Conference Coverage

SAN FRANCISCO – A trio of psychiatrists urged colleagues at the annual meeting of the American Psychiatric Association to embrace the venerable antipsychotic clozapine in patients with treatment-resistant schizophrenia. They cautioned that clinicians may overestimate the true risk of the adverse effect of neutropenia in minority populations.

“Although clozapine is known to be a life-improving and even potentially lifesaving treatment, it remains underutilized in the U.S.,” said Claire C. Holderness, MD, a psychiatrist at Columbia University Irving Medical Center, New York. “It’s been estimated that between 35% and 40% of all patients with schizophrenia should be considered for a clozapine trial. However, only 4%-5% of patients with schizophrenia in the U.S. have ever received clozapine. This is in sharp contrast to other industrialized countries where approximately 20% or more of patients with schizophrenia are treated with clozapine.”

According to Dr. Holderness, research has shown that clozapine is even less likely to be prescribed to racial and ethnic minorities. A 2022 systematic review, for example, found that Black patients in the United States had between one-third and two-thirds the odds of being treated with the drug, compared with White patients after adjustment for potential confounders such as demographics. Hispanic/Latino patients were also less likely than Whites to be prescribed the drug.

As Dr. Holderness put it, the drug “been shown to be more effective in treatment-resistant schizophrenia than any other antipsychotic medication. Clozapine is also the most cost-effective treatment for treatment-resistant schizophrenia.” So why does this disparity exist despite clozapine’s benefits?

A 2018 systematic review of barriers to the drug’s usage identified several factors: “mandatory blood testing, fear of serious side-effects and lack of adherence by the patients, difficulty in identifying suitable patients, service fragmentation, and inadequate training in or exposure to using clozapine.” A 2016 British study, meanwhile, looked at the reasons that 45% of 316 patients stopped clozapine before 2 years. More than half of these patients stopped because of adverse effects.
 

Risk of neutropenia

At the APA presentation, psychiatrist Laura Clarke, MD, also of Columbia University Irving Medical Center, noted that there’s concern about one adverse effect in particular: neutropenia, or an abnormally low white blood cell count. Clozapine, she said, has a boxed warning about severe neutropenia that can lead to death.

However, she cautioned that white blood cell counts can be misleading. Some people in non-White ethnic groups have a condition known as benign ethnic neutropenia: their white blood cell counts are abnormal by the standards of people of European heritage, but they’re otherwise healthy. “These individuals do not show an increased risk of infections, and their response to infection is similar to those without them,” she said.

As many as 25%-50% of people of African ancestry may have benign ethnic neutropenia, making their blood levels appear abnormally low. Others with higher levels of the condition include certain Middle Eastern ethnicities and other ethnic groups with darker skin.

In these patents, “clinicians may avoid prescribing clozapine out of the mistaken concern that it can worsen neutropenia,” Dr. Clarke said. In fact, benign ethnic neutropenia “does not increase the risk of clozapine-induced severe neutropenia.”

Dr. Clarke highlighted drug use guidelines from the Clozapine Risk Evaluation and Mitigation Strategy, a Food and Drug Administration–mandated safety program designed to prevent severe neutropenia in patients taking clozapine. The guidelines note that the recommended absolute neutrophil count monitoring algorithm differs when patients are diagnosed with benign ethnic neutropenia.

T. Scott Stroup, MD, MPH, a psychiatrist at Columbia University, New York, urged his colleagues to consider clozapine early on in treatment-resistant schizophrenia. “Don’t go through three, four, or five antipsychotics. Even after trying two, I’d encourage people to [try clozapine].”

However, he acknowledged that “not everyone believes that. Many of my colleagues think that, before you try clozapine, you should have a trial of long-acting injectable medications to rule out pseudo–treatment resistance. I don’t totally agree with that, but I’ve more or less lost that battle,” he added.

In the big picture, Dr. Stroup said, clozapine “is good when other things aren’t working efficacy wise.”

Dr. Holderness and Dr. Clarke have no disclosures. Dr. Stroup discloses grants from the National Institutes of Health and royalties from APA Publishing and UpToDate.

SAN FRANCISCO – A trio of psychiatrists urged colleagues at the annual meeting of the American Psychiatric Association to embrace the venerable antipsychotic clozapine in patients with treatment-resistant schizophrenia. They cautioned that clinicians may overestimate the true risk of the adverse effect of neutropenia in minority populations.

“Although clozapine is known to be a life-improving and even potentially lifesaving treatment, it remains underutilized in the U.S.,” said Claire C. Holderness, MD, a psychiatrist at Columbia University Irving Medical Center, New York. “It’s been estimated that between 35% and 40% of all patients with schizophrenia should be considered for a clozapine trial. However, only 4%-5% of patients with schizophrenia in the U.S. have ever received clozapine. This is in sharp contrast to other industrialized countries where approximately 20% or more of patients with schizophrenia are treated with clozapine.”

According to Dr. Holderness, research has shown that clozapine is even less likely to be prescribed to racial and ethnic minorities. A 2022 systematic review, for example, found that Black patients in the United States had between one-third and two-thirds the odds of being treated with the drug, compared with White patients after adjustment for potential confounders such as demographics. Hispanic/Latino patients were also less likely than Whites to be prescribed the drug.

As Dr. Holderness put it, the drug “been shown to be more effective in treatment-resistant schizophrenia than any other antipsychotic medication. Clozapine is also the most cost-effective treatment for treatment-resistant schizophrenia.” So why does this disparity exist despite clozapine’s benefits?

A 2018 systematic review of barriers to the drug’s usage identified several factors: “mandatory blood testing, fear of serious side-effects and lack of adherence by the patients, difficulty in identifying suitable patients, service fragmentation, and inadequate training in or exposure to using clozapine.” A 2016 British study, meanwhile, looked at the reasons that 45% of 316 patients stopped clozapine before 2 years. More than half of these patients stopped because of adverse effects.
 

Risk of neutropenia

At the APA presentation, psychiatrist Laura Clarke, MD, also of Columbia University Irving Medical Center, noted that there’s concern about one adverse effect in particular: neutropenia, or an abnormally low white blood cell count. Clozapine, she said, has a boxed warning about severe neutropenia that can lead to death.

However, she cautioned that white blood cell counts can be misleading. Some people in non-White ethnic groups have a condition known as benign ethnic neutropenia: their white blood cell counts are abnormal by the standards of people of European heritage, but they’re otherwise healthy. “These individuals do not show an increased risk of infections, and their response to infection is similar to those without them,” she said.

As many as 25%-50% of people of African ancestry may have benign ethnic neutropenia, making their blood levels appear abnormally low. Others with higher levels of the condition include certain Middle Eastern ethnicities and other ethnic groups with darker skin.

In these patents, “clinicians may avoid prescribing clozapine out of the mistaken concern that it can worsen neutropenia,” Dr. Clarke said. In fact, benign ethnic neutropenia “does not increase the risk of clozapine-induced severe neutropenia.”

Dr. Clarke highlighted drug use guidelines from the Clozapine Risk Evaluation and Mitigation Strategy, a Food and Drug Administration–mandated safety program designed to prevent severe neutropenia in patients taking clozapine. The guidelines note that the recommended absolute neutrophil count monitoring algorithm differs when patients are diagnosed with benign ethnic neutropenia.

T. Scott Stroup, MD, MPH, a psychiatrist at Columbia University, New York, urged his colleagues to consider clozapine early on in treatment-resistant schizophrenia. “Don’t go through three, four, or five antipsychotics. Even after trying two, I’d encourage people to [try clozapine].”

However, he acknowledged that “not everyone believes that. Many of my colleagues think that, before you try clozapine, you should have a trial of long-acting injectable medications to rule out pseudo–treatment resistance. I don’t totally agree with that, but I’ve more or less lost that battle,” he added.

In the big picture, Dr. Stroup said, clozapine “is good when other things aren’t working efficacy wise.”

Dr. Holderness and Dr. Clarke have no disclosures. Dr. Stroup discloses grants from the National Institutes of Health and royalties from APA Publishing and UpToDate.

SAN FRANCISCO – A trio of psychiatrists urged colleagues at the annual meeting of the American Psychiatric Association to embrace the venerable antipsychotic clozapine in patients with treatment-resistant schizophrenia. They cautioned that clinicians may overestimate the true risk of the adverse effect of neutropenia in minority populations.

“Although clozapine is known to be a life-improving and even potentially lifesaving treatment, it remains underutilized in the U.S.,” said Claire C. Holderness, MD, a psychiatrist at Columbia University Irving Medical Center, New York. “It’s been estimated that between 35% and 40% of all patients with schizophrenia should be considered for a clozapine trial. However, only 4%-5% of patients with schizophrenia in the U.S. have ever received clozapine. This is in sharp contrast to other industrialized countries where approximately 20% or more of patients with schizophrenia are treated with clozapine.”

According to Dr. Holderness, research has shown that clozapine is even less likely to be prescribed to racial and ethnic minorities. A 2022 systematic review, for example, found that Black patients in the United States had between one-third and two-thirds the odds of being treated with the drug, compared with White patients after adjustment for potential confounders such as demographics. Hispanic/Latino patients were also less likely than Whites to be prescribed the drug.

As Dr. Holderness put it, the drug “been shown to be more effective in treatment-resistant schizophrenia than any other antipsychotic medication. Clozapine is also the most cost-effective treatment for treatment-resistant schizophrenia.” So why does this disparity exist despite clozapine’s benefits?

A 2018 systematic review of barriers to the drug’s usage identified several factors: “mandatory blood testing, fear of serious side-effects and lack of adherence by the patients, difficulty in identifying suitable patients, service fragmentation, and inadequate training in or exposure to using clozapine.” A 2016 British study, meanwhile, looked at the reasons that 45% of 316 patients stopped clozapine before 2 years. More than half of these patients stopped because of adverse effects.
 

Risk of neutropenia

At the APA presentation, psychiatrist Laura Clarke, MD, also of Columbia University Irving Medical Center, noted that there’s concern about one adverse effect in particular: neutropenia, or an abnormally low white blood cell count. Clozapine, she said, has a boxed warning about severe neutropenia that can lead to death.

However, she cautioned that white blood cell counts can be misleading. Some people in non-White ethnic groups have a condition known as benign ethnic neutropenia: their white blood cell counts are abnormal by the standards of people of European heritage, but they’re otherwise healthy. “These individuals do not show an increased risk of infections, and their response to infection is similar to those without them,” she said.

As many as 25%-50% of people of African ancestry may have benign ethnic neutropenia, making their blood levels appear abnormally low. Others with higher levels of the condition include certain Middle Eastern ethnicities and other ethnic groups with darker skin.

In these patents, “clinicians may avoid prescribing clozapine out of the mistaken concern that it can worsen neutropenia,” Dr. Clarke said. In fact, benign ethnic neutropenia “does not increase the risk of clozapine-induced severe neutropenia.”

Dr. Clarke highlighted drug use guidelines from the Clozapine Risk Evaluation and Mitigation Strategy, a Food and Drug Administration–mandated safety program designed to prevent severe neutropenia in patients taking clozapine. The guidelines note that the recommended absolute neutrophil count monitoring algorithm differs when patients are diagnosed with benign ethnic neutropenia.

T. Scott Stroup, MD, MPH, a psychiatrist at Columbia University, New York, urged his colleagues to consider clozapine early on in treatment-resistant schizophrenia. “Don’t go through three, four, or five antipsychotics. Even after trying two, I’d encourage people to [try clozapine].”

However, he acknowledged that “not everyone believes that. Many of my colleagues think that, before you try clozapine, you should have a trial of long-acting injectable medications to rule out pseudo–treatment resistance. I don’t totally agree with that, but I’ve more or less lost that battle,” he added.

In the big picture, Dr. Stroup said, clozapine “is good when other things aren’t working efficacy wise.”

Dr. Holderness and Dr. Clarke have no disclosures. Dr. Stroup discloses grants from the National Institutes of Health and royalties from APA Publishing and UpToDate.

SAN FRANCISCO – A new study from an addiction clinic adds to the growing evidence that higher early doses of buprenorphine are advisable in certain patients with opioid use disorder. Eighty-five percent of patients who were titrated up to 32 mg remained in treatment for 1 year vs. 22% of those who never went higher than 16 mg, and those on higher doses stayed in treatment 3.83 times longer than those who didn’t.

“Simply put, we demonstrated better retention in treatment if patients were given higher buprenorphine doses when they complained of opioid craving,” said Andrew Gilbert, a medical student at California Northstate University, Elk Grove, Calif. He is lead author of a poster presented at the 2023 annual meeting of the American Psychiatric Association.

There’s an ongoing debate over ideal doses of buprenorphine (Suboxone), an opioid that’s used to help treat withdrawal symptoms in users of drugs such as heroin and fentanyl. Some sources recommend lower doses. The Substance Abuse and Mental Health Administration, for example, says “ideally, average dosing does not exceed 16 mg” in a guide to the drug’s usage, referring to the sublingual form. (A long-lasting injectable is also available.) Drugs.com says 24 mg is the maximum, and “higher doses have not shown a clinical advantage.

However, some emergency departments have begun providing doses up to 28 mg or higher amid the increased use of the powerful opioid fentanyl. “There are mountains of evidence demonstrating the safety of higher doses at 32 mg, and even several-fold higher than that,” study coauthor Phillip Summers MD, MPH, medical director of the harm-reduction organization Safer Alternatives Thru Networking and Education, Sacramento, Calif., said in an interview. “The question is: Is there clinical benefit to these higher doses?”
 

‘Significantly higher’ retention

For the new study, researchers tracked 328 patients who were treated for opioid use disorder at the Transitions Buprenorphine Clinic of Sacramento from 2010 to 2017. They were followed until 2022. Their average age was 36, 37.2% were female, 75.0% were White, and 24.1% had a history of overdose.

Clinicians titrated up the doses of buprenorphine to address withdrawal and craving. Five patients never went past 4 mg, and two of them stayed in treatment for a year. Nine of 19 who went up to 8 mg stayed in treatment for 1 year, and 4 of 21 did among those who reached 12 mg.

“Our data suggest that the highest rate of patient dropout is at the beginning of treatment, and that there is significantly higher treatment retention in patients on greater than 24 mg or higher of buprenorphine,” the researchers wrote.

Mr. Gilbert said clinicians start at 8 mg the first day in patients who haven’t taken buprenorphine before, then they go to 16 mg the second day. “We then reevaluate in at least 1 week, oftentimes sooner if the patient’s opioid craving is uncontrolled, and determine if 16 mg is too low, too high, or the correct dosage for the patient.”

If a dose of over 32 mg is needed, clinicians turn to the long-lasting injectable form of the drug, study coauthor Neil Flynn MD, MPH, former medical director of the Transitions Buprenorphine Clinic of Sacramento, said in an interview. “We controlled craving with this form for every patient that did not have opioid craving relief with 32 mg. We believe this form achieved opioid craving cessation due to increased buprenorphine blood levels and increased ratio of unmetabolized buprenorphine to metabolized buprenorphine in our patients.”

According to Dr. Summers, it’s clear that too-low doses hurt the recovery process. “If we prescribe subtherapeutic doses of buprenorphine, our patients will experience opioid craving, which leads to treatment dropout and most likely to relapse. Higher doses of buprenorphine are more likely to cease opioid cravings, leading patients to remain in treatment for longer periods of time.”

Mr. Gilbert said buprenorphine has few side effects, which include decreased libido and hot flashes in both men and women. Testosterone therapy can relieve these symptoms in men, he said, but “unfortunately, we do not have any good medications for reversing this side effect in women. Further research should investigate eliminating this side effect in women.”

Mr. Gilbert declined to comment on the extra cost of higher doses since that is outside the scope of the study.
 

Medication is the ‘star’

In an interview, addiction specialist Dave Cundiff, MD, MPH, of Ilwaco, Wash., praised the study and agreed with its conclusions about the value of high doses of buprenorphine.

“They’re confirming what the science has already shown, but the world does not accept,” he said, adding that “for opioid use disorder, the medication is the star of the show, although counseling is a necessary adjunct for some patients.”

Dr. Cundiff said he’s coauthored a pending review article that finds that studies support higher doses of buprenorphine.

MaryAnne Murray, DNP, EdD, MBA, a psychiatric mental health nurse practitioner who’s married to Dr. Cundiff, said in an interview that the evolution of the opioid epidemic supports the use of higher doses. “The old way we used to do with heroin users was to wait until they’re in moderate withdrawal, and then start up buprenorphine, usually slowly. With fentanyl, it takes longer, and the wait is often less bearable – unbearable for many people.”

Transitions Buprenorphine Clinic of Sacramento funded the study. The authors, Dr. Cundiff, and Dr. Murray have no disclosures.

SAN FRANCISCO – A new study from an addiction clinic adds to the growing evidence that higher early doses of buprenorphine are advisable in certain patients with opioid use disorder. Eighty-five percent of patients who were titrated up to 32 mg remained in treatment for 1 year vs. 22% of those who never went higher than 16 mg, and those on higher doses stayed in treatment 3.83 times longer than those who didn’t.

“Simply put, we demonstrated better retention in treatment if patients were given higher buprenorphine doses when they complained of opioid craving,” said Andrew Gilbert, a medical student at California Northstate University, Elk Grove, Calif. He is lead author of a poster presented at the 2023 annual meeting of the American Psychiatric Association.

There’s an ongoing debate over ideal doses of buprenorphine (Suboxone), an opioid that’s used to help treat withdrawal symptoms in users of drugs such as heroin and fentanyl. Some sources recommend lower doses. The Substance Abuse and Mental Health Administration, for example, says “ideally, average dosing does not exceed 16 mg” in a guide to the drug’s usage, referring to the sublingual form. (A long-lasting injectable is also available.) Drugs.com says 24 mg is the maximum, and “higher doses have not shown a clinical advantage.

However, some emergency departments have begun providing doses up to 28 mg or higher amid the increased use of the powerful opioid fentanyl. “There are mountains of evidence demonstrating the safety of higher doses at 32 mg, and even several-fold higher than that,” study coauthor Phillip Summers MD, MPH, medical director of the harm-reduction organization Safer Alternatives Thru Networking and Education, Sacramento, Calif., said in an interview. “The question is: Is there clinical benefit to these higher doses?”
 

‘Significantly higher’ retention

For the new study, researchers tracked 328 patients who were treated for opioid use disorder at the Transitions Buprenorphine Clinic of Sacramento from 2010 to 2017. They were followed until 2022. Their average age was 36, 37.2% were female, 75.0% were White, and 24.1% had a history of overdose.

Clinicians titrated up the doses of buprenorphine to address withdrawal and craving. Five patients never went past 4 mg, and two of them stayed in treatment for a year. Nine of 19 who went up to 8 mg stayed in treatment for 1 year, and 4 of 21 did among those who reached 12 mg.

“Our data suggest that the highest rate of patient dropout is at the beginning of treatment, and that there is significantly higher treatment retention in patients on greater than 24 mg or higher of buprenorphine,” the researchers wrote.

Mr. Gilbert said clinicians start at 8 mg the first day in patients who haven’t taken buprenorphine before, then they go to 16 mg the second day. “We then reevaluate in at least 1 week, oftentimes sooner if the patient’s opioid craving is uncontrolled, and determine if 16 mg is too low, too high, or the correct dosage for the patient.”

If a dose of over 32 mg is needed, clinicians turn to the long-lasting injectable form of the drug, study coauthor Neil Flynn MD, MPH, former medical director of the Transitions Buprenorphine Clinic of Sacramento, said in an interview. “We controlled craving with this form for every patient that did not have opioid craving relief with 32 mg. We believe this form achieved opioid craving cessation due to increased buprenorphine blood levels and increased ratio of unmetabolized buprenorphine to metabolized buprenorphine in our patients.”

According to Dr. Summers, it’s clear that too-low doses hurt the recovery process. “If we prescribe subtherapeutic doses of buprenorphine, our patients will experience opioid craving, which leads to treatment dropout and most likely to relapse. Higher doses of buprenorphine are more likely to cease opioid cravings, leading patients to remain in treatment for longer periods of time.”

Mr. Gilbert said buprenorphine has few side effects, which include decreased libido and hot flashes in both men and women. Testosterone therapy can relieve these symptoms in men, he said, but “unfortunately, we do not have any good medications for reversing this side effect in women. Further research should investigate eliminating this side effect in women.”

Mr. Gilbert declined to comment on the extra cost of higher doses since that is outside the scope of the study.
 

Medication is the ‘star’

In an interview, addiction specialist Dave Cundiff, MD, MPH, of Ilwaco, Wash., praised the study and agreed with its conclusions about the value of high doses of buprenorphine.

“They’re confirming what the science has already shown, but the world does not accept,” he said, adding that “for opioid use disorder, the medication is the star of the show, although counseling is a necessary adjunct for some patients.”

Dr. Cundiff said he’s coauthored a pending review article that finds that studies support higher doses of buprenorphine.

MaryAnne Murray, DNP, EdD, MBA, a psychiatric mental health nurse practitioner who’s married to Dr. Cundiff, said in an interview that the evolution of the opioid epidemic supports the use of higher doses. “The old way we used to do with heroin users was to wait until they’re in moderate withdrawal, and then start up buprenorphine, usually slowly. With fentanyl, it takes longer, and the wait is often less bearable – unbearable for many people.”

Transitions Buprenorphine Clinic of Sacramento funded the study. The authors, Dr. Cundiff, and Dr. Murray have no disclosures.

SAN FRANCISCO – A new study from an addiction clinic adds to the growing evidence that higher early doses of buprenorphine are advisable in certain patients with opioid use disorder. Eighty-five percent of patients who were titrated up to 32 mg remained in treatment for 1 year vs. 22% of those who never went higher than 16 mg, and those on higher doses stayed in treatment 3.83 times longer than those who didn’t.

“Simply put, we demonstrated better retention in treatment if patients were given higher buprenorphine doses when they complained of opioid craving,” said Andrew Gilbert, a medical student at California Northstate University, Elk Grove, Calif. He is lead author of a poster presented at the 2023 annual meeting of the American Psychiatric Association.

There’s an ongoing debate over ideal doses of buprenorphine (Suboxone), an opioid that’s used to help treat withdrawal symptoms in users of drugs such as heroin and fentanyl. Some sources recommend lower doses. The Substance Abuse and Mental Health Administration, for example, says “ideally, average dosing does not exceed 16 mg” in a guide to the drug’s usage, referring to the sublingual form. (A long-lasting injectable is also available.) Drugs.com says 24 mg is the maximum, and “higher doses have not shown a clinical advantage.

However, some emergency departments have begun providing doses up to 28 mg or higher amid the increased use of the powerful opioid fentanyl. “There are mountains of evidence demonstrating the safety of higher doses at 32 mg, and even several-fold higher than that,” study coauthor Phillip Summers MD, MPH, medical director of the harm-reduction organization Safer Alternatives Thru Networking and Education, Sacramento, Calif., said in an interview. “The question is: Is there clinical benefit to these higher doses?”
 

‘Significantly higher’ retention

For the new study, researchers tracked 328 patients who were treated for opioid use disorder at the Transitions Buprenorphine Clinic of Sacramento from 2010 to 2017. They were followed until 2022. Their average age was 36, 37.2% were female, 75.0% were White, and 24.1% had a history of overdose.

Clinicians titrated up the doses of buprenorphine to address withdrawal and craving. Five patients never went past 4 mg, and two of them stayed in treatment for a year. Nine of 19 who went up to 8 mg stayed in treatment for 1 year, and 4 of 21 did among those who reached 12 mg.

“Our data suggest that the highest rate of patient dropout is at the beginning of treatment, and that there is significantly higher treatment retention in patients on greater than 24 mg or higher of buprenorphine,” the researchers wrote.

Mr. Gilbert said clinicians start at 8 mg the first day in patients who haven’t taken buprenorphine before, then they go to 16 mg the second day. “We then reevaluate in at least 1 week, oftentimes sooner if the patient’s opioid craving is uncontrolled, and determine if 16 mg is too low, too high, or the correct dosage for the patient.”

If a dose of over 32 mg is needed, clinicians turn to the long-lasting injectable form of the drug, study coauthor Neil Flynn MD, MPH, former medical director of the Transitions Buprenorphine Clinic of Sacramento, said in an interview. “We controlled craving with this form for every patient that did not have opioid craving relief with 32 mg. We believe this form achieved opioid craving cessation due to increased buprenorphine blood levels and increased ratio of unmetabolized buprenorphine to metabolized buprenorphine in our patients.”

According to Dr. Summers, it’s clear that too-low doses hurt the recovery process. “If we prescribe subtherapeutic doses of buprenorphine, our patients will experience opioid craving, which leads to treatment dropout and most likely to relapse. Higher doses of buprenorphine are more likely to cease opioid cravings, leading patients to remain in treatment for longer periods of time.”

Mr. Gilbert said buprenorphine has few side effects, which include decreased libido and hot flashes in both men and women. Testosterone therapy can relieve these symptoms in men, he said, but “unfortunately, we do not have any good medications for reversing this side effect in women. Further research should investigate eliminating this side effect in women.”

Mr. Gilbert declined to comment on the extra cost of higher doses since that is outside the scope of the study.
 

Medication is the ‘star’

In an interview, addiction specialist Dave Cundiff, MD, MPH, of Ilwaco, Wash., praised the study and agreed with its conclusions about the value of high doses of buprenorphine.

“They’re confirming what the science has already shown, but the world does not accept,” he said, adding that “for opioid use disorder, the medication is the star of the show, although counseling is a necessary adjunct for some patients.”

Dr. Cundiff said he’s coauthored a pending review article that finds that studies support higher doses of buprenorphine.

MaryAnne Murray, DNP, EdD, MBA, a psychiatric mental health nurse practitioner who’s married to Dr. Cundiff, said in an interview that the evolution of the opioid epidemic supports the use of higher doses. “The old way we used to do with heroin users was to wait until they’re in moderate withdrawal, and then start up buprenorphine, usually slowly. With fentanyl, it takes longer, and the wait is often less bearable – unbearable for many people.”

Transitions Buprenorphine Clinic of Sacramento funded the study. The authors, Dr. Cundiff, and Dr. Murray have no disclosures.

CHICAGO – In the phase 3 MIRASOL study, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere, ImmunoGen) produced an overall survival benefit in women with platinum-resistant ovarian cancer.

The conclusion of this study marks the first time that a novel therapy has demonstrated an overall survival (OS) improvement in any phase 3 trial in this population, according to lead investigator Kathleen Moore, MD.

“We believe these data are practice changing and position mirvetuximab [soravtansine] as the new standard of care for patients with folate receptor–alpha positive, platinum-resistant ovarian cancer,” said Dr. Moore during a presentation of the study at a special session of the annual meeting of the American Society of Clinical Oncology devoted solely to the MIRASOL study.
 

New standard of care

Following Dr. Moore’s presentation, Roisin Eilish O’Cearbhaill, MD, served as a discussant, and she confirmed the trial’s importance.

“It has firmly established the role of mirvetuximab [soravtansine] in folate receptor–alpha high-expression, platinum-resistant ovarian cancer,” said Dr. O’Cearbhaill, who is Research director of the gynecologic medical oncology service and clinical director of the solid tumor, cellular therapy service at Memorial Sloan Kettering Cancer Center, New York.

Mirvetuximab soravtansine received accelerated FDA approval in November based on the results of the single-arm SORAYA trial, which demonstrated a progression-free survival (PFS) benefit in platinum-resistant patients who had been previously treated with one to three treatment regimens, at least one of which having included bevacizumab.

The new study compared MIRV with physician choice chemotherapy and found both a PFS and OS benefit in the MIRV arm. The results garnered significant enthusiasm from the audience, and others reacted positively as well.

“The results that she presented are just astounding, with a significant improvement in both progression-free and overall survival. I think certainly the overall survival needs to be highlighted here, because this is a patient population that’s notoriously difficult to treat,” said Ana Valente, MD, a gynecologic oncologist at the Ochsner Health System in New Orleans. Dr. Valente, who did not attend the presentation but was asked to comment on the study, is also a member of the Society of Gynecological Oncologist communications committee.

Unlike SORAYA, MIRASOL was open to patients who had not received bevacizumab, and Dr. Moore and colleagues found similar survival benefits in patients who had not received bevacizumab as in those who had, said Dr. Moore, who is the associate director of clinical research at Stephenson Cancer Center and director of the Oklahoma TSET Phase 1 Program, both in Oklahoma City. This opens the possibility of using MIRV instead of bevacizumab combined with chemotherapy in platinum-resistant patients.

“I think this data really shows you can move right to mirvetuximab [soravtansine] and feel pretty solid about the decision in a biomarker selected [population],” Dr. Moore said, during an interview.
 

Not just for high expression levels

MIRASOL was restricted to patients with high levels of expression of folate receptor–alpha, which is MIRV’s target on the surface of tumor cells. High expression is defined as at least 75% of viable tumor cells exhibiting a minimum of 2+ level membrane staining intensity by immunohistochemistry. That represents about 35% of patients, according to Dr. Moore, but she said that the drug also shows promise in patients with medium levels of folate receptor–alpha expression.

“I think it’s just going to be now starting to get those label extension studies launched to branch it out. Then you account for 60% of your population which [have] medium to high [expression levels], and that’s really where you see benefit,” said Dr. Moore. Medium expression levels of folate receptor–alpha are defined as 50% to greater than 75% of tumor cells with 2+ level membrane staining intensity.

She also noted that the FORWARD II trial combining mirvetuximab soravtansine with bevacizumab in platinum-resistant ovarian cancer is showing good results.

“We have really beautiful data [from FORWARD II]. If I have a medium expresser, I’m using the doublet [of MIRV and bevacizumab], and it works,” said Dr. Moore, while also pointing out that this remains an off-label use.

It’s possible that the drug could be extended even to low expression levels, defined as 25% to less than 50% of tumor cells with 2+ level membrane staining intensity. “[We are] currently working on that strategy with already available data,” said Dr. Moore.

She speculated that the improved OS may be attributed to the reduced toxicity of MIRV, compared with chemotherapy agents, which leaves patients feeling better and more able to pursue other treatments, which in turn may increase survival odds.

Dr. O’Cearbhaill touted the benefits of ADCs and their ability to target powerful cytotoxic agents while limiting side effects, and she is looking forward to more new therapies on the horizon.

“There are four [ADCs] in late stages of development [for platinum-resistant ovarian cancer], so hopefully there will be other ones coming online as well,” Dr. O’Cearbhaill said in an interview. “Then we’ll have to figure out how to sequence them, which drug will be best in class. Will we be just giving one or will be giving ADC followed by ADC?”
 

Study methods and results

The study enrolled 453 patients and randomized them to treatment with MIRV or investigator’s choice of chemotherapy, which could be paclitaxel, pegylated liposomal doxorubicin, or topotecan. The MIRV dose was 6 mg/kg adjusted ideal body weight every 3 weeks. The median age was 62 in the chemotherapy arm and 63 years in the MIRV arm. About 63% of the chemotherapy arm had prior bevacizumab exposure, as did 61% of the MIRV arm.

Median PFS was 5.62 months in the MIRV arm and 3.98 months in the chemotherapy arm (hazard ratio, 0.65; P less than .0001). The overall response rate was 42% in the MIRV arm and 16% in the chemotherapy arm (P < .0001).

The safety outcomes also favored MIRV: 42% experienced grade 3 or higher treatment-emergent adverse events (TEAEs) versus 54% in the chemotherapy group. Severe adverse events were also lower in MIRV, 24% versus 33%. Just 9% of patients in the MIRV discontinued because of TEAEs, compared with 16% in the chemotherapy arm.

MIRV was associated with blurred vision (41%), keratopathy (32%), and dry eye (28%), but these issues were generally manageable through collaboration with optometrists or ophthalmologists.

Dr. Moore and Dr. O’Cearbhaill reported receiving honoraria, research funding, and travel expenses from numerous pharmaceutical companies. Dr. O’Cearbhaill has consulted for or advised Aptitude Health, Bayer, Carina Biotech, Fresenius Kabi, GlaxoSmithKline, GOG Foundation, Immunogen, R-Pharm, Regeneron, and Seagen.

CHICAGO – In the phase 3 MIRASOL study, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere, ImmunoGen) produced an overall survival benefit in women with platinum-resistant ovarian cancer.

The conclusion of this study marks the first time that a novel therapy has demonstrated an overall survival (OS) improvement in any phase 3 trial in this population, according to lead investigator Kathleen Moore, MD.

“We believe these data are practice changing and position mirvetuximab [soravtansine] as the new standard of care for patients with folate receptor–alpha positive, platinum-resistant ovarian cancer,” said Dr. Moore during a presentation of the study at a special session of the annual meeting of the American Society of Clinical Oncology devoted solely to the MIRASOL study.
 

New standard of care

Following Dr. Moore’s presentation, Roisin Eilish O’Cearbhaill, MD, served as a discussant, and she confirmed the trial’s importance.

“It has firmly established the role of mirvetuximab [soravtansine] in folate receptor–alpha high-expression, platinum-resistant ovarian cancer,” said Dr. O’Cearbhaill, who is Research director of the gynecologic medical oncology service and clinical director of the solid tumor, cellular therapy service at Memorial Sloan Kettering Cancer Center, New York.

Mirvetuximab soravtansine received accelerated FDA approval in November based on the results of the single-arm SORAYA trial, which demonstrated a progression-free survival (PFS) benefit in platinum-resistant patients who had been previously treated with one to three treatment regimens, at least one of which having included bevacizumab.

The new study compared MIRV with physician choice chemotherapy and found both a PFS and OS benefit in the MIRV arm. The results garnered significant enthusiasm from the audience, and others reacted positively as well.

“The results that she presented are just astounding, with a significant improvement in both progression-free and overall survival. I think certainly the overall survival needs to be highlighted here, because this is a patient population that’s notoriously difficult to treat,” said Ana Valente, MD, a gynecologic oncologist at the Ochsner Health System in New Orleans. Dr. Valente, who did not attend the presentation but was asked to comment on the study, is also a member of the Society of Gynecological Oncologist communications committee.

Unlike SORAYA, MIRASOL was open to patients who had not received bevacizumab, and Dr. Moore and colleagues found similar survival benefits in patients who had not received bevacizumab as in those who had, said Dr. Moore, who is the associate director of clinical research at Stephenson Cancer Center and director of the Oklahoma TSET Phase 1 Program, both in Oklahoma City. This opens the possibility of using MIRV instead of bevacizumab combined with chemotherapy in platinum-resistant patients.

“I think this data really shows you can move right to mirvetuximab [soravtansine] and feel pretty solid about the decision in a biomarker selected [population],” Dr. Moore said, during an interview.
 

Not just for high expression levels

MIRASOL was restricted to patients with high levels of expression of folate receptor–alpha, which is MIRV’s target on the surface of tumor cells. High expression is defined as at least 75% of viable tumor cells exhibiting a minimum of 2+ level membrane staining intensity by immunohistochemistry. That represents about 35% of patients, according to Dr. Moore, but she said that the drug also shows promise in patients with medium levels of folate receptor–alpha expression.

“I think it’s just going to be now starting to get those label extension studies launched to branch it out. Then you account for 60% of your population which [have] medium to high [expression levels], and that’s really where you see benefit,” said Dr. Moore. Medium expression levels of folate receptor–alpha are defined as 50% to greater than 75% of tumor cells with 2+ level membrane staining intensity.

She also noted that the FORWARD II trial combining mirvetuximab soravtansine with bevacizumab in platinum-resistant ovarian cancer is showing good results.

“We have really beautiful data [from FORWARD II]. If I have a medium expresser, I’m using the doublet [of MIRV and bevacizumab], and it works,” said Dr. Moore, while also pointing out that this remains an off-label use.

It’s possible that the drug could be extended even to low expression levels, defined as 25% to less than 50% of tumor cells with 2+ level membrane staining intensity. “[We are] currently working on that strategy with already available data,” said Dr. Moore.

She speculated that the improved OS may be attributed to the reduced toxicity of MIRV, compared with chemotherapy agents, which leaves patients feeling better and more able to pursue other treatments, which in turn may increase survival odds.

Dr. O’Cearbhaill touted the benefits of ADCs and their ability to target powerful cytotoxic agents while limiting side effects, and she is looking forward to more new therapies on the horizon.

“There are four [ADCs] in late stages of development [for platinum-resistant ovarian cancer], so hopefully there will be other ones coming online as well,” Dr. O’Cearbhaill said in an interview. “Then we’ll have to figure out how to sequence them, which drug will be best in class. Will we be just giving one or will be giving ADC followed by ADC?”
 

Study methods and results

The study enrolled 453 patients and randomized them to treatment with MIRV or investigator’s choice of chemotherapy, which could be paclitaxel, pegylated liposomal doxorubicin, or topotecan. The MIRV dose was 6 mg/kg adjusted ideal body weight every 3 weeks. The median age was 62 in the chemotherapy arm and 63 years in the MIRV arm. About 63% of the chemotherapy arm had prior bevacizumab exposure, as did 61% of the MIRV arm.

Median PFS was 5.62 months in the MIRV arm and 3.98 months in the chemotherapy arm (hazard ratio, 0.65; P less than .0001). The overall response rate was 42% in the MIRV arm and 16% in the chemotherapy arm (P < .0001).

The safety outcomes also favored MIRV: 42% experienced grade 3 or higher treatment-emergent adverse events (TEAEs) versus 54% in the chemotherapy group. Severe adverse events were also lower in MIRV, 24% versus 33%. Just 9% of patients in the MIRV discontinued because of TEAEs, compared with 16% in the chemotherapy arm.

MIRV was associated with blurred vision (41%), keratopathy (32%), and dry eye (28%), but these issues were generally manageable through collaboration with optometrists or ophthalmologists.

Dr. Moore and Dr. O’Cearbhaill reported receiving honoraria, research funding, and travel expenses from numerous pharmaceutical companies. Dr. O’Cearbhaill has consulted for or advised Aptitude Health, Bayer, Carina Biotech, Fresenius Kabi, GlaxoSmithKline, GOG Foundation, Immunogen, R-Pharm, Regeneron, and Seagen.

CHICAGO – In the phase 3 MIRASOL study, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere, ImmunoGen) produced an overall survival benefit in women with platinum-resistant ovarian cancer.

The conclusion of this study marks the first time that a novel therapy has demonstrated an overall survival (OS) improvement in any phase 3 trial in this population, according to lead investigator Kathleen Moore, MD.

“We believe these data are practice changing and position mirvetuximab [soravtansine] as the new standard of care for patients with folate receptor–alpha positive, platinum-resistant ovarian cancer,” said Dr. Moore during a presentation of the study at a special session of the annual meeting of the American Society of Clinical Oncology devoted solely to the MIRASOL study.
 

New standard of care

Following Dr. Moore’s presentation, Roisin Eilish O’Cearbhaill, MD, served as a discussant, and she confirmed the trial’s importance.

“It has firmly established the role of mirvetuximab [soravtansine] in folate receptor–alpha high-expression, platinum-resistant ovarian cancer,” said Dr. O’Cearbhaill, who is Research director of the gynecologic medical oncology service and clinical director of the solid tumor, cellular therapy service at Memorial Sloan Kettering Cancer Center, New York.

Mirvetuximab soravtansine received accelerated FDA approval in November based on the results of the single-arm SORAYA trial, which demonstrated a progression-free survival (PFS) benefit in platinum-resistant patients who had been previously treated with one to three treatment regimens, at least one of which having included bevacizumab.

The new study compared MIRV with physician choice chemotherapy and found both a PFS and OS benefit in the MIRV arm. The results garnered significant enthusiasm from the audience, and others reacted positively as well.

“The results that she presented are just astounding, with a significant improvement in both progression-free and overall survival. I think certainly the overall survival needs to be highlighted here, because this is a patient population that’s notoriously difficult to treat,” said Ana Valente, MD, a gynecologic oncologist at the Ochsner Health System in New Orleans. Dr. Valente, who did not attend the presentation but was asked to comment on the study, is also a member of the Society of Gynecological Oncologist communications committee.

Unlike SORAYA, MIRASOL was open to patients who had not received bevacizumab, and Dr. Moore and colleagues found similar survival benefits in patients who had not received bevacizumab as in those who had, said Dr. Moore, who is the associate director of clinical research at Stephenson Cancer Center and director of the Oklahoma TSET Phase 1 Program, both in Oklahoma City. This opens the possibility of using MIRV instead of bevacizumab combined with chemotherapy in platinum-resistant patients.

“I think this data really shows you can move right to mirvetuximab [soravtansine] and feel pretty solid about the decision in a biomarker selected [population],” Dr. Moore said, during an interview.
 

Not just for high expression levels

MIRASOL was restricted to patients with high levels of expression of folate receptor–alpha, which is MIRV’s target on the surface of tumor cells. High expression is defined as at least 75% of viable tumor cells exhibiting a minimum of 2+ level membrane staining intensity by immunohistochemistry. That represents about 35% of patients, according to Dr. Moore, but she said that the drug also shows promise in patients with medium levels of folate receptor–alpha expression.

“I think it’s just going to be now starting to get those label extension studies launched to branch it out. Then you account for 60% of your population which [have] medium to high [expression levels], and that’s really where you see benefit,” said Dr. Moore. Medium expression levels of folate receptor–alpha are defined as 50% to greater than 75% of tumor cells with 2+ level membrane staining intensity.

She also noted that the FORWARD II trial combining mirvetuximab soravtansine with bevacizumab in platinum-resistant ovarian cancer is showing good results.

“We have really beautiful data [from FORWARD II]. If I have a medium expresser, I’m using the doublet [of MIRV and bevacizumab], and it works,” said Dr. Moore, while also pointing out that this remains an off-label use.

It’s possible that the drug could be extended even to low expression levels, defined as 25% to less than 50% of tumor cells with 2+ level membrane staining intensity. “[We are] currently working on that strategy with already available data,” said Dr. Moore.

She speculated that the improved OS may be attributed to the reduced toxicity of MIRV, compared with chemotherapy agents, which leaves patients feeling better and more able to pursue other treatments, which in turn may increase survival odds.

Dr. O’Cearbhaill touted the benefits of ADCs and their ability to target powerful cytotoxic agents while limiting side effects, and she is looking forward to more new therapies on the horizon.

“There are four [ADCs] in late stages of development [for platinum-resistant ovarian cancer], so hopefully there will be other ones coming online as well,” Dr. O’Cearbhaill said in an interview. “Then we’ll have to figure out how to sequence them, which drug will be best in class. Will we be just giving one or will be giving ADC followed by ADC?”
 

Study methods and results

The study enrolled 453 patients and randomized them to treatment with MIRV or investigator’s choice of chemotherapy, which could be paclitaxel, pegylated liposomal doxorubicin, or topotecan. The MIRV dose was 6 mg/kg adjusted ideal body weight every 3 weeks. The median age was 62 in the chemotherapy arm and 63 years in the MIRV arm. About 63% of the chemotherapy arm had prior bevacizumab exposure, as did 61% of the MIRV arm.

Median PFS was 5.62 months in the MIRV arm and 3.98 months in the chemotherapy arm (hazard ratio, 0.65; P less than .0001). The overall response rate was 42% in the MIRV arm and 16% in the chemotherapy arm (P < .0001).

The safety outcomes also favored MIRV: 42% experienced grade 3 or higher treatment-emergent adverse events (TEAEs) versus 54% in the chemotherapy group. Severe adverse events were also lower in MIRV, 24% versus 33%. Just 9% of patients in the MIRV discontinued because of TEAEs, compared with 16% in the chemotherapy arm.

MIRV was associated with blurred vision (41%), keratopathy (32%), and dry eye (28%), but these issues were generally manageable through collaboration with optometrists or ophthalmologists.

Dr. Moore and Dr. O’Cearbhaill reported receiving honoraria, research funding, and travel expenses from numerous pharmaceutical companies. Dr. O’Cearbhaill has consulted for or advised Aptitude Health, Bayer, Carina Biotech, Fresenius Kabi, GlaxoSmithKline, GOG Foundation, Immunogen, R-Pharm, Regeneron, and Seagen.

BALTIMORE – Poor prenatal sleep may increase the risk of postpartum depression, and prenatal depression may reduce the likelihood of mothers coming to their prenatal appointments, according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Together, the two studies suggest that commonly overlooked experiences in the prenatal period can have negative effects down the line if clinicians aren’t asking patients about them and addressing the issue.

”I think the national conversation around mental health in general will hopefully carry us forward to better supporting the patients who are coming in with preexisting conditions,” lead author Minnie Jang, a 4th-year medical student at Johns Hopkins University, Baltimore, said in an interview.

Most of the attention on mood disorders of pregnancy focus on the postpartum period, but preexisting or new-onset depression during pregnancy deserves more attention, Ms. Jang told attendees. ACOG recommends that clinicians screen all patients at least once during the perinatal period, but that could be anywhere from early pregnancy to the postpartum period. Ms. Jang would like to see recommendations addressing both early pregnancy and the postpartum period.

“I think there’s this framing that postpartum depression is a distinct entity from other mental health conditions whereas it’s really part of a continuum,” Ms. Jang said in an interview.

She retrospectively analyzed the medical records of all pregnant women who completed the Edinburgh Postnatal Depression Scale (EPDS) during their first or second trimesters between 2002 and 2021 at Johns Hopkins Hospital. Among the 718 women who were screened in early pregnancy, 44.6% were Black or African American, 39.7% were white, and 15.7% were of a different race. Nearly all (94%) were not Hispanic/Latino.

Most (59%) were partnered, employed (68%), and had private insurance (58%). Only 7% used tobacco while 11% used alcohol and 6% used illicit drugs.

Twelve percent of the patients scored positive for depression, with a score of at least 10 or an affirmative answer to question 10 regarding self-harm. These women tended to be younger (P = .034), with an median age of 28 at their first visit versus 31 for those who screened negative, and were more likely to be publicly insured (P = .013) and without a partner (P = .005).

Patients who screened positive were more likely to have a history of substance use or history of a previous psychiatric diagnosis (P < .0001 for both). In addition, more patients who screened positive (49%) than those who screened negative (26%) had fetal complications (P < .001).

”There are some interesting subgroups of patients who are screening positive for depressive symptoms early on in pregnancy,” Ms. Jang said. Some come into pregnancy with preexisting mental health conditions while others have situational depressive symptoms, such as the subgroup referred to social work who had diagnosed fetal complications, she said. “Then there’s a whole other group of patients who are developing new symptoms during pregnancy.”

Patients who screened positive tended to start prenatal care later, at a median 12.3 weeks gestational age, than patients who screened negative, at a median 10.7 weeks gestational age (P = .002), the analysis found.

The number of routine prenatal care visits did not significantly differ between those who screened positive and those who screened negative, but patients with positive depression screens were almost half as likely to complete glucose tolerance testing (odds ratio, 0.6) or group B streptococcus testing (OR, 0.56) after adjusting for insurance status, gravidity, and gestational age at the patient’s first visit.

The researchers also identified a significant positive association between higher EPDS scores and the number of labor and delivery triage visits (P = .006). There were no significant differences in the rates of Tdap vaccination or screening for sexually transmitted infections between the two groups.
 

Poor sleep linked to later depression

The other study was prospective, using data from the PATCH Prenatal Care and Maternal and Child Health Outcomes study, which initially “compared health outcomes and satisfaction with prenatal care between patients receiving Centering Pregnancy group prenatal care and patients receiving traditional prenatal care,” the authors explained. This secondary analysis looked at sleep problems and postpartum depression.

“We don’t routinely ask patients about sleep or screen patients for sleeping issues,” lead author Carolyn Sinow, MD, a 4th-year resident at Kaiser Permanente Santa Clara (Calif.) Medical Center, said in an interview. “I think that we need to take sleep complaints more seriously overall, especially in early pregnancy.” While sleep problems in the third trimester often have more to do with discomforts from pregnancy itself, better sleep “in the first and second trimester is something we can really target with good sleep hygiene,” she added.

The 336 pregnant participants were recruited from Health Connect as long as they had a singleton pregnancy, were receiving prenatal care from Kaiser Permanente Northern California, and completed baseline questionnaires about their sleep and depression and anxiety symptoms during their first trimester between August 2020 and April 2021. Those with clinical depression or a high-risk pregnancy were excluded. The participants then completed the questionnaires again between 4 and 8 weeks post partum.

After adjusting for baseline depression and potential confounders, patients with poor sleep quality, indicated by a score greater than 5 on the Pittsburgh Sleep Quality Index (PSQI), were 12% more likely to develop postpartum depression, indicated by a score on the Patient Health Questionnaire depression scale (PHQ-8) of 10 or greater (relative risk, 1.12; 95% confidence interval, 1.01-1.25).

The two aspects of sleep that specifically correlated with postpartum depression were sleep quality and sleep latency, or taking a long time to fall asleep. Those reporting poor sleep quality were twice as likely to develop postpartum depression (relative risk, 2.18; 95% CI, 1.22-3.91), and those who took a while to fall asleep were 52% more likely to develop postpartum depression (RR, 1.52; 95% CI, 1.06-2.17).

Though the study also found prenatal sleep problems correlated with higher postpartum anxiety scores on the General Anxiety Disorder scale (GAD-7), the results were not statistically significant.

Kathleen Morrell, MD, MPH, an ob.gyn. in New York, was not involved in the study and said she was surprised it wasn’t something that had been studied much before because it makes sense.

“I always like it when studies confirm what we think should make sense, so it’s nice to see it,” Dr. Morrell said in an interview. “I think anytime you put something out, research it, and define it with numbers for doctors, that sometimes allows us to [realize], ‘Oh, that’s probably something we should be paying more attention to, especially if we have available treatments for it,’” she added.

“The clinical takeaway is that we really need to be screening for sleep pattern disruptions early in pregnancy, because even though it makes logical sense, it might not be something on our radar to think about,” Dr. Morrell said. “If people aren’t sleeping, well, their mental health is negatively affected.”

The most promising therapy for sleep issues currently is cognitive-behavioral therapy, which can accessed through various apps, Dr. Sinow said in an interview. “There are also safe interventions, such as melatonin and Unisom, that are totally safe in pregnancy that we can use to target sleep in early pregnancy.”

Dr. Morrell added that vitamin B6, often taken for nausea and vomiting during pregnancy, can also sometimes help people sleep and is safe during pregnancy.

“We know that postpartum depression does not necessarily only have a negative effect on the mother, but also has a negative effect on the infant and the family dynamic as well,” Dr. Morrell said. “So, we should be looking and screening for it so that we can offer people potential treatment because we know it can have long-term effects.”

Ms. Jang and Dr. Sinow did not have any disclosures. Dr. Morrell has done training for Nexplanon. Neither study noted external funding.

BALTIMORE – Poor prenatal sleep may increase the risk of postpartum depression, and prenatal depression may reduce the likelihood of mothers coming to their prenatal appointments, according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Together, the two studies suggest that commonly overlooked experiences in the prenatal period can have negative effects down the line if clinicians aren’t asking patients about them and addressing the issue.

”I think the national conversation around mental health in general will hopefully carry us forward to better supporting the patients who are coming in with preexisting conditions,” lead author Minnie Jang, a 4th-year medical student at Johns Hopkins University, Baltimore, said in an interview.

Most of the attention on mood disorders of pregnancy focus on the postpartum period, but preexisting or new-onset depression during pregnancy deserves more attention, Ms. Jang told attendees. ACOG recommends that clinicians screen all patients at least once during the perinatal period, but that could be anywhere from early pregnancy to the postpartum period. Ms. Jang would like to see recommendations addressing both early pregnancy and the postpartum period.

“I think there’s this framing that postpartum depression is a distinct entity from other mental health conditions whereas it’s really part of a continuum,” Ms. Jang said in an interview.

She retrospectively analyzed the medical records of all pregnant women who completed the Edinburgh Postnatal Depression Scale (EPDS) during their first or second trimesters between 2002 and 2021 at Johns Hopkins Hospital. Among the 718 women who were screened in early pregnancy, 44.6% were Black or African American, 39.7% were white, and 15.7% were of a different race. Nearly all (94%) were not Hispanic/Latino.

Most (59%) were partnered, employed (68%), and had private insurance (58%). Only 7% used tobacco while 11% used alcohol and 6% used illicit drugs.

Twelve percent of the patients scored positive for depression, with a score of at least 10 or an affirmative answer to question 10 regarding self-harm. These women tended to be younger (P = .034), with an median age of 28 at their first visit versus 31 for those who screened negative, and were more likely to be publicly insured (P = .013) and without a partner (P = .005).

Patients who screened positive were more likely to have a history of substance use or history of a previous psychiatric diagnosis (P < .0001 for both). In addition, more patients who screened positive (49%) than those who screened negative (26%) had fetal complications (P < .001).

”There are some interesting subgroups of patients who are screening positive for depressive symptoms early on in pregnancy,” Ms. Jang said. Some come into pregnancy with preexisting mental health conditions while others have situational depressive symptoms, such as the subgroup referred to social work who had diagnosed fetal complications, she said. “Then there’s a whole other group of patients who are developing new symptoms during pregnancy.”

Patients who screened positive tended to start prenatal care later, at a median 12.3 weeks gestational age, than patients who screened negative, at a median 10.7 weeks gestational age (P = .002), the analysis found.

The number of routine prenatal care visits did not significantly differ between those who screened positive and those who screened negative, but patients with positive depression screens were almost half as likely to complete glucose tolerance testing (odds ratio, 0.6) or group B streptococcus testing (OR, 0.56) after adjusting for insurance status, gravidity, and gestational age at the patient’s first visit.

The researchers also identified a significant positive association between higher EPDS scores and the number of labor and delivery triage visits (P = .006). There were no significant differences in the rates of Tdap vaccination or screening for sexually transmitted infections between the two groups.
 

Poor sleep linked to later depression

The other study was prospective, using data from the PATCH Prenatal Care and Maternal and Child Health Outcomes study, which initially “compared health outcomes and satisfaction with prenatal care between patients receiving Centering Pregnancy group prenatal care and patients receiving traditional prenatal care,” the authors explained. This secondary analysis looked at sleep problems and postpartum depression.

“We don’t routinely ask patients about sleep or screen patients for sleeping issues,” lead author Carolyn Sinow, MD, a 4th-year resident at Kaiser Permanente Santa Clara (Calif.) Medical Center, said in an interview. “I think that we need to take sleep complaints more seriously overall, especially in early pregnancy.” While sleep problems in the third trimester often have more to do with discomforts from pregnancy itself, better sleep “in the first and second trimester is something we can really target with good sleep hygiene,” she added.

The 336 pregnant participants were recruited from Health Connect as long as they had a singleton pregnancy, were receiving prenatal care from Kaiser Permanente Northern California, and completed baseline questionnaires about their sleep and depression and anxiety symptoms during their first trimester between August 2020 and April 2021. Those with clinical depression or a high-risk pregnancy were excluded. The participants then completed the questionnaires again between 4 and 8 weeks post partum.

After adjusting for baseline depression and potential confounders, patients with poor sleep quality, indicated by a score greater than 5 on the Pittsburgh Sleep Quality Index (PSQI), were 12% more likely to develop postpartum depression, indicated by a score on the Patient Health Questionnaire depression scale (PHQ-8) of 10 or greater (relative risk, 1.12; 95% confidence interval, 1.01-1.25).

The two aspects of sleep that specifically correlated with postpartum depression were sleep quality and sleep latency, or taking a long time to fall asleep. Those reporting poor sleep quality were twice as likely to develop postpartum depression (relative risk, 2.18; 95% CI, 1.22-3.91), and those who took a while to fall asleep were 52% more likely to develop postpartum depression (RR, 1.52; 95% CI, 1.06-2.17).

Though the study also found prenatal sleep problems correlated with higher postpartum anxiety scores on the General Anxiety Disorder scale (GAD-7), the results were not statistically significant.

Kathleen Morrell, MD, MPH, an ob.gyn. in New York, was not involved in the study and said she was surprised it wasn’t something that had been studied much before because it makes sense.

“I always like it when studies confirm what we think should make sense, so it’s nice to see it,” Dr. Morrell said in an interview. “I think anytime you put something out, research it, and define it with numbers for doctors, that sometimes allows us to [realize], ‘Oh, that’s probably something we should be paying more attention to, especially if we have available treatments for it,’” she added.

“The clinical takeaway is that we really need to be screening for sleep pattern disruptions early in pregnancy, because even though it makes logical sense, it might not be something on our radar to think about,” Dr. Morrell said. “If people aren’t sleeping, well, their mental health is negatively affected.”

The most promising therapy for sleep issues currently is cognitive-behavioral therapy, which can accessed through various apps, Dr. Sinow said in an interview. “There are also safe interventions, such as melatonin and Unisom, that are totally safe in pregnancy that we can use to target sleep in early pregnancy.”

Dr. Morrell added that vitamin B6, often taken for nausea and vomiting during pregnancy, can also sometimes help people sleep and is safe during pregnancy.

“We know that postpartum depression does not necessarily only have a negative effect on the mother, but also has a negative effect on the infant and the family dynamic as well,” Dr. Morrell said. “So, we should be looking and screening for it so that we can offer people potential treatment because we know it can have long-term effects.”

Ms. Jang and Dr. Sinow did not have any disclosures. Dr. Morrell has done training for Nexplanon. Neither study noted external funding.

BALTIMORE – Poor prenatal sleep may increase the risk of postpartum depression, and prenatal depression may reduce the likelihood of mothers coming to their prenatal appointments, according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Together, the two studies suggest that commonly overlooked experiences in the prenatal period can have negative effects down the line if clinicians aren’t asking patients about them and addressing the issue.

”I think the national conversation around mental health in general will hopefully carry us forward to better supporting the patients who are coming in with preexisting conditions,” lead author Minnie Jang, a 4th-year medical student at Johns Hopkins University, Baltimore, said in an interview.

Most of the attention on mood disorders of pregnancy focus on the postpartum period, but preexisting or new-onset depression during pregnancy deserves more attention, Ms. Jang told attendees. ACOG recommends that clinicians screen all patients at least once during the perinatal period, but that could be anywhere from early pregnancy to the postpartum period. Ms. Jang would like to see recommendations addressing both early pregnancy and the postpartum period.

“I think there’s this framing that postpartum depression is a distinct entity from other mental health conditions whereas it’s really part of a continuum,” Ms. Jang said in an interview.

She retrospectively analyzed the medical records of all pregnant women who completed the Edinburgh Postnatal Depression Scale (EPDS) during their first or second trimesters between 2002 and 2021 at Johns Hopkins Hospital. Among the 718 women who were screened in early pregnancy, 44.6% were Black or African American, 39.7% were white, and 15.7% were of a different race. Nearly all (94%) were not Hispanic/Latino.

Most (59%) were partnered, employed (68%), and had private insurance (58%). Only 7% used tobacco while 11% used alcohol and 6% used illicit drugs.

Twelve percent of the patients scored positive for depression, with a score of at least 10 or an affirmative answer to question 10 regarding self-harm. These women tended to be younger (P = .034), with an median age of 28 at their first visit versus 31 for those who screened negative, and were more likely to be publicly insured (P = .013) and without a partner (P = .005).

Patients who screened positive were more likely to have a history of substance use or history of a previous psychiatric diagnosis (P < .0001 for both). In addition, more patients who screened positive (49%) than those who screened negative (26%) had fetal complications (P < .001).

”There are some interesting subgroups of patients who are screening positive for depressive symptoms early on in pregnancy,” Ms. Jang said. Some come into pregnancy with preexisting mental health conditions while others have situational depressive symptoms, such as the subgroup referred to social work who had diagnosed fetal complications, she said. “Then there’s a whole other group of patients who are developing new symptoms during pregnancy.”

Patients who screened positive tended to start prenatal care later, at a median 12.3 weeks gestational age, than patients who screened negative, at a median 10.7 weeks gestational age (P = .002), the analysis found.

The number of routine prenatal care visits did not significantly differ between those who screened positive and those who screened negative, but patients with positive depression screens were almost half as likely to complete glucose tolerance testing (odds ratio, 0.6) or group B streptococcus testing (OR, 0.56) after adjusting for insurance status, gravidity, and gestational age at the patient’s first visit.

The researchers also identified a significant positive association between higher EPDS scores and the number of labor and delivery triage visits (P = .006). There were no significant differences in the rates of Tdap vaccination or screening for sexually transmitted infections between the two groups.
 

Poor sleep linked to later depression

The other study was prospective, using data from the PATCH Prenatal Care and Maternal and Child Health Outcomes study, which initially “compared health outcomes and satisfaction with prenatal care between patients receiving Centering Pregnancy group prenatal care and patients receiving traditional prenatal care,” the authors explained. This secondary analysis looked at sleep problems and postpartum depression.

“We don’t routinely ask patients about sleep or screen patients for sleeping issues,” lead author Carolyn Sinow, MD, a 4th-year resident at Kaiser Permanente Santa Clara (Calif.) Medical Center, said in an interview. “I think that we need to take sleep complaints more seriously overall, especially in early pregnancy.” While sleep problems in the third trimester often have more to do with discomforts from pregnancy itself, better sleep “in the first and second trimester is something we can really target with good sleep hygiene,” she added.

The 336 pregnant participants were recruited from Health Connect as long as they had a singleton pregnancy, were receiving prenatal care from Kaiser Permanente Northern California, and completed baseline questionnaires about their sleep and depression and anxiety symptoms during their first trimester between August 2020 and April 2021. Those with clinical depression or a high-risk pregnancy were excluded. The participants then completed the questionnaires again between 4 and 8 weeks post partum.

After adjusting for baseline depression and potential confounders, patients with poor sleep quality, indicated by a score greater than 5 on the Pittsburgh Sleep Quality Index (PSQI), were 12% more likely to develop postpartum depression, indicated by a score on the Patient Health Questionnaire depression scale (PHQ-8) of 10 or greater (relative risk, 1.12; 95% confidence interval, 1.01-1.25).

The two aspects of sleep that specifically correlated with postpartum depression were sleep quality and sleep latency, or taking a long time to fall asleep. Those reporting poor sleep quality were twice as likely to develop postpartum depression (relative risk, 2.18; 95% CI, 1.22-3.91), and those who took a while to fall asleep were 52% more likely to develop postpartum depression (RR, 1.52; 95% CI, 1.06-2.17).

Though the study also found prenatal sleep problems correlated with higher postpartum anxiety scores on the General Anxiety Disorder scale (GAD-7), the results were not statistically significant.

Kathleen Morrell, MD, MPH, an ob.gyn. in New York, was not involved in the study and said she was surprised it wasn’t something that had been studied much before because it makes sense.

“I always like it when studies confirm what we think should make sense, so it’s nice to see it,” Dr. Morrell said in an interview. “I think anytime you put something out, research it, and define it with numbers for doctors, that sometimes allows us to [realize], ‘Oh, that’s probably something we should be paying more attention to, especially if we have available treatments for it,’” she added.

“The clinical takeaway is that we really need to be screening for sleep pattern disruptions early in pregnancy, because even though it makes logical sense, it might not be something on our radar to think about,” Dr. Morrell said. “If people aren’t sleeping, well, their mental health is negatively affected.”

The most promising therapy for sleep issues currently is cognitive-behavioral therapy, which can accessed through various apps, Dr. Sinow said in an interview. “There are also safe interventions, such as melatonin and Unisom, that are totally safe in pregnancy that we can use to target sleep in early pregnancy.”

Dr. Morrell added that vitamin B6, often taken for nausea and vomiting during pregnancy, can also sometimes help people sleep and is safe during pregnancy.

“We know that postpartum depression does not necessarily only have a negative effect on the mother, but also has a negative effect on the infant and the family dynamic as well,” Dr. Morrell said. “So, we should be looking and screening for it so that we can offer people potential treatment because we know it can have long-term effects.”

Ms. Jang and Dr. Sinow did not have any disclosures. Dr. Morrell has done training for Nexplanon. Neither study noted external funding.

DENVER – The use of mindfulness-based interventions for patients with multiple sclerosis (MS), whether delivered in person or through online video conferencing, resulted in improved cognitive function and reduced symptoms of depression, anxiety, and stress, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Two studies assessed the effects of two mindfulness-based stress reduction (MBSR) programs, one primarily in person until the pandemic forced a move to online participation, and the other exclusively online. The in-person course also found, in a subset of the participants, that blood inflammation markers matched the patients’ reported reduction in stress and loneliness.
 

Putting mindfulness to the test

Previous research has found that life stressors are linked to clinical MS flares, Chris Hemond, MD, an assistant professor of neurology at the University of Massachusetts, Worcester, told attendees. He also noted previous research exploring possible explanations for how MBSR programs might improve clinical symptoms of MS. One hypothesis involves an effect on the “forebrain limbic areas responsible for the neurobiological stress response.” Part of this study therefore involved looking for possible MRI changes before and after the MBSR program to test this hypothesis.

The study involved 23 patients, all women with relapsing remitting MS with an median age of 45, and 57% of whom were taking B cell–depleting agents. The patients’ average Expanded Disability Status Scale score was 2, and none experienced any new clinical or MRI disease activity during a 12-week observation period.

Patients volunteered to participate in the free 8-week MBSR program. Half attended MBSR classes in person while the other half had to attend virtual classes due to the pandemic. The program involved eight weekly 2.5-hour classes with daily homework assignments. The program, developed by Jon Kabat-Zinn at the University of Massachusetts, is intended to be “mental training for nonjudgmental awareness of moment-to-moment experience” that aims to “improve accuracy of perception, acceptance of intractable health-related changes, realistic sense of control, and appreciation of available life experiences,” Dr. Hemond said.

Among the 91% of participants who completed the course, 57% underwent both pre- and postcourse structural MRI scans, and 83% completed both the pre- and postcourse questionnaires. A subset of patients (53%) also provided blood samples for analysis of inflammatory gene expression markers.

“The conserved transcriptional response to adversity (CTRA) score was determined using well-established methods from 53 prespecified blood gene expression markers representing a composite of inflammation, interferon response, and immunoglobulin expression,” Dr. Hemond explained.

Participants’ average scores both pre- and post questionnaires revealed statistically significant improvements in stress, anxiety, depression, fatigue, loneliness, well-being, and interoceptive awareness (P < .01 for all).

Although precise values were not provided in the presentation, patients’ scores significantly decreased on the Brief Inventory of Perceived Stress (BIPS) for “lack of control,” “pushed,” and “conflict” (P < .03). Average scores also improved (decreased) on the Modified Fatigue Inventory Scale, the UCLA Loneliness Scale, and all three subscales of the Depression Anxiety Stress Scales assessment (P <.01). Participants’ scores increased on the Mental Health Continuum “hedonic” and “eudaimonic well-being” scales (P < .05).

Improvements on the Multidimensional Assessment of Interoceptive Awareness included self-regulation, attention regulation, “noticing” (P = .02), “not worrying” (P < .01), “emotional awareness” (P < .01), “body listening” (P < .01), and “trusting” (P < .01).

After adjustment for age, race, body mass index, medical therapy and time, the researchers found changes in inflammatory gene expression in the 12 participants who provided blood samples, and these changes correlated inversely with changes in their reported loneliness (P =.002), pain (P <.001), several interoception aspects (P < .01), and stress (P < .0001), particularly regarding feeling a lack of control.

Although no structural MRI changes were observed in the amygdala or prefrontal cortex, the researchers did see a 1% volume increase on the right-side hippocampus. Though the increase was significant (P < .01) and right hippocampal enlargement has been linked with MBSR in past studies, Dr. Hemond acknowledged the study’s small sample size and urged caution in interpreting that finding.

Dr. Hemond also reported that interaction between higher CTRA and the MSBR training attenuated the right hippocampal volume increase that was seen with MBSR, a finding which raises more questions than it answers.

The primary finding, however, was that “mindfulness-based stress reduction was associated with substantial improvement in multiple patient-reported outcomes of the debilitating ‘silent symptoms’ of MS,” Dr. Hemond told attendees. Though the study is limited by its small sample size, observational biases, and missing data, the findings suggest the possibility that MBSR is also associated with structural limbic brain changes, especially in the right hippocampus.
 

Another tool for managing MS

Ellen Mowry, MD, MCR, a professor of neurology and epidemiology at Johns Hopkins University, Baltimore, who attended the presentation, said she was very enthusiastic about this research.

“People with MS often are seeking ways that they can have self-efficacy and managing the symptoms of their disease, and we know that the disease-modifying therapies make a big difference, but we need additional therapies that can help people feel better and live better with MS,” Dr. Mowry commented.

She also acknowledged the challenges, however, in developing a mindfulness program that is accessible by a broad range of MS patients. This particular program involved several hours of work per day.

“People with MS often are either on the younger side, and they’re working and raising their family and doing all the same stuff that everybody else is doing, or they might be quite disabled and have more fatigue and other things that might make it really challenging to persist through that long of an intervention,” Dr. Mowry said.

The ideal program would be one that’s financially accessible, either through insurance, society more broadly, or another source, and which is logistically feasible for a wide range of patients. Finding a “sweet spot” with a program that doesn’t “require such a lengthy amount of time in order to see a success would be really great,” Dr. Mowry said. “You have to start somewhere, though, and you have to start with a program that’s already been tried and true and work from there.”
 

An online-only mindfulness program

One possible way to find that sweet spot is through an all-online program that patients access from home, similar to the 8-week MBSR program offered by Concord (N.H.) Hospital featured in the second study. The program was conducted via Zoom during once weekly synchronous meetings throughout 2021 and 2022 for eight cohorts of 5-15 participants each. The time of day the program was offered alternated between evening and daytime courses each quarter and was free for patients because of a hospital grant, according to Nicole Delcourt, BSN, RN, MSCN, of Concord Hospital Neurology, who facilitated patient sign-ups for the program.

Before and after each 8-week course, participants completed the PHQ-9, the PROMIS Cognitive Function, the PROMIS Fatigue–MS, and the Wasson Health Confidence assessments. Among the total 77 participating adults with MS, the completion rate was 81%, with 73% completing the preprogram assessments and 53% completed the postprogram assessments.

The assessments revealed a statistically significant increase in cognitive function and health confidence and decrease in depressive symptoms and fatigue following the program. Participants’ average PROMIS Cognitive Function scores increased from 16.7 before the program to 22.4 after, and their average Wasson Health Confidence score increased from 13.6 to 15.3 (P < .01 for both). Meanwhile, improvement in depressive symptoms was seen in participants’ decrease in Patient Health Questionnaire–9 scores from an average 6.9 to 4.6 (P = .01), and their average PROMIS Fatigue scores fell slightly but significantly from 59.3 to 55.3 (P < .05).

The participants “really felt like they were more in touch with their own feelings and emotions, and it helped them self-regulate,” Ms. Delcourt sad, “so it was really exciting.”

Patients also expressed satisfaction more subjectively in their feedback surveys. “I feel more aware of my body’s reactions to food and movement, and things that make me feel better physically,” one participant said. Another said that the class’s “lasting value ... will be to remember my own needs and how to become one with them.” Another participant praised the relevance of the printed and course materials, the speed of feedback on homework, and the quality of the video conference.

Dr. Hemond owns stock in VIVIO health. No other authors of either study reported other disclosures. Dr. Mowry has received grant funding from Biogen and Genentech. Ms. Delcourt had no disclosures. The in-person program study was funded by CMSC. Funding information for the Concord online program was unavailable.

DENVER – The use of mindfulness-based interventions for patients with multiple sclerosis (MS), whether delivered in person or through online video conferencing, resulted in improved cognitive function and reduced symptoms of depression, anxiety, and stress, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Two studies assessed the effects of two mindfulness-based stress reduction (MBSR) programs, one primarily in person until the pandemic forced a move to online participation, and the other exclusively online. The in-person course also found, in a subset of the participants, that blood inflammation markers matched the patients’ reported reduction in stress and loneliness.
 

Putting mindfulness to the test

Previous research has found that life stressors are linked to clinical MS flares, Chris Hemond, MD, an assistant professor of neurology at the University of Massachusetts, Worcester, told attendees. He also noted previous research exploring possible explanations for how MBSR programs might improve clinical symptoms of MS. One hypothesis involves an effect on the “forebrain limbic areas responsible for the neurobiological stress response.” Part of this study therefore involved looking for possible MRI changes before and after the MBSR program to test this hypothesis.

The study involved 23 patients, all women with relapsing remitting MS with an median age of 45, and 57% of whom were taking B cell–depleting agents. The patients’ average Expanded Disability Status Scale score was 2, and none experienced any new clinical or MRI disease activity during a 12-week observation period.

Patients volunteered to participate in the free 8-week MBSR program. Half attended MBSR classes in person while the other half had to attend virtual classes due to the pandemic. The program involved eight weekly 2.5-hour classes with daily homework assignments. The program, developed by Jon Kabat-Zinn at the University of Massachusetts, is intended to be “mental training for nonjudgmental awareness of moment-to-moment experience” that aims to “improve accuracy of perception, acceptance of intractable health-related changes, realistic sense of control, and appreciation of available life experiences,” Dr. Hemond said.

Among the 91% of participants who completed the course, 57% underwent both pre- and postcourse structural MRI scans, and 83% completed both the pre- and postcourse questionnaires. A subset of patients (53%) also provided blood samples for analysis of inflammatory gene expression markers.

“The conserved transcriptional response to adversity (CTRA) score was determined using well-established methods from 53 prespecified blood gene expression markers representing a composite of inflammation, interferon response, and immunoglobulin expression,” Dr. Hemond explained.

Participants’ average scores both pre- and post questionnaires revealed statistically significant improvements in stress, anxiety, depression, fatigue, loneliness, well-being, and interoceptive awareness (P < .01 for all).

Although precise values were not provided in the presentation, patients’ scores significantly decreased on the Brief Inventory of Perceived Stress (BIPS) for “lack of control,” “pushed,” and “conflict” (P < .03). Average scores also improved (decreased) on the Modified Fatigue Inventory Scale, the UCLA Loneliness Scale, and all three subscales of the Depression Anxiety Stress Scales assessment (P <.01). Participants’ scores increased on the Mental Health Continuum “hedonic” and “eudaimonic well-being” scales (P < .05).

Improvements on the Multidimensional Assessment of Interoceptive Awareness included self-regulation, attention regulation, “noticing” (P = .02), “not worrying” (P < .01), “emotional awareness” (P < .01), “body listening” (P < .01), and “trusting” (P < .01).

After adjustment for age, race, body mass index, medical therapy and time, the researchers found changes in inflammatory gene expression in the 12 participants who provided blood samples, and these changes correlated inversely with changes in their reported loneliness (P =.002), pain (P <.001), several interoception aspects (P < .01), and stress (P < .0001), particularly regarding feeling a lack of control.

Although no structural MRI changes were observed in the amygdala or prefrontal cortex, the researchers did see a 1% volume increase on the right-side hippocampus. Though the increase was significant (P < .01) and right hippocampal enlargement has been linked with MBSR in past studies, Dr. Hemond acknowledged the study’s small sample size and urged caution in interpreting that finding.

Dr. Hemond also reported that interaction between higher CTRA and the MSBR training attenuated the right hippocampal volume increase that was seen with MBSR, a finding which raises more questions than it answers.

The primary finding, however, was that “mindfulness-based stress reduction was associated with substantial improvement in multiple patient-reported outcomes of the debilitating ‘silent symptoms’ of MS,” Dr. Hemond told attendees. Though the study is limited by its small sample size, observational biases, and missing data, the findings suggest the possibility that MBSR is also associated with structural limbic brain changes, especially in the right hippocampus.
 

Another tool for managing MS

Ellen Mowry, MD, MCR, a professor of neurology and epidemiology at Johns Hopkins University, Baltimore, who attended the presentation, said she was very enthusiastic about this research.

“People with MS often are seeking ways that they can have self-efficacy and managing the symptoms of their disease, and we know that the disease-modifying therapies make a big difference, but we need additional therapies that can help people feel better and live better with MS,” Dr. Mowry commented.

She also acknowledged the challenges, however, in developing a mindfulness program that is accessible by a broad range of MS patients. This particular program involved several hours of work per day.

“People with MS often are either on the younger side, and they’re working and raising their family and doing all the same stuff that everybody else is doing, or they might be quite disabled and have more fatigue and other things that might make it really challenging to persist through that long of an intervention,” Dr. Mowry said.

The ideal program would be one that’s financially accessible, either through insurance, society more broadly, or another source, and which is logistically feasible for a wide range of patients. Finding a “sweet spot” with a program that doesn’t “require such a lengthy amount of time in order to see a success would be really great,” Dr. Mowry said. “You have to start somewhere, though, and you have to start with a program that’s already been tried and true and work from there.”
 

An online-only mindfulness program

One possible way to find that sweet spot is through an all-online program that patients access from home, similar to the 8-week MBSR program offered by Concord (N.H.) Hospital featured in the second study. The program was conducted via Zoom during once weekly synchronous meetings throughout 2021 and 2022 for eight cohorts of 5-15 participants each. The time of day the program was offered alternated between evening and daytime courses each quarter and was free for patients because of a hospital grant, according to Nicole Delcourt, BSN, RN, MSCN, of Concord Hospital Neurology, who facilitated patient sign-ups for the program.

Before and after each 8-week course, participants completed the PHQ-9, the PROMIS Cognitive Function, the PROMIS Fatigue–MS, and the Wasson Health Confidence assessments. Among the total 77 participating adults with MS, the completion rate was 81%, with 73% completing the preprogram assessments and 53% completed the postprogram assessments.

The assessments revealed a statistically significant increase in cognitive function and health confidence and decrease in depressive symptoms and fatigue following the program. Participants’ average PROMIS Cognitive Function scores increased from 16.7 before the program to 22.4 after, and their average Wasson Health Confidence score increased from 13.6 to 15.3 (P < .01 for both). Meanwhile, improvement in depressive symptoms was seen in participants’ decrease in Patient Health Questionnaire–9 scores from an average 6.9 to 4.6 (P = .01), and their average PROMIS Fatigue scores fell slightly but significantly from 59.3 to 55.3 (P < .05).

The participants “really felt like they were more in touch with their own feelings and emotions, and it helped them self-regulate,” Ms. Delcourt sad, “so it was really exciting.”

Patients also expressed satisfaction more subjectively in their feedback surveys. “I feel more aware of my body’s reactions to food and movement, and things that make me feel better physically,” one participant said. Another said that the class’s “lasting value ... will be to remember my own needs and how to become one with them.” Another participant praised the relevance of the printed and course materials, the speed of feedback on homework, and the quality of the video conference.

Dr. Hemond owns stock in VIVIO health. No other authors of either study reported other disclosures. Dr. Mowry has received grant funding from Biogen and Genentech. Ms. Delcourt had no disclosures. The in-person program study was funded by CMSC. Funding information for the Concord online program was unavailable.

DENVER – The use of mindfulness-based interventions for patients with multiple sclerosis (MS), whether delivered in person or through online video conferencing, resulted in improved cognitive function and reduced symptoms of depression, anxiety, and stress, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Two studies assessed the effects of two mindfulness-based stress reduction (MBSR) programs, one primarily in person until the pandemic forced a move to online participation, and the other exclusively online. The in-person course also found, in a subset of the participants, that blood inflammation markers matched the patients’ reported reduction in stress and loneliness.
 

Putting mindfulness to the test

Previous research has found that life stressors are linked to clinical MS flares, Chris Hemond, MD, an assistant professor of neurology at the University of Massachusetts, Worcester, told attendees. He also noted previous research exploring possible explanations for how MBSR programs might improve clinical symptoms of MS. One hypothesis involves an effect on the “forebrain limbic areas responsible for the neurobiological stress response.” Part of this study therefore involved looking for possible MRI changes before and after the MBSR program to test this hypothesis.

The study involved 23 patients, all women with relapsing remitting MS with an median age of 45, and 57% of whom were taking B cell–depleting agents. The patients’ average Expanded Disability Status Scale score was 2, and none experienced any new clinical or MRI disease activity during a 12-week observation period.

Patients volunteered to participate in the free 8-week MBSR program. Half attended MBSR classes in person while the other half had to attend virtual classes due to the pandemic. The program involved eight weekly 2.5-hour classes with daily homework assignments. The program, developed by Jon Kabat-Zinn at the University of Massachusetts, is intended to be “mental training for nonjudgmental awareness of moment-to-moment experience” that aims to “improve accuracy of perception, acceptance of intractable health-related changes, realistic sense of control, and appreciation of available life experiences,” Dr. Hemond said.

Among the 91% of participants who completed the course, 57% underwent both pre- and postcourse structural MRI scans, and 83% completed both the pre- and postcourse questionnaires. A subset of patients (53%) also provided blood samples for analysis of inflammatory gene expression markers.

“The conserved transcriptional response to adversity (CTRA) score was determined using well-established methods from 53 prespecified blood gene expression markers representing a composite of inflammation, interferon response, and immunoglobulin expression,” Dr. Hemond explained.

Participants’ average scores both pre- and post questionnaires revealed statistically significant improvements in stress, anxiety, depression, fatigue, loneliness, well-being, and interoceptive awareness (P < .01 for all).

Although precise values were not provided in the presentation, patients’ scores significantly decreased on the Brief Inventory of Perceived Stress (BIPS) for “lack of control,” “pushed,” and “conflict” (P < .03). Average scores also improved (decreased) on the Modified Fatigue Inventory Scale, the UCLA Loneliness Scale, and all three subscales of the Depression Anxiety Stress Scales assessment (P <.01). Participants’ scores increased on the Mental Health Continuum “hedonic” and “eudaimonic well-being” scales (P < .05).

Improvements on the Multidimensional Assessment of Interoceptive Awareness included self-regulation, attention regulation, “noticing” (P = .02), “not worrying” (P < .01), “emotional awareness” (P < .01), “body listening” (P < .01), and “trusting” (P < .01).

After adjustment for age, race, body mass index, medical therapy and time, the researchers found changes in inflammatory gene expression in the 12 participants who provided blood samples, and these changes correlated inversely with changes in their reported loneliness (P =.002), pain (P <.001), several interoception aspects (P < .01), and stress (P < .0001), particularly regarding feeling a lack of control.

Although no structural MRI changes were observed in the amygdala or prefrontal cortex, the researchers did see a 1% volume increase on the right-side hippocampus. Though the increase was significant (P < .01) and right hippocampal enlargement has been linked with MBSR in past studies, Dr. Hemond acknowledged the study’s small sample size and urged caution in interpreting that finding.

Dr. Hemond also reported that interaction between higher CTRA and the MSBR training attenuated the right hippocampal volume increase that was seen with MBSR, a finding which raises more questions than it answers.

The primary finding, however, was that “mindfulness-based stress reduction was associated with substantial improvement in multiple patient-reported outcomes of the debilitating ‘silent symptoms’ of MS,” Dr. Hemond told attendees. Though the study is limited by its small sample size, observational biases, and missing data, the findings suggest the possibility that MBSR is also associated with structural limbic brain changes, especially in the right hippocampus.
 

Another tool for managing MS

Ellen Mowry, MD, MCR, a professor of neurology and epidemiology at Johns Hopkins University, Baltimore, who attended the presentation, said she was very enthusiastic about this research.

“People with MS often are seeking ways that they can have self-efficacy and managing the symptoms of their disease, and we know that the disease-modifying therapies make a big difference, but we need additional therapies that can help people feel better and live better with MS,” Dr. Mowry commented.

She also acknowledged the challenges, however, in developing a mindfulness program that is accessible by a broad range of MS patients. This particular program involved several hours of work per day.

“People with MS often are either on the younger side, and they’re working and raising their family and doing all the same stuff that everybody else is doing, or they might be quite disabled and have more fatigue and other things that might make it really challenging to persist through that long of an intervention,” Dr. Mowry said.

The ideal program would be one that’s financially accessible, either through insurance, society more broadly, or another source, and which is logistically feasible for a wide range of patients. Finding a “sweet spot” with a program that doesn’t “require such a lengthy amount of time in order to see a success would be really great,” Dr. Mowry said. “You have to start somewhere, though, and you have to start with a program that’s already been tried and true and work from there.”
 

An online-only mindfulness program

One possible way to find that sweet spot is through an all-online program that patients access from home, similar to the 8-week MBSR program offered by Concord (N.H.) Hospital featured in the second study. The program was conducted via Zoom during once weekly synchronous meetings throughout 2021 and 2022 for eight cohorts of 5-15 participants each. The time of day the program was offered alternated between evening and daytime courses each quarter and was free for patients because of a hospital grant, according to Nicole Delcourt, BSN, RN, MSCN, of Concord Hospital Neurology, who facilitated patient sign-ups for the program.

Before and after each 8-week course, participants completed the PHQ-9, the PROMIS Cognitive Function, the PROMIS Fatigue–MS, and the Wasson Health Confidence assessments. Among the total 77 participating adults with MS, the completion rate was 81%, with 73% completing the preprogram assessments and 53% completed the postprogram assessments.

The assessments revealed a statistically significant increase in cognitive function and health confidence and decrease in depressive symptoms and fatigue following the program. Participants’ average PROMIS Cognitive Function scores increased from 16.7 before the program to 22.4 after, and their average Wasson Health Confidence score increased from 13.6 to 15.3 (P < .01 for both). Meanwhile, improvement in depressive symptoms was seen in participants’ decrease in Patient Health Questionnaire–9 scores from an average 6.9 to 4.6 (P = .01), and their average PROMIS Fatigue scores fell slightly but significantly from 59.3 to 55.3 (P < .05).

The participants “really felt like they were more in touch with their own feelings and emotions, and it helped them self-regulate,” Ms. Delcourt sad, “so it was really exciting.”

Patients also expressed satisfaction more subjectively in their feedback surveys. “I feel more aware of my body’s reactions to food and movement, and things that make me feel better physically,” one participant said. Another said that the class’s “lasting value ... will be to remember my own needs and how to become one with them.” Another participant praised the relevance of the printed and course materials, the speed of feedback on homework, and the quality of the video conference.

Dr. Hemond owns stock in VIVIO health. No other authors of either study reported other disclosures. Dr. Mowry has received grant funding from Biogen and Genentech. Ms. Delcourt had no disclosures. The in-person program study was funded by CMSC. Funding information for the Concord online program was unavailable.

WASHINGTON – The LIBERTY AD open-label extension study of dupilumab is closing after 5 years with the small number of remaining patients showing stable and sustained improvements in skin lesions and pruritus and no new emergent side effects, Lisa Beck, MD, reported during a late-breaking session at the annual Revolutionizing Atopic Dermatitis conference.

Other recent research on the biologic has shown that it improves lesional skin barrier function and rapidly reduces the abundance of Staphylococcus aureus on lesional skin, Dr. Beck, professor of dermatology at the University of Rochester (N.Y.), said during another session at the meeting on long-term control of AD. Dr. Beck directs a laboratory at the University of Rochester Medical Center that focuses on understanding AD and is involved in the National Institute of Allergy and Infectious Diseases (NIAID)-funded Atopic Dermatitis Research Network (ADRN).

The LIBERTY AD open-label extension (OLE) study was a phase 3 trial of 2,677 adults with moderate to severe AD who had participated in previous dupilumab clinical trials and were treated with 300 mg dupilumab weekly or every other week. Concomitant treatments were permitted, including topical corticosteroids and topical calcineurin inhibitors. (The proportion of patients dosed on an every-other-week or weekly dosing schedule was not available.)

Of 334 patients (12.5%) who remained in the trial at week 260, or 5 years, 88.9% achieved at least a 75% improvement in lesion extent and severity (Eczema Area and Severity Index [EASI]-75), and 76.2% achieved an EASI-90. The proportion achieving at least a 4-point reduction in the Peak Pruritus Numerical Rating Scale (NRS) or a score of 0 was 66.5%. At 5 years, improvements “seem very stable,” with “no loss in efficacy,” Dr. Beck said.

The majority of patients who withdrew from the open-label extension trial did so because the study was terminated at their site or because of the drug’s approval and commercialization – not for a medical reason, Dr. Beck said. Over the course of the extension trial, 4% of those enrolled withdrew because of adverse events and about 2% withdrew because of lack of efficacy.

Safety of dupilumab

The extension trial lacked a control arm, so Dr. Beck and her colleagues compared safety results to those in the final data set for patients in the LIBERTY AD CHRONOS study who received dupilumab 300 mg weekly with concomitant corticosteroids. The CHRONOS study was a 1-year randomized, double-blinded placebo-controlled phase 3 trial.

The exposure-adjusted incidence rate of severe treatment-emergent adverse events (TEAE) was lower at the close of the extension trial (5 patients/100 patient years [PY]) than at the end of the CHRONOS study (5.9 patients/100 PY). The incidence of serious adverse events related to treatment was 0.6 patients/100 PY in the final open label extension study data set, compared with 0.7 patients/100 PY in the CHRONOS final data set.

Adverse event rates “are really, if anything, slightly less in the OLE study versus the CHRONOS study, which was 1 year of treatment,” Dr. Beck said. And “no new adverse events have emerged.”

During a question and answer period, Dr. Beck pointed out that existing and future “real world” registries of patients on dupilumab and other new therapies will better inform dermatologists of adverse events than clinical trials have done.
 

Ocular surface disease

In a separate presentation on the safety of biologics, Andrew Blauvelt, MD, MBA, of the Oregon Medical Research Center, Portland, said that in routine care, ocular surface disease is the most predominant side effect associated with dupilumab. “We don’t know the mechanism of action. But it’s not infectious, it’s not pink eye, and importantly, it’s not allergic conjunctivitis,” he said, noting that the spectrum of disease ranges from dry eye and eye itching to “frank conjunctivitis” and keratitis.

Most cases are mild to moderate and can often be managed with lubricating eye drops and periodic use of corticosteroid eye drops. Co-management with an ophthalmologist is often advisable, he said.

Dupilumab-associated erythema/eczema of the face was “not seen much” in clinical trials but is also being reported in the literature, largely by European researchers, Dr. Blauvelt said. “We hear a lot about red face, but I don’t think it’s much of an issue,” he said. “Most of the time, in my experience, it will [reflect] breakthrough residual AD, and I like to treat it with non-steroidal topicals.”

Occasionally, the withdrawal of steroids or allergic contact dermatitis are at play, Dr. Blauvelt said. “If you see red face in a person on dupilumab, use your clinical prowess, do a differential diagnosis, and treat accordingly.”
 

Effect on S. aureus

The vast majority of adults with moderate to severe AD have skin colonization with S. aureus, Dr. Beck said during the session on long-term control of AD. The presence of S. aureus in skin cultures correlates strongly with AD severity, type 2 immunity polarization, skin barrier disruption, and allergen sensitization, she said.

“So if we could do something to get rid of the staph and keep it away, one might imagine that would help” control the AD disease process, she said.

An ADRN study evaluated S. aureus in the skin of 71 patients who were randomized to receive dupilumab or placebo and found a “profound” effect of the biologic. “We were truly shocked by how quickly we saw a reduction in Staph aureus ... in lesional skin as early as 3 days” into treatment with dupilumab, she said of the unpublished findings. “And there is a pretty nice association with improvement in disease severity.”

Dr. Beck reported consultancy/advisory board work with Regeneron, Sanofi/Genzyme, among other disclosures. Dr. Blauvelt reported consultancy/advisory board work for Regeneron and Sanofi Genzyme and has received speakers bureau/honoraria for non-CME work for Regeneron and Sanofi, among other disclosures.

WASHINGTON – The LIBERTY AD open-label extension study of dupilumab is closing after 5 years with the small number of remaining patients showing stable and sustained improvements in skin lesions and pruritus and no new emergent side effects, Lisa Beck, MD, reported during a late-breaking session at the annual Revolutionizing Atopic Dermatitis conference.

Other recent research on the biologic has shown that it improves lesional skin barrier function and rapidly reduces the abundance of Staphylococcus aureus on lesional skin, Dr. Beck, professor of dermatology at the University of Rochester (N.Y.), said during another session at the meeting on long-term control of AD. Dr. Beck directs a laboratory at the University of Rochester Medical Center that focuses on understanding AD and is involved in the National Institute of Allergy and Infectious Diseases (NIAID)-funded Atopic Dermatitis Research Network (ADRN).

The LIBERTY AD open-label extension (OLE) study was a phase 3 trial of 2,677 adults with moderate to severe AD who had participated in previous dupilumab clinical trials and were treated with 300 mg dupilumab weekly or every other week. Concomitant treatments were permitted, including topical corticosteroids and topical calcineurin inhibitors. (The proportion of patients dosed on an every-other-week or weekly dosing schedule was not available.)

Of 334 patients (12.5%) who remained in the trial at week 260, or 5 years, 88.9% achieved at least a 75% improvement in lesion extent and severity (Eczema Area and Severity Index [EASI]-75), and 76.2% achieved an EASI-90. The proportion achieving at least a 4-point reduction in the Peak Pruritus Numerical Rating Scale (NRS) or a score of 0 was 66.5%. At 5 years, improvements “seem very stable,” with “no loss in efficacy,” Dr. Beck said.

The majority of patients who withdrew from the open-label extension trial did so because the study was terminated at their site or because of the drug’s approval and commercialization – not for a medical reason, Dr. Beck said. Over the course of the extension trial, 4% of those enrolled withdrew because of adverse events and about 2% withdrew because of lack of efficacy.

Safety of dupilumab

The extension trial lacked a control arm, so Dr. Beck and her colleagues compared safety results to those in the final data set for patients in the LIBERTY AD CHRONOS study who received dupilumab 300 mg weekly with concomitant corticosteroids. The CHRONOS study was a 1-year randomized, double-blinded placebo-controlled phase 3 trial.

The exposure-adjusted incidence rate of severe treatment-emergent adverse events (TEAE) was lower at the close of the extension trial (5 patients/100 patient years [PY]) than at the end of the CHRONOS study (5.9 patients/100 PY). The incidence of serious adverse events related to treatment was 0.6 patients/100 PY in the final open label extension study data set, compared with 0.7 patients/100 PY in the CHRONOS final data set.

Adverse event rates “are really, if anything, slightly less in the OLE study versus the CHRONOS study, which was 1 year of treatment,” Dr. Beck said. And “no new adverse events have emerged.”

During a question and answer period, Dr. Beck pointed out that existing and future “real world” registries of patients on dupilumab and other new therapies will better inform dermatologists of adverse events than clinical trials have done.
 

Ocular surface disease

In a separate presentation on the safety of biologics, Andrew Blauvelt, MD, MBA, of the Oregon Medical Research Center, Portland, said that in routine care, ocular surface disease is the most predominant side effect associated with dupilumab. “We don’t know the mechanism of action. But it’s not infectious, it’s not pink eye, and importantly, it’s not allergic conjunctivitis,” he said, noting that the spectrum of disease ranges from dry eye and eye itching to “frank conjunctivitis” and keratitis.

Most cases are mild to moderate and can often be managed with lubricating eye drops and periodic use of corticosteroid eye drops. Co-management with an ophthalmologist is often advisable, he said.

Dupilumab-associated erythema/eczema of the face was “not seen much” in clinical trials but is also being reported in the literature, largely by European researchers, Dr. Blauvelt said. “We hear a lot about red face, but I don’t think it’s much of an issue,” he said. “Most of the time, in my experience, it will [reflect] breakthrough residual AD, and I like to treat it with non-steroidal topicals.”

Occasionally, the withdrawal of steroids or allergic contact dermatitis are at play, Dr. Blauvelt said. “If you see red face in a person on dupilumab, use your clinical prowess, do a differential diagnosis, and treat accordingly.”
 

Effect on S. aureus

The vast majority of adults with moderate to severe AD have skin colonization with S. aureus, Dr. Beck said during the session on long-term control of AD. The presence of S. aureus in skin cultures correlates strongly with AD severity, type 2 immunity polarization, skin barrier disruption, and allergen sensitization, she said.

“So if we could do something to get rid of the staph and keep it away, one might imagine that would help” control the AD disease process, she said.

An ADRN study evaluated S. aureus in the skin of 71 patients who were randomized to receive dupilumab or placebo and found a “profound” effect of the biologic. “We were truly shocked by how quickly we saw a reduction in Staph aureus ... in lesional skin as early as 3 days” into treatment with dupilumab, she said of the unpublished findings. “And there is a pretty nice association with improvement in disease severity.”

Dr. Beck reported consultancy/advisory board work with Regeneron, Sanofi/Genzyme, among other disclosures. Dr. Blauvelt reported consultancy/advisory board work for Regeneron and Sanofi Genzyme and has received speakers bureau/honoraria for non-CME work for Regeneron and Sanofi, among other disclosures.

WASHINGTON – The LIBERTY AD open-label extension study of dupilumab is closing after 5 years with the small number of remaining patients showing stable and sustained improvements in skin lesions and pruritus and no new emergent side effects, Lisa Beck, MD, reported during a late-breaking session at the annual Revolutionizing Atopic Dermatitis conference.

Other recent research on the biologic has shown that it improves lesional skin barrier function and rapidly reduces the abundance of Staphylococcus aureus on lesional skin, Dr. Beck, professor of dermatology at the University of Rochester (N.Y.), said during another session at the meeting on long-term control of AD. Dr. Beck directs a laboratory at the University of Rochester Medical Center that focuses on understanding AD and is involved in the National Institute of Allergy and Infectious Diseases (NIAID)-funded Atopic Dermatitis Research Network (ADRN).

The LIBERTY AD open-label extension (OLE) study was a phase 3 trial of 2,677 adults with moderate to severe AD who had participated in previous dupilumab clinical trials and were treated with 300 mg dupilumab weekly or every other week. Concomitant treatments were permitted, including topical corticosteroids and topical calcineurin inhibitors. (The proportion of patients dosed on an every-other-week or weekly dosing schedule was not available.)

Of 334 patients (12.5%) who remained in the trial at week 260, or 5 years, 88.9% achieved at least a 75% improvement in lesion extent and severity (Eczema Area and Severity Index [EASI]-75), and 76.2% achieved an EASI-90. The proportion achieving at least a 4-point reduction in the Peak Pruritus Numerical Rating Scale (NRS) or a score of 0 was 66.5%. At 5 years, improvements “seem very stable,” with “no loss in efficacy,” Dr. Beck said.

The majority of patients who withdrew from the open-label extension trial did so because the study was terminated at their site or because of the drug’s approval and commercialization – not for a medical reason, Dr. Beck said. Over the course of the extension trial, 4% of those enrolled withdrew because of adverse events and about 2% withdrew because of lack of efficacy.

Safety of dupilumab

The extension trial lacked a control arm, so Dr. Beck and her colleagues compared safety results to those in the final data set for patients in the LIBERTY AD CHRONOS study who received dupilumab 300 mg weekly with concomitant corticosteroids. The CHRONOS study was a 1-year randomized, double-blinded placebo-controlled phase 3 trial.

The exposure-adjusted incidence rate of severe treatment-emergent adverse events (TEAE) was lower at the close of the extension trial (5 patients/100 patient years [PY]) than at the end of the CHRONOS study (5.9 patients/100 PY). The incidence of serious adverse events related to treatment was 0.6 patients/100 PY in the final open label extension study data set, compared with 0.7 patients/100 PY in the CHRONOS final data set.

Adverse event rates “are really, if anything, slightly less in the OLE study versus the CHRONOS study, which was 1 year of treatment,” Dr. Beck said. And “no new adverse events have emerged.”

During a question and answer period, Dr. Beck pointed out that existing and future “real world” registries of patients on dupilumab and other new therapies will better inform dermatologists of adverse events than clinical trials have done.
 

Ocular surface disease

In a separate presentation on the safety of biologics, Andrew Blauvelt, MD, MBA, of the Oregon Medical Research Center, Portland, said that in routine care, ocular surface disease is the most predominant side effect associated with dupilumab. “We don’t know the mechanism of action. But it’s not infectious, it’s not pink eye, and importantly, it’s not allergic conjunctivitis,” he said, noting that the spectrum of disease ranges from dry eye and eye itching to “frank conjunctivitis” and keratitis.

Most cases are mild to moderate and can often be managed with lubricating eye drops and periodic use of corticosteroid eye drops. Co-management with an ophthalmologist is often advisable, he said.

Dupilumab-associated erythema/eczema of the face was “not seen much” in clinical trials but is also being reported in the literature, largely by European researchers, Dr. Blauvelt said. “We hear a lot about red face, but I don’t think it’s much of an issue,” he said. “Most of the time, in my experience, it will [reflect] breakthrough residual AD, and I like to treat it with non-steroidal topicals.”

Occasionally, the withdrawal of steroids or allergic contact dermatitis are at play, Dr. Blauvelt said. “If you see red face in a person on dupilumab, use your clinical prowess, do a differential diagnosis, and treat accordingly.”
 

Effect on S. aureus

The vast majority of adults with moderate to severe AD have skin colonization with S. aureus, Dr. Beck said during the session on long-term control of AD. The presence of S. aureus in skin cultures correlates strongly with AD severity, type 2 immunity polarization, skin barrier disruption, and allergen sensitization, she said.

“So if we could do something to get rid of the staph and keep it away, one might imagine that would help” control the AD disease process, she said.

An ADRN study evaluated S. aureus in the skin of 71 patients who were randomized to receive dupilumab or placebo and found a “profound” effect of the biologic. “We were truly shocked by how quickly we saw a reduction in Staph aureus ... in lesional skin as early as 3 days” into treatment with dupilumab, she said of the unpublished findings. “And there is a pretty nice association with improvement in disease severity.”

Dr. Beck reported consultancy/advisory board work with Regeneron, Sanofi/Genzyme, among other disclosures. Dr. Blauvelt reported consultancy/advisory board work for Regeneron and Sanofi Genzyme and has received speakers bureau/honoraria for non-CME work for Regeneron and Sanofi, among other disclosures.

MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.

Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.

“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.

“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.

The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.

“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.

Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.

In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.

A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.

“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.

He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”

“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.

The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.

Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.

Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.

“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.

Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”

Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”

Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”

Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.

MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.

Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.

“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.

“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.

The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.

“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.

Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.

In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.

A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.

“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.

He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”

“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.

The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.

Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.

Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.

“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.

Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”

Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”

Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”

Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.

MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.

Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.

“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.

“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.

The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.

“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.

Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.

In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.

A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.

“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.

He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”

“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.

The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.

Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.

Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.

“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.

Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”

Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”

Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”

Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.

MILAN – About 80% of patients with gout who took the investigational selective uric acid transporter 1 (URAT1) inhibitor AR882 over 3 months reduced their serum uric acid levels to below recommended thresholds (below 5 or 4 mg/dL) for better flare and tophi reduction in a phase 2b study.

The drug was well tolerated, and patients with comorbidities did not require any adjustments in disease management.

At 75 mg, the highest tested dose of AR882, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy in the intent-to-treat population, whereas in the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

Becky McCall/MDedge News

“These efficacy results are not typically what you see with a once-daily oral medication, so it is really exciting,” Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, San Diego, said in presenting the results at the annual European Congress of Rheumatology.

“Regardless of whether you’re treating subclinical, hidden crystal deposition, versus clinically visible tophi, versus chronic, debilitating gout, we believe that AR882 has the potential to treat the entire gout spectrum with a once-daily monotherapy,” Dr. Keenan asserted.

“Currently, most gout patients around the world do not have a safe, effective, and easy to use alternative to allopurinol or febuxostat, which decrease the production of uric acid,” he said. “AR882 is a URAT1 inhibitor that goes to the root of the problem in over 90% of gout patients, helping the kidneys eliminate uric acid to levels similar to all those without hyperuricemia and gout.”

Abhishek Abhishek, MD, professor of rheumatology at the University of Nottingham (England), welcomed the study. “It’s a promising study and the reduction in uric acid was substantial. It was a small study and a larger phase 3 study is needed, but it does offer real hope for patients with gout as a third treatment option because we only have allopurinol and febuxostat, so if it is shown efficacious and safe and gets approved, then it’ll help more patients with gout.”

Anne-Kathrin Tausche, MD, a rheumatologist from University Clinic Dresden (Germany), said: “These results are really impressive. We’ve lost lesinurad now because Grünenthal no longer produces it, so this might be a good alternative for patients with severe gout.

“It is favorable with [few] side effects. With allopurinol, we have to titrate it in patients with poor renal function, but it doesn’t seem to be the case with this drug. I really hope they start phase 3 soon,” she added.
 

Phase 2 study, but promising results

Results of the global phase 2b, randomized, double-blind trial compared the safety, tolerability, and efficacy of AR882 against placebo in patients with gout.

A total of 140 patients with gout, aged 18-75 years with an estimated glomerular filtration rate (eGFR) > 30 mL/min, were recruited across the United States, Australia, and Taiwan. Patients received either once-daily AR882 50 mg (n = 46) for 12 weeks, AR882 50 mg for 2 weeks and then AR882 75 mg (n = 47) for 10 weeks, or matching placebo for 12 weeks (n = 47). Flare prophylaxis with daily colchicine started 10 days prior to the first dose and continued throughout the study.

“Patient characteristics were typical for gout trials except for having a very diverse population,” he said. The trial included 57.9% White, 27.9% Asian, and 15% Black patients. They had a mean age of 55 years, body mass index 31-32 kg/m². There was a range of comorbidities including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, evenly distributed across placebo and AR882 treatment groups.

The efficacy endpoints were the proportion of patients who reached serum uric acid below 6, 5, 4, and 3 mg/dL, at 6 weeks of therapy, while safety was also monitored throughout the study. Reductions in serum uric acid at weeks 2, 4, 6, 12 were exploratory endpoints.

The primary endpoint of the percentage of patients below < 6 mg/dL at 6 weeks in the intent-to-treat population was met by 66% with AR882 at the lower dose (50 mg) and 84% at the higher dose (75 mg).

With the 50-mg dose, serum uric acid was reduced at week 6 to < 5mg/dL by 41%, < 4mg/dL by 12%, and < 3mg/dL by 2%, whereas these percentages were 68%, 52%, and 23%, respectively, with the 75-mg dose.

Exploratory endpoints showed that by week 12, serum uric acid levels dropped from baseline 8.6 mg/dL to about 5.0 mg/dL with AR882 50 mg and from baseline 8.6 mg/dL to about 3.5 mg/dL with AR882 75 mg. Also at week 12, 55% and 23% reached serum uric acid levels of < 4mg/dL and < 3mg/dL in the intent-to-treat population. No change was observed in the placebo group.

All adverse events were mild to moderate, with the most prevalent being gout flares. There was little difference between doses. There were no clinically significant changes in a total of 778 post-dose measurements of alanine transaminase (ALT) and aspartate transaminase (AST) and 723 post-dose triplicated electrocardiogram (ECG) measurements.

Dr. Keenan is chief medical officer of Arthrosi Therapeutics. Dr. Tausche and Dr. Abhishek have no relevant financial relationships to disclose.

MILAN – About 80% of patients with gout who took the investigational selective uric acid transporter 1 (URAT1) inhibitor AR882 over 3 months reduced their serum uric acid levels to below recommended thresholds (below 5 or 4 mg/dL) for better flare and tophi reduction in a phase 2b study.

The drug was well tolerated, and patients with comorbidities did not require any adjustments in disease management.

At 75 mg, the highest tested dose of AR882, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy in the intent-to-treat population, whereas in the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

Becky McCall/MDedge News

“These efficacy results are not typically what you see with a once-daily oral medication, so it is really exciting,” Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, San Diego, said in presenting the results at the annual European Congress of Rheumatology.

“Regardless of whether you’re treating subclinical, hidden crystal deposition, versus clinically visible tophi, versus chronic, debilitating gout, we believe that AR882 has the potential to treat the entire gout spectrum with a once-daily monotherapy,” Dr. Keenan asserted.

“Currently, most gout patients around the world do not have a safe, effective, and easy to use alternative to allopurinol or febuxostat, which decrease the production of uric acid,” he said. “AR882 is a URAT1 inhibitor that goes to the root of the problem in over 90% of gout patients, helping the kidneys eliminate uric acid to levels similar to all those without hyperuricemia and gout.”

Abhishek Abhishek, MD, professor of rheumatology at the University of Nottingham (England), welcomed the study. “It’s a promising study and the reduction in uric acid was substantial. It was a small study and a larger phase 3 study is needed, but it does offer real hope for patients with gout as a third treatment option because we only have allopurinol and febuxostat, so if it is shown efficacious and safe and gets approved, then it’ll help more patients with gout.”

Anne-Kathrin Tausche, MD, a rheumatologist from University Clinic Dresden (Germany), said: “These results are really impressive. We’ve lost lesinurad now because Grünenthal no longer produces it, so this might be a good alternative for patients with severe gout.

“It is favorable with [few] side effects. With allopurinol, we have to titrate it in patients with poor renal function, but it doesn’t seem to be the case with this drug. I really hope they start phase 3 soon,” she added.
 

Phase 2 study, but promising results

Results of the global phase 2b, randomized, double-blind trial compared the safety, tolerability, and efficacy of AR882 against placebo in patients with gout.

A total of 140 patients with gout, aged 18-75 years with an estimated glomerular filtration rate (eGFR) > 30 mL/min, were recruited across the United States, Australia, and Taiwan. Patients received either once-daily AR882 50 mg (n = 46) for 12 weeks, AR882 50 mg for 2 weeks and then AR882 75 mg (n = 47) for 10 weeks, or matching placebo for 12 weeks (n = 47). Flare prophylaxis with daily colchicine started 10 days prior to the first dose and continued throughout the study.

“Patient characteristics were typical for gout trials except for having a very diverse population,” he said. The trial included 57.9% White, 27.9% Asian, and 15% Black patients. They had a mean age of 55 years, body mass index 31-32 kg/m². There was a range of comorbidities including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, evenly distributed across placebo and AR882 treatment groups.

The efficacy endpoints were the proportion of patients who reached serum uric acid below 6, 5, 4, and 3 mg/dL, at 6 weeks of therapy, while safety was also monitored throughout the study. Reductions in serum uric acid at weeks 2, 4, 6, 12 were exploratory endpoints.

The primary endpoint of the percentage of patients below < 6 mg/dL at 6 weeks in the intent-to-treat population was met by 66% with AR882 at the lower dose (50 mg) and 84% at the higher dose (75 mg).

With the 50-mg dose, serum uric acid was reduced at week 6 to < 5mg/dL by 41%, < 4mg/dL by 12%, and < 3mg/dL by 2%, whereas these percentages were 68%, 52%, and 23%, respectively, with the 75-mg dose.

Exploratory endpoints showed that by week 12, serum uric acid levels dropped from baseline 8.6 mg/dL to about 5.0 mg/dL with AR882 50 mg and from baseline 8.6 mg/dL to about 3.5 mg/dL with AR882 75 mg. Also at week 12, 55% and 23% reached serum uric acid levels of < 4mg/dL and < 3mg/dL in the intent-to-treat population. No change was observed in the placebo group.

All adverse events were mild to moderate, with the most prevalent being gout flares. There was little difference between doses. There were no clinically significant changes in a total of 778 post-dose measurements of alanine transaminase (ALT) and aspartate transaminase (AST) and 723 post-dose triplicated electrocardiogram (ECG) measurements.

Dr. Keenan is chief medical officer of Arthrosi Therapeutics. Dr. Tausche and Dr. Abhishek have no relevant financial relationships to disclose.

MILAN – About 80% of patients with gout who took the investigational selective uric acid transporter 1 (URAT1) inhibitor AR882 over 3 months reduced their serum uric acid levels to below recommended thresholds (below 5 or 4 mg/dL) for better flare and tophi reduction in a phase 2b study.

The drug was well tolerated, and patients with comorbidities did not require any adjustments in disease management.

At 75 mg, the highest tested dose of AR882, 73% of patients had serum uric acid levels < 5 mg/dL and 55% had < 4 mg/dL by week 12 of therapy in the intent-to-treat population, whereas in the per-protocol analysis, 82% had serum uric acid levels < 5 mg/dL and 63% < 4 mg/dL.

Becky McCall/MDedge News

“These efficacy results are not typically what you see with a once-daily oral medication, so it is really exciting,” Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, San Diego, said in presenting the results at the annual European Congress of Rheumatology.

“Regardless of whether you’re treating subclinical, hidden crystal deposition, versus clinically visible tophi, versus chronic, debilitating gout, we believe that AR882 has the potential to treat the entire gout spectrum with a once-daily monotherapy,” Dr. Keenan asserted.

“Currently, most gout patients around the world do not have a safe, effective, and easy to use alternative to allopurinol or febuxostat, which decrease the production of uric acid,” he said. “AR882 is a URAT1 inhibitor that goes to the root of the problem in over 90% of gout patients, helping the kidneys eliminate uric acid to levels similar to all those without hyperuricemia and gout.”

Abhishek Abhishek, MD, professor of rheumatology at the University of Nottingham (England), welcomed the study. “It’s a promising study and the reduction in uric acid was substantial. It was a small study and a larger phase 3 study is needed, but it does offer real hope for patients with gout as a third treatment option because we only have allopurinol and febuxostat, so if it is shown efficacious and safe and gets approved, then it’ll help more patients with gout.”

Anne-Kathrin Tausche, MD, a rheumatologist from University Clinic Dresden (Germany), said: “These results are really impressive. We’ve lost lesinurad now because Grünenthal no longer produces it, so this might be a good alternative for patients with severe gout.

“It is favorable with [few] side effects. With allopurinol, we have to titrate it in patients with poor renal function, but it doesn’t seem to be the case with this drug. I really hope they start phase 3 soon,” she added.
 

Phase 2 study, but promising results

Results of the global phase 2b, randomized, double-blind trial compared the safety, tolerability, and efficacy of AR882 against placebo in patients with gout.

A total of 140 patients with gout, aged 18-75 years with an estimated glomerular filtration rate (eGFR) > 30 mL/min, were recruited across the United States, Australia, and Taiwan. Patients received either once-daily AR882 50 mg (n = 46) for 12 weeks, AR882 50 mg for 2 weeks and then AR882 75 mg (n = 47) for 10 weeks, or matching placebo for 12 weeks (n = 47). Flare prophylaxis with daily colchicine started 10 days prior to the first dose and continued throughout the study.

“Patient characteristics were typical for gout trials except for having a very diverse population,” he said. The trial included 57.9% White, 27.9% Asian, and 15% Black patients. They had a mean age of 55 years, body mass index 31-32 kg/m². There was a range of comorbidities including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, evenly distributed across placebo and AR882 treatment groups.

The efficacy endpoints were the proportion of patients who reached serum uric acid below 6, 5, 4, and 3 mg/dL, at 6 weeks of therapy, while safety was also monitored throughout the study. Reductions in serum uric acid at weeks 2, 4, 6, 12 were exploratory endpoints.

The primary endpoint of the percentage of patients below < 6 mg/dL at 6 weeks in the intent-to-treat population was met by 66% with AR882 at the lower dose (50 mg) and 84% at the higher dose (75 mg).

With the 50-mg dose, serum uric acid was reduced at week 6 to < 5mg/dL by 41%, < 4mg/dL by 12%, and < 3mg/dL by 2%, whereas these percentages were 68%, 52%, and 23%, respectively, with the 75-mg dose.

Exploratory endpoints showed that by week 12, serum uric acid levels dropped from baseline 8.6 mg/dL to about 5.0 mg/dL with AR882 50 mg and from baseline 8.6 mg/dL to about 3.5 mg/dL with AR882 75 mg. Also at week 12, 55% and 23% reached serum uric acid levels of < 4mg/dL and < 3mg/dL in the intent-to-treat population. No change was observed in the placebo group.

All adverse events were mild to moderate, with the most prevalent being gout flares. There was little difference between doses. There were no clinically significant changes in a total of 778 post-dose measurements of alanine transaminase (ALT) and aspartate transaminase (AST) and 723 post-dose triplicated electrocardiogram (ECG) measurements.

Dr. Keenan is chief medical officer of Arthrosi Therapeutics. Dr. Tausche and Dr. Abhishek have no relevant financial relationships to disclose.

CHICAGO – Patients with a certain type of brain tumor could soon be treated with an oral targeted drug instead of undergoing more toxic chemotherapy and radiation, say researchers reporting new results that could potentially change the treatment landscape.

The investigational drug vorasidenib (Servier) is awaiting approval for use in gliomas bearing mutations in IDH1 and IDH2.

Results from the pivotal phase 3 INDIGO trial show that the drug was associated with a significant delay in time to disease progression when compared with placebo.  

The median progression-free survival (PFS) was 27.7 months for patients on vorasidenib, compared with 11.1 months for patients assigned to placebo (hazard ratio for progression or death with vorasidenib of 0.39 (P < .0001).

Vorasidenib was also associated with significantly longer time to the next treatment, and patients generally tolerated the drug well, reported first author Ingo K. Mellinghoff, MD, from Memorial Sloan Kettering Cancer Center, New York.

The results show that “treatment with an oral precision medicine therapy can produce a reduction in the risk of tumor progression by 61%, so that is, we think, a significant sign of efficacy that has potential to change the landscape in this disease,” he commented.

Dr. Mellinghoff spoke at a media briefing prior to presenting the data at a plenary session at the annual meeting of the American Society of Clinical Oncology.

The study was published online in the New England Journal of Medicine to coincide with the presentation.

“What you just heard is a trial that was well done and well thought out: to use an oral, targeted, well-tolerated therapy to see if we could delay the use of our standard chemotherapy and radiation,” commented ASCO expert Glenn Lesser, MD, from Wake Forest Baptist Health in Winston-Salem, N.C., the invited discussant at the briefing.

“The results are quite striking and they’re statistically highly significant, and more importantly, they’re clinically very, very significant,” he continued.

“The results of this study really suggest that, in selected patients with IDH-mutant low-grade gliomas, we can potentially delay the use of these toxic chemotherapies and radiation, maybe for years if not many years, and as a result delay the long-term toxicities of those therapies in a group of patients who typically are experiencing long-term survival,” Dr. Lesser added.
 

Brain-penetrating oral drug

Vorasidenib is an oral inhibitor of the IDH1 and IDH2 enzymes, with the ability to cross the blood-brain barrier. Mutations in IDH1 are found in about 80% of grade 2 gliomas, and IDH2 mutations occur in about 4%.

Adjuvant chemoradiotherapy has become the standard of care for patients with IDH-mutant grade 3 gliomas and patients with IDH-mutant grade 2 tumors who are thought to be a high risk for early progression.

Many patients with IDH-mutant grade 2 gliomas are initially followed with serial MRI scans, with toxic therapies reserved for use after disease progression, Dr. Mellinghoff noted.

Vorasidenib offers the potential for delaying the use of more toxic therapies and the potential to alter the natural history of diffuse glioma while helping patients to maintain a good quality of life, he said.
 

Study details

The INDIGO trial involved 331 patients with grade 2 gliomas with IDH mutations, who were enrolled across 77 centers in 10 countries in North America, Europe, and the Middle East.

Patients were aged 12-80 years and had residual or recurrent grade 2 IDH1- or IDH2-mutated oligodendroglioma or astrocytoma, with measurable nonenhancing disease and no prior treatment for glioma (with the most recent surgery 1-5 years before randomization). They were eligible for the study if they were not in immediate need of chemotherapy and/or radiation.

After stratification by 1p/19q status and baseline tumor size, they were randomly assigned to receive either vorasidenib 40 mg daily or placebo in 28-day cycles.

At the second planned interim analysis data cutoff in September 2022, at a median follow-up of 14.2 months, 226 (68.3%) of the 331 patients remained on treatment.

The primary endpoint was median PFS by blinded independent central review, which as noted above was 16.6 months longer in those on the drug, compared with placebo.

The time to next therapy was also significantly longer with vorasidenib, with a median not yet reached, compared with 17.4 months for placebo (hazard ratio, 0.26, P < .001).

Adverse events of any grade occurring in more than 20% of those receiving vorasidenib were elevated liver enzymes, fatigue, headache, diarrhea, and nausea. Grade 3 or 4 ALT elevations occurred in 9.6% of patients assigned to vorasidenib, but not in the placebo group.

Vorasidenib received fast-track status from the Food and Drug Administration in March. It is currently being studied in a phase 1 trial in combination with pembrolizumab (Keytruda) in patients with grade 2/3 gliomas, and further exploration of the drug in combination with other agents is being considered.

The study was funded by Servier Pharmaceuticals, manufacturer of vorasidenib. Dr. Mellinghoff disclosed honoraria from Roche, a consulting or advisory role with Agios, Black Diamond Therapeutics, Debiopharm Group, Puma Biotechnology, Voyager Therapeutics, research funding from Amgen, General Electric, Lilly, and travel expenses from Agios, AstraZeneca, Puma Biotechnology, Roche, and Voyager Therapeutics. Dr. Lesser disclosed honoraria from SDP Oncology, consulting/advising for Cancer Expert Now, Agio, IN8bio, and Ono Pharmaceutical.

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

CHICAGO – Patients with a certain type of brain tumor could soon be treated with an oral targeted drug instead of undergoing more toxic chemotherapy and radiation, say researchers reporting new results that could potentially change the treatment landscape.

The investigational drug vorasidenib (Servier) is awaiting approval for use in gliomas bearing mutations in IDH1 and IDH2.

Results from the pivotal phase 3 INDIGO trial show that the drug was associated with a significant delay in time to disease progression when compared with placebo.  

The median progression-free survival (PFS) was 27.7 months for patients on vorasidenib, compared with 11.1 months for patients assigned to placebo (hazard ratio for progression or death with vorasidenib of 0.39 (P < .0001).

Vorasidenib was also associated with significantly longer time to the next treatment, and patients generally tolerated the drug well, reported first author Ingo K. Mellinghoff, MD, from Memorial Sloan Kettering Cancer Center, New York.

The results show that “treatment with an oral precision medicine therapy can produce a reduction in the risk of tumor progression by 61%, so that is, we think, a significant sign of efficacy that has potential to change the landscape in this disease,” he commented.

Dr. Mellinghoff spoke at a media briefing prior to presenting the data at a plenary session at the annual meeting of the American Society of Clinical Oncology.

The study was published online in the New England Journal of Medicine to coincide with the presentation.

“What you just heard is a trial that was well done and well thought out: to use an oral, targeted, well-tolerated therapy to see if we could delay the use of our standard chemotherapy and radiation,” commented ASCO expert Glenn Lesser, MD, from Wake Forest Baptist Health in Winston-Salem, N.C., the invited discussant at the briefing.

“The results are quite striking and they’re statistically highly significant, and more importantly, they’re clinically very, very significant,” he continued.

“The results of this study really suggest that, in selected patients with IDH-mutant low-grade gliomas, we can potentially delay the use of these toxic chemotherapies and radiation, maybe for years if not many years, and as a result delay the long-term toxicities of those therapies in a group of patients who typically are experiencing long-term survival,” Dr. Lesser added.
 

Brain-penetrating oral drug

Vorasidenib is an oral inhibitor of the IDH1 and IDH2 enzymes, with the ability to cross the blood-brain barrier. Mutations in IDH1 are found in about 80% of grade 2 gliomas, and IDH2 mutations occur in about 4%.

Adjuvant chemoradiotherapy has become the standard of care for patients with IDH-mutant grade 3 gliomas and patients with IDH-mutant grade 2 tumors who are thought to be a high risk for early progression.

Many patients with IDH-mutant grade 2 gliomas are initially followed with serial MRI scans, with toxic therapies reserved for use after disease progression, Dr. Mellinghoff noted.

Vorasidenib offers the potential for delaying the use of more toxic therapies and the potential to alter the natural history of diffuse glioma while helping patients to maintain a good quality of life, he said.
 

Study details

The INDIGO trial involved 331 patients with grade 2 gliomas with IDH mutations, who were enrolled across 77 centers in 10 countries in North America, Europe, and the Middle East.

Patients were aged 12-80 years and had residual or recurrent grade 2 IDH1- or IDH2-mutated oligodendroglioma or astrocytoma, with measurable nonenhancing disease and no prior treatment for glioma (with the most recent surgery 1-5 years before randomization). They were eligible for the study if they were not in immediate need of chemotherapy and/or radiation.

After stratification by 1p/19q status and baseline tumor size, they were randomly assigned to receive either vorasidenib 40 mg daily or placebo in 28-day cycles.

At the second planned interim analysis data cutoff in September 2022, at a median follow-up of 14.2 months, 226 (68.3%) of the 331 patients remained on treatment.

The primary endpoint was median PFS by blinded independent central review, which as noted above was 16.6 months longer in those on the drug, compared with placebo.

The time to next therapy was also significantly longer with vorasidenib, with a median not yet reached, compared with 17.4 months for placebo (hazard ratio, 0.26, P < .001).

Adverse events of any grade occurring in more than 20% of those receiving vorasidenib were elevated liver enzymes, fatigue, headache, diarrhea, and nausea. Grade 3 or 4 ALT elevations occurred in 9.6% of patients assigned to vorasidenib, but not in the placebo group.

Vorasidenib received fast-track status from the Food and Drug Administration in March. It is currently being studied in a phase 1 trial in combination with pembrolizumab (Keytruda) in patients with grade 2/3 gliomas, and further exploration of the drug in combination with other agents is being considered.

The study was funded by Servier Pharmaceuticals, manufacturer of vorasidenib. Dr. Mellinghoff disclosed honoraria from Roche, a consulting or advisory role with Agios, Black Diamond Therapeutics, Debiopharm Group, Puma Biotechnology, Voyager Therapeutics, research funding from Amgen, General Electric, Lilly, and travel expenses from Agios, AstraZeneca, Puma Biotechnology, Roche, and Voyager Therapeutics. Dr. Lesser disclosed honoraria from SDP Oncology, consulting/advising for Cancer Expert Now, Agio, IN8bio, and Ono Pharmaceutical.

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

CHICAGO – Patients with a certain type of brain tumor could soon be treated with an oral targeted drug instead of undergoing more toxic chemotherapy and radiation, say researchers reporting new results that could potentially change the treatment landscape.

The investigational drug vorasidenib (Servier) is awaiting approval for use in gliomas bearing mutations in IDH1 and IDH2.

Results from the pivotal phase 3 INDIGO trial show that the drug was associated with a significant delay in time to disease progression when compared with placebo.  

The median progression-free survival (PFS) was 27.7 months for patients on vorasidenib, compared with 11.1 months for patients assigned to placebo (hazard ratio for progression or death with vorasidenib of 0.39 (P < .0001).

Vorasidenib was also associated with significantly longer time to the next treatment, and patients generally tolerated the drug well, reported first author Ingo K. Mellinghoff, MD, from Memorial Sloan Kettering Cancer Center, New York.

The results show that “treatment with an oral precision medicine therapy can produce a reduction in the risk of tumor progression by 61%, so that is, we think, a significant sign of efficacy that has potential to change the landscape in this disease,” he commented.

Dr. Mellinghoff spoke at a media briefing prior to presenting the data at a plenary session at the annual meeting of the American Society of Clinical Oncology.

The study was published online in the New England Journal of Medicine to coincide with the presentation.

“What you just heard is a trial that was well done and well thought out: to use an oral, targeted, well-tolerated therapy to see if we could delay the use of our standard chemotherapy and radiation,” commented ASCO expert Glenn Lesser, MD, from Wake Forest Baptist Health in Winston-Salem, N.C., the invited discussant at the briefing.

“The results are quite striking and they’re statistically highly significant, and more importantly, they’re clinically very, very significant,” he continued.

“The results of this study really suggest that, in selected patients with IDH-mutant low-grade gliomas, we can potentially delay the use of these toxic chemotherapies and radiation, maybe for years if not many years, and as a result delay the long-term toxicities of those therapies in a group of patients who typically are experiencing long-term survival,” Dr. Lesser added.
 

Brain-penetrating oral drug

Vorasidenib is an oral inhibitor of the IDH1 and IDH2 enzymes, with the ability to cross the blood-brain barrier. Mutations in IDH1 are found in about 80% of grade 2 gliomas, and IDH2 mutations occur in about 4%.

Adjuvant chemoradiotherapy has become the standard of care for patients with IDH-mutant grade 3 gliomas and patients with IDH-mutant grade 2 tumors who are thought to be a high risk for early progression.

Many patients with IDH-mutant grade 2 gliomas are initially followed with serial MRI scans, with toxic therapies reserved for use after disease progression, Dr. Mellinghoff noted.

Vorasidenib offers the potential for delaying the use of more toxic therapies and the potential to alter the natural history of diffuse glioma while helping patients to maintain a good quality of life, he said.
 

Study details

The INDIGO trial involved 331 patients with grade 2 gliomas with IDH mutations, who were enrolled across 77 centers in 10 countries in North America, Europe, and the Middle East.

Patients were aged 12-80 years and had residual or recurrent grade 2 IDH1- or IDH2-mutated oligodendroglioma or astrocytoma, with measurable nonenhancing disease and no prior treatment for glioma (with the most recent surgery 1-5 years before randomization). They were eligible for the study if they were not in immediate need of chemotherapy and/or radiation.

After stratification by 1p/19q status and baseline tumor size, they were randomly assigned to receive either vorasidenib 40 mg daily or placebo in 28-day cycles.

At the second planned interim analysis data cutoff in September 2022, at a median follow-up of 14.2 months, 226 (68.3%) of the 331 patients remained on treatment.

The primary endpoint was median PFS by blinded independent central review, which as noted above was 16.6 months longer in those on the drug, compared with placebo.

The time to next therapy was also significantly longer with vorasidenib, with a median not yet reached, compared with 17.4 months for placebo (hazard ratio, 0.26, P < .001).

Adverse events of any grade occurring in more than 20% of those receiving vorasidenib were elevated liver enzymes, fatigue, headache, diarrhea, and nausea. Grade 3 or 4 ALT elevations occurred in 9.6% of patients assigned to vorasidenib, but not in the placebo group.

Vorasidenib received fast-track status from the Food and Drug Administration in March. It is currently being studied in a phase 1 trial in combination with pembrolizumab (Keytruda) in patients with grade 2/3 gliomas, and further exploration of the drug in combination with other agents is being considered.

The study was funded by Servier Pharmaceuticals, manufacturer of vorasidenib. Dr. Mellinghoff disclosed honoraria from Roche, a consulting or advisory role with Agios, Black Diamond Therapeutics, Debiopharm Group, Puma Biotechnology, Voyager Therapeutics, research funding from Amgen, General Electric, Lilly, and travel expenses from Agios, AstraZeneca, Puma Biotechnology, Roche, and Voyager Therapeutics. Dr. Lesser disclosed honoraria from SDP Oncology, consulting/advising for Cancer Expert Now, Agio, IN8bio, and Ono Pharmaceutical.

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

A new standard of care for patients with chemotherapy-naive persistent, recurrent, or metastatic cervical cancer is first-line therapy with the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) with platinum-based chemotherapy and paclitaxel – with or without bevacizumab.

This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).

“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.

He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.

“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.

At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.

“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”

Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.

“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
 

Promising start

Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.

Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.

In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.

Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
 

Latest results

Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.

In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).

In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).

Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).

Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.

The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
 

Regimen details

Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.

The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.

Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).

KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.

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

A new standard of care for patients with chemotherapy-naive persistent, recurrent, or metastatic cervical cancer is first-line therapy with the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) with platinum-based chemotherapy and paclitaxel – with or without bevacizumab.

This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).

“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.

He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.

“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.

At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.

“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”

Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.

“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
 

Promising start

Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.

Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.

In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.

Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
 

Latest results

Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.

In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).

In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).

Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).

Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.

The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
 

Regimen details

Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.

The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.

Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).

KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.

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

A new standard of care for patients with chemotherapy-naive persistent, recurrent, or metastatic cervical cancer is first-line therapy with the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) with platinum-based chemotherapy and paclitaxel – with or without bevacizumab.

This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).

“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.

He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.

“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.

At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.

“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”

Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.

“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
 

Promising start

Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.

Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.

In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.

Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
 

Latest results

Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.

In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).

In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).

Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).

Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.

The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
 

Regimen details

Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.

The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.

Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).

KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.

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