral bisphosphonates and denosumab (Prolia), she added. Given the relatively low risk, the American Dental Association states that there is “no need to discontinue bisphosphonates prior to procedures.” Based on current evidence, bisphosphonate treatment outweighs the low risk of medication-related osteonecrosis of the jaw in patients in need of osteoporosis treatment because of the high risk of fragility fractures in the osteoporosis population, she emphasized.
When will I need another dual x-ray absorptiometry scan?
Osteoporosis develops in fewer than 10% of older postmenopausal women using a 15-year screening interval for those with normal bone mineral density or mild osteopenia at an initial scan, with T-scores of –1.49 or higher, she noted. Therefore, the need for repeat dual x-ray absorptiometry (DXA) scans should be individualized, so some patients with normal bone density or osteopenia and few comorbidities and risk factors for osteoporosis may not need frequent DXA scans, she added.
Although little evidence exists to specifically demonstrate the value of monitoring bone mineral density during a 5-year drug treatment period, as is noted by the American College of Physicians 2017 clinical practice guideline published in Annals of Internal Medicine, Dr. Bolster said that a DXA scan showing loss of bone mineral density during treatment could indicate incorrect drug use or noncompliance, or a secondary cause for bone loss that may otherwise go unnoticed. For IV zoledronic acid in particular, a DXA scan at 3-4 years can determine whether a drug holiday is warranted, or for patients with severe osteoporosis, whether another 3 years of treatment is necessary. She suggested considering a DXA scan at 2-3 years with alendronate and at 3-4 years with IV zoledronic acid.
Will I need a new medication if I fracture while on treatment?
For patients who ask whether to change medications following a new fracture, Dr. Bolster said it is important to evaluate the patient’s compliance with the treatment regimen and also consider the presence of secondary causes of bone loss. Consideration can be given to keeping the patient on the same regimen because osteoporosis treatment regimens have demonstrated a 50%-70% fracture-risk reduction so they do not prevent all fractures, she said. “It is therefore reasonable, after confirming compliance and ruling out secondary causes of bone loss, to keep a patient on the same regimen following a fracture. For patients using denosumab, there is an increased risk of rapid bone loss and sustaining multiple vertebral fracture with missed doses or discontinuation,” she said.
It is important to evaluate patients who fracture while on therapy for secondary causes of bone loss, assess compliance, and consider strategies such as modifying the route of administration, seeking a different mechanism of action, or continuing on the same regimen, Dr. Bolster noted.
Dr. Bolster disclosed participation in clinical trials for Corbus, Cumberland, and Genentech, as well as research grants from the Rheumatology Research Foundation. She also disclosed serving on advisory boards for Gilead Sciences and Clinical Learning Designs, serving on the American College of Rheumatology’s Committee on Marketing and Communications, and holding investments in Johnson & Johnson.
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FROM PRD 2020