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Infectious disease experts say testing is key to reopening
The key to opening up the American economy rests on the ability to conduct mass testing, according to the Infectious Diseases Society of America (IDSA).
As policymakers weigh how to safely reopen parts of the United States, the IDSA, along with its HIV Medicine Association, issued a set of recommendations outlining the steps that would be necessary in order to begin easing physical distancing measures.
“A stepwise approach to reopening should reflect early diagnosis and enhanced surveillance for COVID-19 cases, linkage of cases to appropriate levels of care, isolation and/or quarantine, contact tracing, and data processing capabilities for state and local public health departments,” according to the recommendation document.
Some of the recommended steps include the following:
- Widespread testing and surveillance, including use of validated nucleic acid amplification assays and anti–SARS-CoV-2 antibody detection.
- The ability to diagnose, treat, and isolate individuals with COVID-19.
- Scaling up of health care capacity and supplies to manage recurrent episodic outbreaks.
- Maintaining a degree of physical distancing to prevent recurrent outbreaks, including use of masks, limiting gatherings, and continued distancing for susceptible adults.
“The recommendations stress that physical distancing policy changes must be based on relevant data and adequate public health resources and capacities and calls for a rolling and incremental approach to lifting these restrictions, ” Thomas File Jr., MD, IDSA president and a professor at Northeastern Ohio Universities, Rootstown, said during an April 17 press briefing.
The rolling approach “must reflect state and regional capacities for diagnosing, isolating, and treating people with the virus, tracing their contacts, protecting health care workers, and addressing the needs of populations disproportionately affected by COVID-19,” he continued.
In order to fully lift physical distancing restrictions, there would need to be effective treatments for COVID-19 and a protective vaccine that can be deployed to key at-risk populations, according to the recommendations.
During the call, Tina Q. Tan, MD, professor of pediatrics at Northwestern University, Chicago, and a member of the IDSA board of directors, said that easing social distancing requirements requires comprehensive data and that “one of the major missing data points” is the number of people who are currently infected or have been infected. She warned that easing restrictions too soon could have “disastrous consequences,” including an increase in spread of infection, hospitalization, and death rates, as well as overwhelming health care facilities.
“In order to reopen, we have to have the ability to safely, successfully, and rapidly diagnose and treat, as well as isolate, individuals with COVID-19, as well as track their contacts,” she said.
The implementation of more widespread, comprehensive testing would better enable targeting of resources, such as personal protective equipment, ICU beds, and ventilators, Dr. Tan said. “This is needed in order to ensure that, if there is an outbreak and it does occur again, the health care system and the first responders are ready for this,” she said.
The key to opening up the American economy rests on the ability to conduct mass testing, according to the Infectious Diseases Society of America (IDSA).
As policymakers weigh how to safely reopen parts of the United States, the IDSA, along with its HIV Medicine Association, issued a set of recommendations outlining the steps that would be necessary in order to begin easing physical distancing measures.
“A stepwise approach to reopening should reflect early diagnosis and enhanced surveillance for COVID-19 cases, linkage of cases to appropriate levels of care, isolation and/or quarantine, contact tracing, and data processing capabilities for state and local public health departments,” according to the recommendation document.
Some of the recommended steps include the following:
- Widespread testing and surveillance, including use of validated nucleic acid amplification assays and anti–SARS-CoV-2 antibody detection.
- The ability to diagnose, treat, and isolate individuals with COVID-19.
- Scaling up of health care capacity and supplies to manage recurrent episodic outbreaks.
- Maintaining a degree of physical distancing to prevent recurrent outbreaks, including use of masks, limiting gatherings, and continued distancing for susceptible adults.
“The recommendations stress that physical distancing policy changes must be based on relevant data and adequate public health resources and capacities and calls for a rolling and incremental approach to lifting these restrictions, ” Thomas File Jr., MD, IDSA president and a professor at Northeastern Ohio Universities, Rootstown, said during an April 17 press briefing.
The rolling approach “must reflect state and regional capacities for diagnosing, isolating, and treating people with the virus, tracing their contacts, protecting health care workers, and addressing the needs of populations disproportionately affected by COVID-19,” he continued.
In order to fully lift physical distancing restrictions, there would need to be effective treatments for COVID-19 and a protective vaccine that can be deployed to key at-risk populations, according to the recommendations.
During the call, Tina Q. Tan, MD, professor of pediatrics at Northwestern University, Chicago, and a member of the IDSA board of directors, said that easing social distancing requirements requires comprehensive data and that “one of the major missing data points” is the number of people who are currently infected or have been infected. She warned that easing restrictions too soon could have “disastrous consequences,” including an increase in spread of infection, hospitalization, and death rates, as well as overwhelming health care facilities.
“In order to reopen, we have to have the ability to safely, successfully, and rapidly diagnose and treat, as well as isolate, individuals with COVID-19, as well as track their contacts,” she said.
The implementation of more widespread, comprehensive testing would better enable targeting of resources, such as personal protective equipment, ICU beds, and ventilators, Dr. Tan said. “This is needed in order to ensure that, if there is an outbreak and it does occur again, the health care system and the first responders are ready for this,” she said.
The key to opening up the American economy rests on the ability to conduct mass testing, according to the Infectious Diseases Society of America (IDSA).
As policymakers weigh how to safely reopen parts of the United States, the IDSA, along with its HIV Medicine Association, issued a set of recommendations outlining the steps that would be necessary in order to begin easing physical distancing measures.
“A stepwise approach to reopening should reflect early diagnosis and enhanced surveillance for COVID-19 cases, linkage of cases to appropriate levels of care, isolation and/or quarantine, contact tracing, and data processing capabilities for state and local public health departments,” according to the recommendation document.
Some of the recommended steps include the following:
- Widespread testing and surveillance, including use of validated nucleic acid amplification assays and anti–SARS-CoV-2 antibody detection.
- The ability to diagnose, treat, and isolate individuals with COVID-19.
- Scaling up of health care capacity and supplies to manage recurrent episodic outbreaks.
- Maintaining a degree of physical distancing to prevent recurrent outbreaks, including use of masks, limiting gatherings, and continued distancing for susceptible adults.
“The recommendations stress that physical distancing policy changes must be based on relevant data and adequate public health resources and capacities and calls for a rolling and incremental approach to lifting these restrictions, ” Thomas File Jr., MD, IDSA president and a professor at Northeastern Ohio Universities, Rootstown, said during an April 17 press briefing.
The rolling approach “must reflect state and regional capacities for diagnosing, isolating, and treating people with the virus, tracing their contacts, protecting health care workers, and addressing the needs of populations disproportionately affected by COVID-19,” he continued.
In order to fully lift physical distancing restrictions, there would need to be effective treatments for COVID-19 and a protective vaccine that can be deployed to key at-risk populations, according to the recommendations.
During the call, Tina Q. Tan, MD, professor of pediatrics at Northwestern University, Chicago, and a member of the IDSA board of directors, said that easing social distancing requirements requires comprehensive data and that “one of the major missing data points” is the number of people who are currently infected or have been infected. She warned that easing restrictions too soon could have “disastrous consequences,” including an increase in spread of infection, hospitalization, and death rates, as well as overwhelming health care facilities.
“In order to reopen, we have to have the ability to safely, successfully, and rapidly diagnose and treat, as well as isolate, individuals with COVID-19, as well as track their contacts,” she said.
The implementation of more widespread, comprehensive testing would better enable targeting of resources, such as personal protective equipment, ICU beds, and ventilators, Dr. Tan said. “This is needed in order to ensure that, if there is an outbreak and it does occur again, the health care system and the first responders are ready for this,” she said.
Small-molecule CGRP receptor antagonists may pose a risk during stroke
“It turns out that these drugs make the blood vessels of the brain dysfunctional, such that the collateral channels that bring in blood to the region that is having the stroke are impaired,” explains the study’s lead author, Cenk Ayata, MD, associate professor of neurology and radiology at Harvard Medical School, Boston.
In an interview, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, talks with Dr. Ayata about his study findings, and about CGRP receptor antagonists’ potential effects if a patient has an ischemic event.
This article was updated 4/21/20.
“It turns out that these drugs make the blood vessels of the brain dysfunctional, such that the collateral channels that bring in blood to the region that is having the stroke are impaired,” explains the study’s lead author, Cenk Ayata, MD, associate professor of neurology and radiology at Harvard Medical School, Boston.
In an interview, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, talks with Dr. Ayata about his study findings, and about CGRP receptor antagonists’ potential effects if a patient has an ischemic event.
This article was updated 4/21/20.
“It turns out that these drugs make the blood vessels of the brain dysfunctional, such that the collateral channels that bring in blood to the region that is having the stroke are impaired,” explains the study’s lead author, Cenk Ayata, MD, associate professor of neurology and radiology at Harvard Medical School, Boston.
In an interview, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, talks with Dr. Ayata about his study findings, and about CGRP receptor antagonists’ potential effects if a patient has an ischemic event.
This article was updated 4/21/20.
HFpEF: Gender difference in sacubitril/valsartan response remains mystery
The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.
“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.
The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).
In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.
Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.
Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.
Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.
The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.
Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.
“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.
Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.
Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.
SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.
The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.
“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.
The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).
In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.
Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.
Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.
Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.
The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.
Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.
“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.
Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.
Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.
SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.
The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.
“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.
The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).
In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.
Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.
Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.
Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.
The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.
Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.
“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.
Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.
Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.
SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.
FROM ACC 2020
Update confirms survival benefit with trastuzumab in uterine serous carcinoma
Adding trastuzumab to carboplatin/paclitaxel improved survival in patients with advanced or recurrent HER2/Neu-positive uterine serous carcinoma (USC), according to an updated analysis from a phase 2 trial.
At a median follow-up of 25.9 months, the median progression-free survival (PFS) was 12.9 months in patients who received trastuzumab plus carboplatin/paclitaxel and 8.0 months in patients who received only carboplatin/paclitaxel. The median overall survival (OS) was 29.6 months and 24.4 months, respectively.
Amanda Nickles Fader, MD, of Johns Hopkins Medicine, Baltimore, and colleagues reported these findings in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
Confirmed benefit
The phase 2 trial was designed to assess whether trastuzumab, a humanized monoclonal antibody that targets HER2/neu – a growth factor receptor found in almost all USC cases and overexpressed in 30% of cases – would improve survival in patients with USC, Dr. Nickles Fader explained in an interview. She noted that trastuzumab has been shown to provide benefit in breast cancer patients with HER2/neu overexpression.
“[U]terine serous carcinoma ... is a very aggressive high-grade endometrial cancer subtype that is associated with really poor clinical outcomes and significant mortality,” Dr. Nickles Fader said. “It represents fewer than 10% of all uterine cancer cases, but it actually accounts for a disproportionate 40% of all deaths from uterine cancer.”
The overall survival among USC patients is about 45%, compared with 91% for more common lower-grade types of uterine cancers, she added.
“The conventional treatments for uterine serous carcinoma include surgery and then chemotherapy, but we’ve only really gotten so far by using a sort of one-size-fits-all treatment philosophy,” Dr. Nickles Fader said.
Based on preliminary findings from the current trial (J Clin Oncol. 2018 Jul 10;36[20]:2044-51), trastuzumab plus carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu-positive USC, and this updated analysis confirms the benefits of adding trastuzumab, she said.
PFS, OS, and toxicity
There were 58 evaluable patients with primary stage III-IV or recurrent USC who were randomized to receive six cycles of carboplatin/paclitaxel alone or in combination with intravenous trastuzumab given until toxicity or progression.
The median PFS at a median follow-up of 25.9 months “very significantly favored” the trastuzumab arm, Dr. Nickles Fader said. The median PFS was 12.9 months in the trastuzumab arm and 8.0 months in the carboplatin/paclitaxel arm (hazard ratio, 0.46; P = .005).
In the 41 patients undergoing primary treatment, the median PFS was 17.7 months in the trastuzumab arm and 9.3 months in the control arm (HR, 0.44; P = .015). In the 17 patients with recurrent disease, the median PFS was 9.2 months and 7.0 months, respectively (HR, 0.12; P = .004).
“We were very pleased to see that there was also an overall survival benefit of about 5 months in the trastuzumab arm, compared to the control arm,” Dr. Nickles Fader said. The median OS was 29.6 months and 24.4 months, respectively (HR, 0.58; P = .046).
The PFS and OS benefit was “particularly striking” in the stage III-IV patients, according to Dr. Nickles Fader and colleagues. In this subgroup, the median OS was not reached in the trastuzumab arm, and it was 25.4 months in the control arm (HR, 0.49; P = .041).
Long-term toxicity did not differ between the treatment arms.
Applications and next steps
“The take-home message here is women should be tested if they have this subtype,” Dr. Nickles Fader said. “If they’re newly diagnosed, they should be tested for the HER2/neu receptor, and if [it is overexpressed] and they have advanced disease, we do recommend treatment with not only the conventional treatment, but with trastuzumab added to that, because that’s where we saw the most benefit.”
This is the only trial that has ever shown a major PFS and OS difference with combination targeted therapy and conventional chemotherapy in USC, Dr. Nickles Fader noted.
“So it was really exciting to see that,” she said, adding that a “much larger cooperative group trial” is being designed by the National Cancer Institute and NRG Oncology Group to look at this approach in HER2-positive, advanced-stage uterine cancers. The trial will include patients with USC, but it will extend to other uterine cancer types as well.
“We’re looking at different combinations of anti-HER2 therapies to sort of validate the results of this trial, but also to study this in other tumors that are HER2 positive,” Dr. Nickles Fader explained.
She also stressed the importance of addressing racial disparities in survival among women with USC, as African American women have higher rates of USC and related mortality than do other groups.
“It’s going to be important to look at not only molecular targets and improving survival but also racial inequalities and potentially epigenetics to really improve survival across the board,” Dr. Nickles Fader said.
She reported having no disclosures. The trial was sponsored by Yale University in collaboration with Genentech.
SOURCE: Nickles Fader A et al. SGO 2020, Abstract 12.
Adding trastuzumab to carboplatin/paclitaxel improved survival in patients with advanced or recurrent HER2/Neu-positive uterine serous carcinoma (USC), according to an updated analysis from a phase 2 trial.
At a median follow-up of 25.9 months, the median progression-free survival (PFS) was 12.9 months in patients who received trastuzumab plus carboplatin/paclitaxel and 8.0 months in patients who received only carboplatin/paclitaxel. The median overall survival (OS) was 29.6 months and 24.4 months, respectively.
Amanda Nickles Fader, MD, of Johns Hopkins Medicine, Baltimore, and colleagues reported these findings in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
Confirmed benefit
The phase 2 trial was designed to assess whether trastuzumab, a humanized monoclonal antibody that targets HER2/neu – a growth factor receptor found in almost all USC cases and overexpressed in 30% of cases – would improve survival in patients with USC, Dr. Nickles Fader explained in an interview. She noted that trastuzumab has been shown to provide benefit in breast cancer patients with HER2/neu overexpression.
“[U]terine serous carcinoma ... is a very aggressive high-grade endometrial cancer subtype that is associated with really poor clinical outcomes and significant mortality,” Dr. Nickles Fader said. “It represents fewer than 10% of all uterine cancer cases, but it actually accounts for a disproportionate 40% of all deaths from uterine cancer.”
The overall survival among USC patients is about 45%, compared with 91% for more common lower-grade types of uterine cancers, she added.
“The conventional treatments for uterine serous carcinoma include surgery and then chemotherapy, but we’ve only really gotten so far by using a sort of one-size-fits-all treatment philosophy,” Dr. Nickles Fader said.
Based on preliminary findings from the current trial (J Clin Oncol. 2018 Jul 10;36[20]:2044-51), trastuzumab plus carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu-positive USC, and this updated analysis confirms the benefits of adding trastuzumab, she said.
PFS, OS, and toxicity
There were 58 evaluable patients with primary stage III-IV or recurrent USC who were randomized to receive six cycles of carboplatin/paclitaxel alone or in combination with intravenous trastuzumab given until toxicity or progression.
The median PFS at a median follow-up of 25.9 months “very significantly favored” the trastuzumab arm, Dr. Nickles Fader said. The median PFS was 12.9 months in the trastuzumab arm and 8.0 months in the carboplatin/paclitaxel arm (hazard ratio, 0.46; P = .005).
In the 41 patients undergoing primary treatment, the median PFS was 17.7 months in the trastuzumab arm and 9.3 months in the control arm (HR, 0.44; P = .015). In the 17 patients with recurrent disease, the median PFS was 9.2 months and 7.0 months, respectively (HR, 0.12; P = .004).
“We were very pleased to see that there was also an overall survival benefit of about 5 months in the trastuzumab arm, compared to the control arm,” Dr. Nickles Fader said. The median OS was 29.6 months and 24.4 months, respectively (HR, 0.58; P = .046).
The PFS and OS benefit was “particularly striking” in the stage III-IV patients, according to Dr. Nickles Fader and colleagues. In this subgroup, the median OS was not reached in the trastuzumab arm, and it was 25.4 months in the control arm (HR, 0.49; P = .041).
Long-term toxicity did not differ between the treatment arms.
Applications and next steps
“The take-home message here is women should be tested if they have this subtype,” Dr. Nickles Fader said. “If they’re newly diagnosed, they should be tested for the HER2/neu receptor, and if [it is overexpressed] and they have advanced disease, we do recommend treatment with not only the conventional treatment, but with trastuzumab added to that, because that’s where we saw the most benefit.”
This is the only trial that has ever shown a major PFS and OS difference with combination targeted therapy and conventional chemotherapy in USC, Dr. Nickles Fader noted.
“So it was really exciting to see that,” she said, adding that a “much larger cooperative group trial” is being designed by the National Cancer Institute and NRG Oncology Group to look at this approach in HER2-positive, advanced-stage uterine cancers. The trial will include patients with USC, but it will extend to other uterine cancer types as well.
“We’re looking at different combinations of anti-HER2 therapies to sort of validate the results of this trial, but also to study this in other tumors that are HER2 positive,” Dr. Nickles Fader explained.
She also stressed the importance of addressing racial disparities in survival among women with USC, as African American women have higher rates of USC and related mortality than do other groups.
“It’s going to be important to look at not only molecular targets and improving survival but also racial inequalities and potentially epigenetics to really improve survival across the board,” Dr. Nickles Fader said.
She reported having no disclosures. The trial was sponsored by Yale University in collaboration with Genentech.
SOURCE: Nickles Fader A et al. SGO 2020, Abstract 12.
Adding trastuzumab to carboplatin/paclitaxel improved survival in patients with advanced or recurrent HER2/Neu-positive uterine serous carcinoma (USC), according to an updated analysis from a phase 2 trial.
At a median follow-up of 25.9 months, the median progression-free survival (PFS) was 12.9 months in patients who received trastuzumab plus carboplatin/paclitaxel and 8.0 months in patients who received only carboplatin/paclitaxel. The median overall survival (OS) was 29.6 months and 24.4 months, respectively.
Amanda Nickles Fader, MD, of Johns Hopkins Medicine, Baltimore, and colleagues reported these findings in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
Confirmed benefit
The phase 2 trial was designed to assess whether trastuzumab, a humanized monoclonal antibody that targets HER2/neu – a growth factor receptor found in almost all USC cases and overexpressed in 30% of cases – would improve survival in patients with USC, Dr. Nickles Fader explained in an interview. She noted that trastuzumab has been shown to provide benefit in breast cancer patients with HER2/neu overexpression.
“[U]terine serous carcinoma ... is a very aggressive high-grade endometrial cancer subtype that is associated with really poor clinical outcomes and significant mortality,” Dr. Nickles Fader said. “It represents fewer than 10% of all uterine cancer cases, but it actually accounts for a disproportionate 40% of all deaths from uterine cancer.”
The overall survival among USC patients is about 45%, compared with 91% for more common lower-grade types of uterine cancers, she added.
“The conventional treatments for uterine serous carcinoma include surgery and then chemotherapy, but we’ve only really gotten so far by using a sort of one-size-fits-all treatment philosophy,” Dr. Nickles Fader said.
Based on preliminary findings from the current trial (J Clin Oncol. 2018 Jul 10;36[20]:2044-51), trastuzumab plus carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu-positive USC, and this updated analysis confirms the benefits of adding trastuzumab, she said.
PFS, OS, and toxicity
There were 58 evaluable patients with primary stage III-IV or recurrent USC who were randomized to receive six cycles of carboplatin/paclitaxel alone or in combination with intravenous trastuzumab given until toxicity or progression.
The median PFS at a median follow-up of 25.9 months “very significantly favored” the trastuzumab arm, Dr. Nickles Fader said. The median PFS was 12.9 months in the trastuzumab arm and 8.0 months in the carboplatin/paclitaxel arm (hazard ratio, 0.46; P = .005).
In the 41 patients undergoing primary treatment, the median PFS was 17.7 months in the trastuzumab arm and 9.3 months in the control arm (HR, 0.44; P = .015). In the 17 patients with recurrent disease, the median PFS was 9.2 months and 7.0 months, respectively (HR, 0.12; P = .004).
“We were very pleased to see that there was also an overall survival benefit of about 5 months in the trastuzumab arm, compared to the control arm,” Dr. Nickles Fader said. The median OS was 29.6 months and 24.4 months, respectively (HR, 0.58; P = .046).
The PFS and OS benefit was “particularly striking” in the stage III-IV patients, according to Dr. Nickles Fader and colleagues. In this subgroup, the median OS was not reached in the trastuzumab arm, and it was 25.4 months in the control arm (HR, 0.49; P = .041).
Long-term toxicity did not differ between the treatment arms.
Applications and next steps
“The take-home message here is women should be tested if they have this subtype,” Dr. Nickles Fader said. “If they’re newly diagnosed, they should be tested for the HER2/neu receptor, and if [it is overexpressed] and they have advanced disease, we do recommend treatment with not only the conventional treatment, but with trastuzumab added to that, because that’s where we saw the most benefit.”
This is the only trial that has ever shown a major PFS and OS difference with combination targeted therapy and conventional chemotherapy in USC, Dr. Nickles Fader noted.
“So it was really exciting to see that,” she said, adding that a “much larger cooperative group trial” is being designed by the National Cancer Institute and NRG Oncology Group to look at this approach in HER2-positive, advanced-stage uterine cancers. The trial will include patients with USC, but it will extend to other uterine cancer types as well.
“We’re looking at different combinations of anti-HER2 therapies to sort of validate the results of this trial, but also to study this in other tumors that are HER2 positive,” Dr. Nickles Fader explained.
She also stressed the importance of addressing racial disparities in survival among women with USC, as African American women have higher rates of USC and related mortality than do other groups.
“It’s going to be important to look at not only molecular targets and improving survival but also racial inequalities and potentially epigenetics to really improve survival across the board,” Dr. Nickles Fader said.
She reported having no disclosures. The trial was sponsored by Yale University in collaboration with Genentech.
SOURCE: Nickles Fader A et al. SGO 2020, Abstract 12.
FROM SGO 2020
How do neurologists choose an acute treatment for migraine?
STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. efficacy and tolerability according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.
Choosing an initial treatment
Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.
Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.
Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.
Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.
The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.
Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.
If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
Addressing treatment failure
If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.
Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
Treating migraine during pregnancy
Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.
Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.
Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.
Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.
Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.
Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.
STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. efficacy and tolerability according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.
Choosing an initial treatment
Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.
Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.
Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.
Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.
The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.
Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.
If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
Addressing treatment failure
If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.
Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
Treating migraine during pregnancy
Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.
Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.
Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.
Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.
Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.
Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.
STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. efficacy and tolerability according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.
Choosing an initial treatment
Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.
Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.
Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.
Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.
The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.
Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.
If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
Addressing treatment failure
If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.
Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
Treating migraine during pregnancy
Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.
Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.
Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.
Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.
Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.
Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.
REPORTING FROM HCNE 2020
Should ART for HIV be initiated prior to tuberculosis testing results?
Tuberculosis symptoms as defined by the World Health Organization were effective in identifying patients with TB for the purposes of same-day antiretroviral therapy (ART) initiation in patients diagnosed with HIV, according to a pooled study of patients in two clinical trials. Guidelines suggest that patients with one or more TB symptoms be investigated for active TB before initiation of ART.
However, more than 80% of patients with TB symptoms did not have the disease and faced a delay of ART initiation, despite the many benefits of same-day ART initiation, according to the study presented online at the Conference on Retroviruses & Opportunistic Infections. This year CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
In her presentation, Alana T. Brennan, PhD, of the Boston University School of Public Health discussed the pooled results of 834 patients in the SLATE (Simple Algorithm for Treatment Eligibility) I and SLATE II trials. These two trials, conducted in South Africa and Kenya, respectively, assessed two variations of a simplified algorithm for eligibility for same-day ART initiation.
A total of 834 patients at baseline reported any self-described symptoms of TB using the WHO four-symptom TB screen (cough, fever, weight loss, night sweats). Those patients with any TB symptoms were assessed by sputum samples. The outcomes were prevalence of TB symptoms, TB diagnosis, and treatment.
Among the 834 patients, 493 (60%) reported no symptoms; 215 (26%) reported one to two symptoms, and 120 (14%) reported three to four symptoms. Only 66% of the patients with one to two symptoms were tested for TB; 78% of the patients with three to four symptoms were tested. Of these, only 1% of the patients with one to two symptoms tested positive for TB, and only 2% of the patients with three to four symptoms tested positive, according to Dr. Brennan.
“More than 80% of patients with TB symptoms did not have TB, but faced delay in ART initiation. No same-day [ART] initiators reported adverse events, so we hope that there would be some reconsideration of the requirement of TB testing prior to ART initiation due to any symptom of TB. … A potential consideration of the severity of the symptoms a patient has is necessary,” Dr. Brennan concluded.
Dr. Brennan reported that there were no disclosures.
SOURCE: Brennan AT et al. CROI 2020, Abstract 720.
Tuberculosis symptoms as defined by the World Health Organization were effective in identifying patients with TB for the purposes of same-day antiretroviral therapy (ART) initiation in patients diagnosed with HIV, according to a pooled study of patients in two clinical trials. Guidelines suggest that patients with one or more TB symptoms be investigated for active TB before initiation of ART.
However, more than 80% of patients with TB symptoms did not have the disease and faced a delay of ART initiation, despite the many benefits of same-day ART initiation, according to the study presented online at the Conference on Retroviruses & Opportunistic Infections. This year CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
In her presentation, Alana T. Brennan, PhD, of the Boston University School of Public Health discussed the pooled results of 834 patients in the SLATE (Simple Algorithm for Treatment Eligibility) I and SLATE II trials. These two trials, conducted in South Africa and Kenya, respectively, assessed two variations of a simplified algorithm for eligibility for same-day ART initiation.
A total of 834 patients at baseline reported any self-described symptoms of TB using the WHO four-symptom TB screen (cough, fever, weight loss, night sweats). Those patients with any TB symptoms were assessed by sputum samples. The outcomes were prevalence of TB symptoms, TB diagnosis, and treatment.
Among the 834 patients, 493 (60%) reported no symptoms; 215 (26%) reported one to two symptoms, and 120 (14%) reported three to four symptoms. Only 66% of the patients with one to two symptoms were tested for TB; 78% of the patients with three to four symptoms were tested. Of these, only 1% of the patients with one to two symptoms tested positive for TB, and only 2% of the patients with three to four symptoms tested positive, according to Dr. Brennan.
“More than 80% of patients with TB symptoms did not have TB, but faced delay in ART initiation. No same-day [ART] initiators reported adverse events, so we hope that there would be some reconsideration of the requirement of TB testing prior to ART initiation due to any symptom of TB. … A potential consideration of the severity of the symptoms a patient has is necessary,” Dr. Brennan concluded.
Dr. Brennan reported that there were no disclosures.
SOURCE: Brennan AT et al. CROI 2020, Abstract 720.
Tuberculosis symptoms as defined by the World Health Organization were effective in identifying patients with TB for the purposes of same-day antiretroviral therapy (ART) initiation in patients diagnosed with HIV, according to a pooled study of patients in two clinical trials. Guidelines suggest that patients with one or more TB symptoms be investigated for active TB before initiation of ART.
However, more than 80% of patients with TB symptoms did not have the disease and faced a delay of ART initiation, despite the many benefits of same-day ART initiation, according to the study presented online at the Conference on Retroviruses & Opportunistic Infections. This year CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
In her presentation, Alana T. Brennan, PhD, of the Boston University School of Public Health discussed the pooled results of 834 patients in the SLATE (Simple Algorithm for Treatment Eligibility) I and SLATE II trials. These two trials, conducted in South Africa and Kenya, respectively, assessed two variations of a simplified algorithm for eligibility for same-day ART initiation.
A total of 834 patients at baseline reported any self-described symptoms of TB using the WHO four-symptom TB screen (cough, fever, weight loss, night sweats). Those patients with any TB symptoms were assessed by sputum samples. The outcomes were prevalence of TB symptoms, TB diagnosis, and treatment.
Among the 834 patients, 493 (60%) reported no symptoms; 215 (26%) reported one to two symptoms, and 120 (14%) reported three to four symptoms. Only 66% of the patients with one to two symptoms were tested for TB; 78% of the patients with three to four symptoms were tested. Of these, only 1% of the patients with one to two symptoms tested positive for TB, and only 2% of the patients with three to four symptoms tested positive, according to Dr. Brennan.
“More than 80% of patients with TB symptoms did not have TB, but faced delay in ART initiation. No same-day [ART] initiators reported adverse events, so we hope that there would be some reconsideration of the requirement of TB testing prior to ART initiation due to any symptom of TB. … A potential consideration of the severity of the symptoms a patient has is necessary,” Dr. Brennan concluded.
Dr. Brennan reported that there were no disclosures.
SOURCE: Brennan AT et al. CROI 2020, Abstract 720.
FROM CROI 2020
Sodium nitrite disappoints in cardiac arrest
Among patients who had an out-of-hospital cardiac arrest, intravenous sodium nitrite given by paramedics during resuscitation did not significantly improve their chances of being admitted to or discharged from the hospital alive.
The study was presented at the recent “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).
Lead investigator Francis Kim, MD, professor of medicine at the University of Washington, Seattle, explained that sodium nitrate is an antioxidant; animal studies have suggested that under conditions of hypoxia, it is converted into the vasodilator nitric oxide, which can increase blood flow to the brain and heart tissues.
In animal models of cardiac arrest, the use of sodium nitrite during resuscitation increased survival by almost 50%.
For the current study, 1,502 patients who had an out-of-hospital cardiac arrest were randomly assigned to receive either a low dose (45 mg) or a high dose (60 mg) of sodium nitrite or a placebo. The average age of the patients who were included in the study was 64 years, and 66% were male; 22% had ventricular fibrillation, 43% had asystole, and 29% had pulseless electrical activity.
Results showed no statistically significant differences between the groups who received placebo, low-dose sodium nitrite, or high-dose sodium nitrite on survival to hospital admission (the primary endpoint) or on hospital discharge (the secondary endpoint). There was also no difference in either endpoint in the subgroup with ventricular fibrillation.
“Our results are disappointing, especially after the promising findings in animal studies, but we feel this trial shuts the door on using this drug in this indication,” Kim said.
Discussing the study at an ACC press conference, Dhanunjaya Lakkireddy, MD, University of Kansas Hospital and Medical Center and ACC Electrophysiology Council chair, said this was “an excellent trial in the unending quest to try to improve survival in out-of-hospital cardiac arrest.
“As we all aware, if we don’t get blood circulation to the brain for more than 5 seconds, we pass out, and if don’t get blood circulation to the brain for more than 5 minutes, brain death occurs. When people suffer out-of-hospital cardiac arrest, the rate of survival is therefore dramatically lower when the ability to resuscitate goes beyond 5 minutes,” Lakkireddy noted.
He questioned why the current trial showed no effect when there had been significant early promise in animal studies. He suggested factors that could have been relevant included the time to intervention ― which was an average of 22 minutes from call to randomization ― perfusion of the brain, whether the drug cleared the blood-brain barrier, whether nitric oxide levels in the brain were sufficient, and the patient population that was included in the study.
“A large percentage of patients had asystole or pulseless electrical activity ― these are known to have worse outcomes ― and 60% of patients in the study did not have a witnessed arrest and could have been down for much longer and therefore could have had a significantly higher level of irreversible brain damage,” Lakkireddy pointed out.
“If we can understand some of the issues, we may be able to do another trial in a different subset of patients in whom the duration of arrest is significantly lower,” he commented.
The study was funded by the National Heart, Lung, and Blood Institute. Kim has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Among patients who had an out-of-hospital cardiac arrest, intravenous sodium nitrite given by paramedics during resuscitation did not significantly improve their chances of being admitted to or discharged from the hospital alive.
The study was presented at the recent “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).
Lead investigator Francis Kim, MD, professor of medicine at the University of Washington, Seattle, explained that sodium nitrate is an antioxidant; animal studies have suggested that under conditions of hypoxia, it is converted into the vasodilator nitric oxide, which can increase blood flow to the brain and heart tissues.
In animal models of cardiac arrest, the use of sodium nitrite during resuscitation increased survival by almost 50%.
For the current study, 1,502 patients who had an out-of-hospital cardiac arrest were randomly assigned to receive either a low dose (45 mg) or a high dose (60 mg) of sodium nitrite or a placebo. The average age of the patients who were included in the study was 64 years, and 66% were male; 22% had ventricular fibrillation, 43% had asystole, and 29% had pulseless electrical activity.
Results showed no statistically significant differences between the groups who received placebo, low-dose sodium nitrite, or high-dose sodium nitrite on survival to hospital admission (the primary endpoint) or on hospital discharge (the secondary endpoint). There was also no difference in either endpoint in the subgroup with ventricular fibrillation.
“Our results are disappointing, especially after the promising findings in animal studies, but we feel this trial shuts the door on using this drug in this indication,” Kim said.
Discussing the study at an ACC press conference, Dhanunjaya Lakkireddy, MD, University of Kansas Hospital and Medical Center and ACC Electrophysiology Council chair, said this was “an excellent trial in the unending quest to try to improve survival in out-of-hospital cardiac arrest.
“As we all aware, if we don’t get blood circulation to the brain for more than 5 seconds, we pass out, and if don’t get blood circulation to the brain for more than 5 minutes, brain death occurs. When people suffer out-of-hospital cardiac arrest, the rate of survival is therefore dramatically lower when the ability to resuscitate goes beyond 5 minutes,” Lakkireddy noted.
He questioned why the current trial showed no effect when there had been significant early promise in animal studies. He suggested factors that could have been relevant included the time to intervention ― which was an average of 22 minutes from call to randomization ― perfusion of the brain, whether the drug cleared the blood-brain barrier, whether nitric oxide levels in the brain were sufficient, and the patient population that was included in the study.
“A large percentage of patients had asystole or pulseless electrical activity ― these are known to have worse outcomes ― and 60% of patients in the study did not have a witnessed arrest and could have been down for much longer and therefore could have had a significantly higher level of irreversible brain damage,” Lakkireddy pointed out.
“If we can understand some of the issues, we may be able to do another trial in a different subset of patients in whom the duration of arrest is significantly lower,” he commented.
The study was funded by the National Heart, Lung, and Blood Institute. Kim has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Among patients who had an out-of-hospital cardiac arrest, intravenous sodium nitrite given by paramedics during resuscitation did not significantly improve their chances of being admitted to or discharged from the hospital alive.
The study was presented at the recent “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).
Lead investigator Francis Kim, MD, professor of medicine at the University of Washington, Seattle, explained that sodium nitrate is an antioxidant; animal studies have suggested that under conditions of hypoxia, it is converted into the vasodilator nitric oxide, which can increase blood flow to the brain and heart tissues.
In animal models of cardiac arrest, the use of sodium nitrite during resuscitation increased survival by almost 50%.
For the current study, 1,502 patients who had an out-of-hospital cardiac arrest were randomly assigned to receive either a low dose (45 mg) or a high dose (60 mg) of sodium nitrite or a placebo. The average age of the patients who were included in the study was 64 years, and 66% were male; 22% had ventricular fibrillation, 43% had asystole, and 29% had pulseless electrical activity.
Results showed no statistically significant differences between the groups who received placebo, low-dose sodium nitrite, or high-dose sodium nitrite on survival to hospital admission (the primary endpoint) or on hospital discharge (the secondary endpoint). There was also no difference in either endpoint in the subgroup with ventricular fibrillation.
“Our results are disappointing, especially after the promising findings in animal studies, but we feel this trial shuts the door on using this drug in this indication,” Kim said.
Discussing the study at an ACC press conference, Dhanunjaya Lakkireddy, MD, University of Kansas Hospital and Medical Center and ACC Electrophysiology Council chair, said this was “an excellent trial in the unending quest to try to improve survival in out-of-hospital cardiac arrest.
“As we all aware, if we don’t get blood circulation to the brain for more than 5 seconds, we pass out, and if don’t get blood circulation to the brain for more than 5 minutes, brain death occurs. When people suffer out-of-hospital cardiac arrest, the rate of survival is therefore dramatically lower when the ability to resuscitate goes beyond 5 minutes,” Lakkireddy noted.
He questioned why the current trial showed no effect when there had been significant early promise in animal studies. He suggested factors that could have been relevant included the time to intervention ― which was an average of 22 minutes from call to randomization ― perfusion of the brain, whether the drug cleared the blood-brain barrier, whether nitric oxide levels in the brain were sufficient, and the patient population that was included in the study.
“A large percentage of patients had asystole or pulseless electrical activity ― these are known to have worse outcomes ― and 60% of patients in the study did not have a witnessed arrest and could have been down for much longer and therefore could have had a significantly higher level of irreversible brain damage,” Lakkireddy pointed out.
“If we can understand some of the issues, we may be able to do another trial in a different subset of patients in whom the duration of arrest is significantly lower,” he commented.
The study was funded by the National Heart, Lung, and Blood Institute. Kim has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Bone density slow to rebound after lactation in women with HIV
Women with HIV had more bone mobilization during lactation, and attenuated skeletal recovery after lactation, compared with HIV-negative women, according to research presented during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
The study “demonstrated that there were reductions as expected in BMD during breastfeeding, and there was recovery at the end of breastfeeding, which was higher among women who were not HIV-infected compared to HIV-infected women,” said Mary Glenn Fowler, MD, speaking in a video presentation during the virtual conference. The differences between women who had HIV and the HIV-negative reference group were statistically significant (P = .003 for lumbar spine and P less than .001 for whole-body aBMD).
“We also saw that for whole-body BMD, there was recovery at the end of breastfeeding for women who were not HIV infected, but a dampened response of recovery for BMD for HIV-infected women,” she went on, adding: “These findings held after adjustment for parity, age, body mass, breastfeeding practices, duration of breastfeeding, use of [injectable medroxyprogesterone acetate], and resumption of menses.”
Dr. Fowler presented the study’s results on behalf of lead author Florence Nabwire, PhD, an investigator scientist in the nutrition and bone health group of the United Kingdom’s Medical Research Council (Cambridge).
Although it’s known that antiretroviral therapy (ART) is associated with bone loss, Dr. Fowler explained that there are only limited data in HIV-positive women who are lactating. It’s important to see what happens during lactation for this group of women because of the potential sequelae later in life of insufficient recovery from the physiological bone mobilization that occurs during lactation. The study looked at changes in areal bone mineral density (aBMD) both during and after lactation for women with HIV living in Uganda who were taking Option B+ ART, a regimen that includes tenofovir, 3TC, and efavirenz. These women were compared with a reference group of HIV-negative women.
In all, 95 women with HIV and 96 HIV negative women were recruited into the study during pregnancy. Participants were followed postpartum at weeks 2, 14, and 26, and at a final visit that occurred 14 weeks after lactation stopped.
In addition to lumbar spine, total hip, and femoral neck aBMD measurements, the investigators also obtained whole body-less-head reading.
For total hip and femoral neck aBMD, the nadir of density was seen at 26 postpartum, when a drop of about 6% was seen from baseline readings. By the final post-lactation visit, women without HIV had recovered to their baseline; for women with HIV, some recovery also occurred, but the effect was dampened, with a persistent bone density deficit of about 3% from baseline. The differences between HIV-positive and HIV-negative women in these measurements were also statistically significant, at P less than .001 for total hip aBMD differences and P = .0008 for femoral neck differences. Again, correction for multiple confounders didn’t attenuate the results, said Dr. Fowler.
“In conclusion, these data showed accentuated mobilization of hip and whole body aBMD during lactation,” said Dr. Fowler, who also noted “slower skeletal recovery post lactation for HIV-infected women.” Clinical implications of these findings aren’t currently known, she said. Further ongoing studies are aiming to tease out both mechanisms and longer-term consequences for the bone health of HIV-infected women and their children, who may also see differences in bone mineral accretion and growth.
Session moderator Risa Hoffman, MD, in introductory remarks, set the findings in some context. “As we know, HIV-positive adults have low bone mineral density, and this appears to be a result of interactions of HIV, traditional risk factors for loss of bone density, and antiretroviral therapy,” said Dr. Hoffman, director of the global health program at the University of California, Los Angeles. She added that previous work had shown that “middle-aged HIV-positive women have higher 10-year fracture incidence compared to their HIV-negative counterparts.” The current study, she said, “has both short- and long-term implications for women as they go through multiple pregnancies and multiple periods of breastfeeding.”
The study was funded by the United Kingdom’s Medical Research Council and Department for International Development as well as the Alborada Trust and the Gates Cambridge Scholarship. The authors reported no conflicts of interest.
SOURCE: Nabwire F et al. CROI 2020, Abstract 768.
Women with HIV had more bone mobilization during lactation, and attenuated skeletal recovery after lactation, compared with HIV-negative women, according to research presented during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
The study “demonstrated that there were reductions as expected in BMD during breastfeeding, and there was recovery at the end of breastfeeding, which was higher among women who were not HIV-infected compared to HIV-infected women,” said Mary Glenn Fowler, MD, speaking in a video presentation during the virtual conference. The differences between women who had HIV and the HIV-negative reference group were statistically significant (P = .003 for lumbar spine and P less than .001 for whole-body aBMD).
“We also saw that for whole-body BMD, there was recovery at the end of breastfeeding for women who were not HIV infected, but a dampened response of recovery for BMD for HIV-infected women,” she went on, adding: “These findings held after adjustment for parity, age, body mass, breastfeeding practices, duration of breastfeeding, use of [injectable medroxyprogesterone acetate], and resumption of menses.”
Dr. Fowler presented the study’s results on behalf of lead author Florence Nabwire, PhD, an investigator scientist in the nutrition and bone health group of the United Kingdom’s Medical Research Council (Cambridge).
Although it’s known that antiretroviral therapy (ART) is associated with bone loss, Dr. Fowler explained that there are only limited data in HIV-positive women who are lactating. It’s important to see what happens during lactation for this group of women because of the potential sequelae later in life of insufficient recovery from the physiological bone mobilization that occurs during lactation. The study looked at changes in areal bone mineral density (aBMD) both during and after lactation for women with HIV living in Uganda who were taking Option B+ ART, a regimen that includes tenofovir, 3TC, and efavirenz. These women were compared with a reference group of HIV-negative women.
In all, 95 women with HIV and 96 HIV negative women were recruited into the study during pregnancy. Participants were followed postpartum at weeks 2, 14, and 26, and at a final visit that occurred 14 weeks after lactation stopped.
In addition to lumbar spine, total hip, and femoral neck aBMD measurements, the investigators also obtained whole body-less-head reading.
For total hip and femoral neck aBMD, the nadir of density was seen at 26 postpartum, when a drop of about 6% was seen from baseline readings. By the final post-lactation visit, women without HIV had recovered to their baseline; for women with HIV, some recovery also occurred, but the effect was dampened, with a persistent bone density deficit of about 3% from baseline. The differences between HIV-positive and HIV-negative women in these measurements were also statistically significant, at P less than .001 for total hip aBMD differences and P = .0008 for femoral neck differences. Again, correction for multiple confounders didn’t attenuate the results, said Dr. Fowler.
“In conclusion, these data showed accentuated mobilization of hip and whole body aBMD during lactation,” said Dr. Fowler, who also noted “slower skeletal recovery post lactation for HIV-infected women.” Clinical implications of these findings aren’t currently known, she said. Further ongoing studies are aiming to tease out both mechanisms and longer-term consequences for the bone health of HIV-infected women and their children, who may also see differences in bone mineral accretion and growth.
Session moderator Risa Hoffman, MD, in introductory remarks, set the findings in some context. “As we know, HIV-positive adults have low bone mineral density, and this appears to be a result of interactions of HIV, traditional risk factors for loss of bone density, and antiretroviral therapy,” said Dr. Hoffman, director of the global health program at the University of California, Los Angeles. She added that previous work had shown that “middle-aged HIV-positive women have higher 10-year fracture incidence compared to their HIV-negative counterparts.” The current study, she said, “has both short- and long-term implications for women as they go through multiple pregnancies and multiple periods of breastfeeding.”
The study was funded by the United Kingdom’s Medical Research Council and Department for International Development as well as the Alborada Trust and the Gates Cambridge Scholarship. The authors reported no conflicts of interest.
SOURCE: Nabwire F et al. CROI 2020, Abstract 768.
Women with HIV had more bone mobilization during lactation, and attenuated skeletal recovery after lactation, compared with HIV-negative women, according to research presented during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
The study “demonstrated that there were reductions as expected in BMD during breastfeeding, and there was recovery at the end of breastfeeding, which was higher among women who were not HIV-infected compared to HIV-infected women,” said Mary Glenn Fowler, MD, speaking in a video presentation during the virtual conference. The differences between women who had HIV and the HIV-negative reference group were statistically significant (P = .003 for lumbar spine and P less than .001 for whole-body aBMD).
“We also saw that for whole-body BMD, there was recovery at the end of breastfeeding for women who were not HIV infected, but a dampened response of recovery for BMD for HIV-infected women,” she went on, adding: “These findings held after adjustment for parity, age, body mass, breastfeeding practices, duration of breastfeeding, use of [injectable medroxyprogesterone acetate], and resumption of menses.”
Dr. Fowler presented the study’s results on behalf of lead author Florence Nabwire, PhD, an investigator scientist in the nutrition and bone health group of the United Kingdom’s Medical Research Council (Cambridge).
Although it’s known that antiretroviral therapy (ART) is associated with bone loss, Dr. Fowler explained that there are only limited data in HIV-positive women who are lactating. It’s important to see what happens during lactation for this group of women because of the potential sequelae later in life of insufficient recovery from the physiological bone mobilization that occurs during lactation. The study looked at changes in areal bone mineral density (aBMD) both during and after lactation for women with HIV living in Uganda who were taking Option B+ ART, a regimen that includes tenofovir, 3TC, and efavirenz. These women were compared with a reference group of HIV-negative women.
In all, 95 women with HIV and 96 HIV negative women were recruited into the study during pregnancy. Participants were followed postpartum at weeks 2, 14, and 26, and at a final visit that occurred 14 weeks after lactation stopped.
In addition to lumbar spine, total hip, and femoral neck aBMD measurements, the investigators also obtained whole body-less-head reading.
For total hip and femoral neck aBMD, the nadir of density was seen at 26 postpartum, when a drop of about 6% was seen from baseline readings. By the final post-lactation visit, women without HIV had recovered to their baseline; for women with HIV, some recovery also occurred, but the effect was dampened, with a persistent bone density deficit of about 3% from baseline. The differences between HIV-positive and HIV-negative women in these measurements were also statistically significant, at P less than .001 for total hip aBMD differences and P = .0008 for femoral neck differences. Again, correction for multiple confounders didn’t attenuate the results, said Dr. Fowler.
“In conclusion, these data showed accentuated mobilization of hip and whole body aBMD during lactation,” said Dr. Fowler, who also noted “slower skeletal recovery post lactation for HIV-infected women.” Clinical implications of these findings aren’t currently known, she said. Further ongoing studies are aiming to tease out both mechanisms and longer-term consequences for the bone health of HIV-infected women and their children, who may also see differences in bone mineral accretion and growth.
Session moderator Risa Hoffman, MD, in introductory remarks, set the findings in some context. “As we know, HIV-positive adults have low bone mineral density, and this appears to be a result of interactions of HIV, traditional risk factors for loss of bone density, and antiretroviral therapy,” said Dr. Hoffman, director of the global health program at the University of California, Los Angeles. She added that previous work had shown that “middle-aged HIV-positive women have higher 10-year fracture incidence compared to their HIV-negative counterparts.” The current study, she said, “has both short- and long-term implications for women as they go through multiple pregnancies and multiple periods of breastfeeding.”
The study was funded by the United Kingdom’s Medical Research Council and Department for International Development as well as the Alborada Trust and the Gates Cambridge Scholarship. The authors reported no conflicts of interest.
SOURCE: Nabwire F et al. CROI 2020, Abstract 768.
FROM CROI 2020
Survey reveals gender pay discrepancies among gyn-oncs
After controlling for differences between the genders, the male gynecologic oncologists surveyed were 1.28 times more likely than their female counterparts to earn a salary above the median, according to Katherine M. Croft, MD, of the University of Virginia, Charlottesville.
Dr. Croft and colleagues reported findings from the survey in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
Of 263 members of the Society of Gynecologic Oncology who responded to the anonymous survey, 41% were women and 59% were men. The median annual salaries were $380,000 and $500,000 respectively.
“Comparing compensation by gender, there was a $120,000 difference in median salary when you compare them on a surface level,” Dr. Croft said. “Combing through the data further, we found that there were few other differences by gender.”
There were no differences between genders with respect to group size, percentage of protected research time, frequency of call, or geographic location. However, men were more likely to be compensated for extra call and were more likely to respond to obstetrical emergencies, and those differences were statistically significant.
Further, female gynecologic oncologists were younger and had been in practice for fewer years. They also were more likely to work in an academic setting and to work with residents.
“For men, the odds of making above the median salary was 1.28 times that of female providers when controlling for these differences” Dr. Croft said.
Significant compensation differences were noted based on practice setting. When these were substratified by gender, only academic or teaching hospitals and teaching hospital/community hybrids had significant pay differences by gender.
Academic or teaching hospitals comprised the largest subgroup, allowing for further analysis.
“Age and years post fellowship were the only significant differences by gender in this group,” Dr. Croft said. “Again, female providers earned less than their male counterparts, with mean compensation of $349,717, compared with $461,054.”
In fact, less than 25% of women in academic practice in this survey made above the median reported salary, Dr. Croft noted. Controlling not only for differences between male and female providers in this group but also for other known factors affecting compensation, the odds of a male provider making greater than the median salary were 1.77 times that of female providers.
Women represent nearly a third of all practicing physicians, but their salaries continue to lag behind those of men, Dr. Croft noted. She added that “this is the first study that has been presented with regards to gynecologic oncology gender salary discrepancies.”
The findings are limited by survey response bias and a potential lack of data that could explain some of the discrepancies. The study was originally designed to look at on-call compensation, so respondents were not queried about academic ranking or specific work responsibilities. Still, Dr. Croft said the findings point to a need for policy reform to ensure equitable compensation.
“My hope is that these data open a dialogue to further explore discrepancies by gender in our field,” she said.
Dr. Croft reported having no disclosures.
sworcester@mdedge.com
SOURCE: Croft K et al. SGO 2020, Abstract 15.
After controlling for differences between the genders, the male gynecologic oncologists surveyed were 1.28 times more likely than their female counterparts to earn a salary above the median, according to Katherine M. Croft, MD, of the University of Virginia, Charlottesville.
Dr. Croft and colleagues reported findings from the survey in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
Of 263 members of the Society of Gynecologic Oncology who responded to the anonymous survey, 41% were women and 59% were men. The median annual salaries were $380,000 and $500,000 respectively.
“Comparing compensation by gender, there was a $120,000 difference in median salary when you compare them on a surface level,” Dr. Croft said. “Combing through the data further, we found that there were few other differences by gender.”
There were no differences between genders with respect to group size, percentage of protected research time, frequency of call, or geographic location. However, men were more likely to be compensated for extra call and were more likely to respond to obstetrical emergencies, and those differences were statistically significant.
Further, female gynecologic oncologists were younger and had been in practice for fewer years. They also were more likely to work in an academic setting and to work with residents.
“For men, the odds of making above the median salary was 1.28 times that of female providers when controlling for these differences” Dr. Croft said.
Significant compensation differences were noted based on practice setting. When these were substratified by gender, only academic or teaching hospitals and teaching hospital/community hybrids had significant pay differences by gender.
Academic or teaching hospitals comprised the largest subgroup, allowing for further analysis.
“Age and years post fellowship were the only significant differences by gender in this group,” Dr. Croft said. “Again, female providers earned less than their male counterparts, with mean compensation of $349,717, compared with $461,054.”
In fact, less than 25% of women in academic practice in this survey made above the median reported salary, Dr. Croft noted. Controlling not only for differences between male and female providers in this group but also for other known factors affecting compensation, the odds of a male provider making greater than the median salary were 1.77 times that of female providers.
Women represent nearly a third of all practicing physicians, but their salaries continue to lag behind those of men, Dr. Croft noted. She added that “this is the first study that has been presented with regards to gynecologic oncology gender salary discrepancies.”
The findings are limited by survey response bias and a potential lack of data that could explain some of the discrepancies. The study was originally designed to look at on-call compensation, so respondents were not queried about academic ranking or specific work responsibilities. Still, Dr. Croft said the findings point to a need for policy reform to ensure equitable compensation.
“My hope is that these data open a dialogue to further explore discrepancies by gender in our field,” she said.
Dr. Croft reported having no disclosures.
sworcester@mdedge.com
SOURCE: Croft K et al. SGO 2020, Abstract 15.
After controlling for differences between the genders, the male gynecologic oncologists surveyed were 1.28 times more likely than their female counterparts to earn a salary above the median, according to Katherine M. Croft, MD, of the University of Virginia, Charlottesville.
Dr. Croft and colleagues reported findings from the survey in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
Of 263 members of the Society of Gynecologic Oncology who responded to the anonymous survey, 41% were women and 59% were men. The median annual salaries were $380,000 and $500,000 respectively.
“Comparing compensation by gender, there was a $120,000 difference in median salary when you compare them on a surface level,” Dr. Croft said. “Combing through the data further, we found that there were few other differences by gender.”
There were no differences between genders with respect to group size, percentage of protected research time, frequency of call, or geographic location. However, men were more likely to be compensated for extra call and were more likely to respond to obstetrical emergencies, and those differences were statistically significant.
Further, female gynecologic oncologists were younger and had been in practice for fewer years. They also were more likely to work in an academic setting and to work with residents.
“For men, the odds of making above the median salary was 1.28 times that of female providers when controlling for these differences” Dr. Croft said.
Significant compensation differences were noted based on practice setting. When these were substratified by gender, only academic or teaching hospitals and teaching hospital/community hybrids had significant pay differences by gender.
Academic or teaching hospitals comprised the largest subgroup, allowing for further analysis.
“Age and years post fellowship were the only significant differences by gender in this group,” Dr. Croft said. “Again, female providers earned less than their male counterparts, with mean compensation of $349,717, compared with $461,054.”
In fact, less than 25% of women in academic practice in this survey made above the median reported salary, Dr. Croft noted. Controlling not only for differences between male and female providers in this group but also for other known factors affecting compensation, the odds of a male provider making greater than the median salary were 1.77 times that of female providers.
Women represent nearly a third of all practicing physicians, but their salaries continue to lag behind those of men, Dr. Croft noted. She added that “this is the first study that has been presented with regards to gynecologic oncology gender salary discrepancies.”
The findings are limited by survey response bias and a potential lack of data that could explain some of the discrepancies. The study was originally designed to look at on-call compensation, so respondents were not queried about academic ranking or specific work responsibilities. Still, Dr. Croft said the findings point to a need for policy reform to ensure equitable compensation.
“My hope is that these data open a dialogue to further explore discrepancies by gender in our field,” she said.
Dr. Croft reported having no disclosures.
sworcester@mdedge.com
SOURCE: Croft K et al. SGO 2020, Abstract 15.
FROM SGO 2020
Experts review recent winners and losers in the RA pipeline
MAUI, HAWAII – Filgotinib, the oral Janus kinase (JAK) inhibitor now under Food and Drug Administration review for the treatment of RA, has a better safety profile than some of the approved oral JAK inhibitors, but that’s unlikely to save it from being saddled with a black-box safety warning label, experts agreed at the 2020 Rheumatology Winter Clinical Symposium.
“There’s probably a class label out there,” according to Mark C. Genovese, MD, professor of medicine and clinical chief of the division of immunology and rheumatology at Stanford (Calif.) University.
He cited the example of upadacitinib (Rinvoq), approved last year as the third oral JAK inhibitor for RA. Even though venous thromboembolic (VTE) events weren’t seen with any significantly increased frequency, compared with placebo, in the upadacitinib development program – unlike for the earlier-approved tofacitinib (Xeljanz) and baricitinib (Olumiant) –the FDA nevertheless required that upadacitinib’s product labeling include this black-box warning: “Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions.”
“I would fully expect that there’ll be a similar label in the filgotinib package insert saying that VTEs have been seen in other members of the class,” he predicted.
His copanelist Roy Fleischmann, MD, noted that filgotinib displayed a clean long-term safety profile in a pooled analysis of the 24-week results in the 2,088 filgotinib-treated participants in all phase 3 clinical trials for RA. For example, the incidence of herpes zoster in that large treated population was a mere 0.1%.
“Herpes zoster is almost nonexistent across the program,” observed Dr. Fleischmann, a rheumatologist at the University of Texas and medical director of the Metroplex Clinical Research Center, both in Dallas.
That’s consistent with what he’s heard from Japanese investigators about their experience. They tell him that in their studies the incidence of herpes zoster with filgotinib is five times less than with other JAK inhibitors.
The long-term pooled phase 3 filgotinib safety data also show less than a 0.1% incidence of adjudicated VTE/pulmonary embolism through 24 weeks. That’s a substantially lower rate than with tofacitinib or baricitinib, he noted.
The two rheumatologists, long-time observers of the FDA regulatory scene, stressed that they have no inside information regarding what the agency will do about filgotinib. It seems beyond doubt that the JAK inhibitor will be approved. But an open question of practical importance to clinicians is whether the agency will approve only the 100-mg dose or the 200-mg dose as well. The panelists agreed that having access to both would be advantageous since the clinical trials data indicate the higher dose is more effective and this greater efficacy doesn’t come at a cost of additional safety issues.
“If the 100 mg is sufficient, that’s great, but the reality is if you want to push to low disease activity or remission, the 200 mg seems to work better, particularly in patients who’ve already failed TNF [tumor necrosis factor] inhibitors or other biologics,” Dr. Genovese said. “If you’re not having additional safety concerns and you can get additional efficacy, I love the idea of having flexibility.”
Dr. Fleischmann is skeptical that the regulators will see things that way.
“There is a real risk that the FDA will do what it’s done before and say: ‘Well, the 200 works and the 100 works, so we’re going to approve the lower dose.’ But there doesn’t appear to be a big safety difference between 100 and 200. So I can see why they would approve the two doses, but I think that’d be unusual,” according to the rheumatologist.
The RA pipeline
The two speakers also highlighted several agents with novel mechanisms of action moving through the RA developmental pipeline, including olokizumab, otilimab, fenebrutinib, and a promising oral selective interleukin-1 receptor–associated kinase 4 inhibitor (IRAK4).
Olokizumab: This humanized monoclonal antibody targets IL-6. It has a different mechanism of action than the two commercially available IL-6 inhibitors approved for RA, tocilizumab (Actemra) and sarilumab (Kevzara), in that olokizumab uniquely targets the IL-6 ligand.
At the 2019 annual meeting of the American College of Rheumatology, Dr. Genovese presented the positive findings of a double-blind, placebo-controlled, randomized, phase 3 clinical trial of olokizumab in 428 RA patients with an inadequate response to methotrexate. The primary outcome, an ACR 20 response at 12 weeks, occurred in 25.9% of patients on placebo, 63.6% with 64 mg of olokizumab given subcutaneously every 2 weeks, and 70.4% with 64 mg every 4 weeks, with all participants on background methotrexate. An ACR 50 response at week 24 occurred in 7.7%, 42.7%, and 48.6%, respectively, with an acceptable side effect profile.
This was the first phase 3 trial to be presented from a large, ongoing phase 3 olokizumab developmental program for a variety of diseases.
“The results certainly support the idea that a 4-week regimen would probably be quite useful with this medication, although we’ll have to see what happens with the remaining phase 3 trials,” Dr. Genovese said.
Dr. Fleischmann posed a question: Do we really need a third IL-6 inhibitor?
That would make for a crowded field, Dr. Genovese agreed, adding that grabbing a reasonable market share for olokizumab may come down to cost, formulary access, and the convenience factor of once-monthly dosing. Whether the biologic’s unique mechanism of action in blocking the IL-6 ligand makes any practical difference in outcomes is unknown.
IRAK4 inhibitor: PF-06650833 is an oral selective reversible inhibitor of IRAK4, a key signaling kinase for IL-1 and toll-like receptors.
“This should be a really good drug for IL-1-mediated diseases,” according to Dr. Fleischmann.
In a phase 2b, double-blind, randomized, placebo-controlled, 12-week study featuring tofacitinib at 5 mg twice daily as an active comparator, the IRAK4 inhibitor exhibited dose-dependent efficacy for the primary endpoint of improvement from baseline in Simple Disease Activity Index score, compared with placebo. The same was true for the secondary endpoint, change over time in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). The trial results were also presented at the 2019 ACR annual meeting.
“This is a drug they should probably take forward and see how far it goes in RA,” he said.
Dr. Genovese concurred.
“We’re still trying to figure out how we can put together rational combinations in RA, and this might be something that could be considered as a combination play. In fact, Pfizer has already teed up a study looking at a JAK inhibitor/IRAK4 combination. The question will be whether this is a standalone or has an opportunity to be part of a combination approach,” the rheumatologist said.
Otilimab: This monoclonal antibody is a granulocyte-macrophage colony-stimulating factor inhibitor. In a secondary analysis of the BAROQUE trial, a phase 2b, 50-week study in RA inadequately responsive to methotrexate, otilimab demonstrated an impressive effect in terms of pain reduction. This new analysis, which was first presented at the 2019 ACR annual meeting, showed that, at week 12, a minimum clinically important difference in pain was achieved in 29% of placebo-treated controls, compared with 65%-75% of patients on low to higher doses of otilimab.
“The question is: Is this pain effect unique to this molecule, this pathway, or is it a simple reflection of the treated patient population?” Dr. Genovese commented. “It’s an interesting molecule. It’s being developed in RA, and it might have unique benefits on the pain side.”
A tale of two BTK inhibitors: Bruton tyrosine kinase (BTK) is an intracellular kinase viewed as a promising target in autoimmune disease. Fenebrutinib is an oral, noncovalent, reversible, and highly selective BTK inhibitor that performed well in a phase 2, randomized, double-blind, placebo-controlled clinical trial with adalimumab as an active comparator in 480 patients with an inadequate response to methotrexate in one branch, and in 98 patients with an inadequate response to TNF inhibitor therapy in the other. All subjects were on background methotrexate. (The study results were published April 9 in Arthritis & Rheumatology.)
In the group with a prior inadequate response to TNF inhibitors, the ACR 50 response rate at 12 weeks was 25% in the group on fenebrutinib at 200 mg twice daily, significantly better than the 12% rate in placebo. And there were favorable effects on biomarkers: The reduction in erythrocyte sedimentation rate from baseline was nearly twice as great with fenebrutinib, the drop in CRP was nearly three times greater than with placebo, and there was also a significantly greater decrease over time in DAS28-CRP.
In the methotrexate-inadequate responders, the ACR50 rates were 28% and 35% with the BTK inhibitor at 150 and 200 mg once daily, respectively, compared with 15% in controls.
The safety picture was encouraging, with similarly low adverse event rates across all treatment arms.
In contrast to the fenebrutinib experience, Dr. Genovese was lead investigator in a 250-patient, phase 2 study of another oral BTK inhibitor, poseltinib, which differs from fenebrutinib in that it is an irreversible covalent inhibitor. It was a failed study, with no significant difference between poseltinib and placebo in ACR 20 response at 12 weeks. It’s unclear whether the problem was insufficient dosing or that poseltinib is a failed molecule, perhaps because of its irreversible covalent binding to BTK, he said.
Other notable failures
The spleen tyrosine kinase (Syk) inhibitor known as GS-9876 showed no clinical efficacy in a phase 2, double-blind, randomized trial in 83 RA patients with an inadequate response to methotrexate or a biologic DMARD.
“This is like the fourth Syk inhibitor that’s failed. Syk inhibition is not sick, Syk is dead,” Dr. Fleischmann declared.
Cadherin-11 is an inflammatory cytokine expressed on fibroblasts in RA joints. In a phase 2, double-blind, randomized trial in 109 patients with RA inadequately responsive to TNF inhibitors, RG6125, a humanized monoclonal antibody directed against cadherin-11, failed to outperform placebo.
“It should have worked. It didn’t. So the question is whether this pathway is not an appropriate pathway, or the molecule was not quite the right molecule. I have a feeling it was possibly not the right molecule and the pathway may be viable,” according to Dr. Fleischmann.
He reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Genovese also reported financial relationships with more than a dozen pharmaceutical companies.
MAUI, HAWAII – Filgotinib, the oral Janus kinase (JAK) inhibitor now under Food and Drug Administration review for the treatment of RA, has a better safety profile than some of the approved oral JAK inhibitors, but that’s unlikely to save it from being saddled with a black-box safety warning label, experts agreed at the 2020 Rheumatology Winter Clinical Symposium.
“There’s probably a class label out there,” according to Mark C. Genovese, MD, professor of medicine and clinical chief of the division of immunology and rheumatology at Stanford (Calif.) University.
He cited the example of upadacitinib (Rinvoq), approved last year as the third oral JAK inhibitor for RA. Even though venous thromboembolic (VTE) events weren’t seen with any significantly increased frequency, compared with placebo, in the upadacitinib development program – unlike for the earlier-approved tofacitinib (Xeljanz) and baricitinib (Olumiant) –the FDA nevertheless required that upadacitinib’s product labeling include this black-box warning: “Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions.”
“I would fully expect that there’ll be a similar label in the filgotinib package insert saying that VTEs have been seen in other members of the class,” he predicted.
His copanelist Roy Fleischmann, MD, noted that filgotinib displayed a clean long-term safety profile in a pooled analysis of the 24-week results in the 2,088 filgotinib-treated participants in all phase 3 clinical trials for RA. For example, the incidence of herpes zoster in that large treated population was a mere 0.1%.
“Herpes zoster is almost nonexistent across the program,” observed Dr. Fleischmann, a rheumatologist at the University of Texas and medical director of the Metroplex Clinical Research Center, both in Dallas.
That’s consistent with what he’s heard from Japanese investigators about their experience. They tell him that in their studies the incidence of herpes zoster with filgotinib is five times less than with other JAK inhibitors.
The long-term pooled phase 3 filgotinib safety data also show less than a 0.1% incidence of adjudicated VTE/pulmonary embolism through 24 weeks. That’s a substantially lower rate than with tofacitinib or baricitinib, he noted.
The two rheumatologists, long-time observers of the FDA regulatory scene, stressed that they have no inside information regarding what the agency will do about filgotinib. It seems beyond doubt that the JAK inhibitor will be approved. But an open question of practical importance to clinicians is whether the agency will approve only the 100-mg dose or the 200-mg dose as well. The panelists agreed that having access to both would be advantageous since the clinical trials data indicate the higher dose is more effective and this greater efficacy doesn’t come at a cost of additional safety issues.
“If the 100 mg is sufficient, that’s great, but the reality is if you want to push to low disease activity or remission, the 200 mg seems to work better, particularly in patients who’ve already failed TNF [tumor necrosis factor] inhibitors or other biologics,” Dr. Genovese said. “If you’re not having additional safety concerns and you can get additional efficacy, I love the idea of having flexibility.”
Dr. Fleischmann is skeptical that the regulators will see things that way.
“There is a real risk that the FDA will do what it’s done before and say: ‘Well, the 200 works and the 100 works, so we’re going to approve the lower dose.’ But there doesn’t appear to be a big safety difference between 100 and 200. So I can see why they would approve the two doses, but I think that’d be unusual,” according to the rheumatologist.
The RA pipeline
The two speakers also highlighted several agents with novel mechanisms of action moving through the RA developmental pipeline, including olokizumab, otilimab, fenebrutinib, and a promising oral selective interleukin-1 receptor–associated kinase 4 inhibitor (IRAK4).
Olokizumab: This humanized monoclonal antibody targets IL-6. It has a different mechanism of action than the two commercially available IL-6 inhibitors approved for RA, tocilizumab (Actemra) and sarilumab (Kevzara), in that olokizumab uniquely targets the IL-6 ligand.
At the 2019 annual meeting of the American College of Rheumatology, Dr. Genovese presented the positive findings of a double-blind, placebo-controlled, randomized, phase 3 clinical trial of olokizumab in 428 RA patients with an inadequate response to methotrexate. The primary outcome, an ACR 20 response at 12 weeks, occurred in 25.9% of patients on placebo, 63.6% with 64 mg of olokizumab given subcutaneously every 2 weeks, and 70.4% with 64 mg every 4 weeks, with all participants on background methotrexate. An ACR 50 response at week 24 occurred in 7.7%, 42.7%, and 48.6%, respectively, with an acceptable side effect profile.
This was the first phase 3 trial to be presented from a large, ongoing phase 3 olokizumab developmental program for a variety of diseases.
“The results certainly support the idea that a 4-week regimen would probably be quite useful with this medication, although we’ll have to see what happens with the remaining phase 3 trials,” Dr. Genovese said.
Dr. Fleischmann posed a question: Do we really need a third IL-6 inhibitor?
That would make for a crowded field, Dr. Genovese agreed, adding that grabbing a reasonable market share for olokizumab may come down to cost, formulary access, and the convenience factor of once-monthly dosing. Whether the biologic’s unique mechanism of action in blocking the IL-6 ligand makes any practical difference in outcomes is unknown.
IRAK4 inhibitor: PF-06650833 is an oral selective reversible inhibitor of IRAK4, a key signaling kinase for IL-1 and toll-like receptors.
“This should be a really good drug for IL-1-mediated diseases,” according to Dr. Fleischmann.
In a phase 2b, double-blind, randomized, placebo-controlled, 12-week study featuring tofacitinib at 5 mg twice daily as an active comparator, the IRAK4 inhibitor exhibited dose-dependent efficacy for the primary endpoint of improvement from baseline in Simple Disease Activity Index score, compared with placebo. The same was true for the secondary endpoint, change over time in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). The trial results were also presented at the 2019 ACR annual meeting.
“This is a drug they should probably take forward and see how far it goes in RA,” he said.
Dr. Genovese concurred.
“We’re still trying to figure out how we can put together rational combinations in RA, and this might be something that could be considered as a combination play. In fact, Pfizer has already teed up a study looking at a JAK inhibitor/IRAK4 combination. The question will be whether this is a standalone or has an opportunity to be part of a combination approach,” the rheumatologist said.
Otilimab: This monoclonal antibody is a granulocyte-macrophage colony-stimulating factor inhibitor. In a secondary analysis of the BAROQUE trial, a phase 2b, 50-week study in RA inadequately responsive to methotrexate, otilimab demonstrated an impressive effect in terms of pain reduction. This new analysis, which was first presented at the 2019 ACR annual meeting, showed that, at week 12, a minimum clinically important difference in pain was achieved in 29% of placebo-treated controls, compared with 65%-75% of patients on low to higher doses of otilimab.
“The question is: Is this pain effect unique to this molecule, this pathway, or is it a simple reflection of the treated patient population?” Dr. Genovese commented. “It’s an interesting molecule. It’s being developed in RA, and it might have unique benefits on the pain side.”
A tale of two BTK inhibitors: Bruton tyrosine kinase (BTK) is an intracellular kinase viewed as a promising target in autoimmune disease. Fenebrutinib is an oral, noncovalent, reversible, and highly selective BTK inhibitor that performed well in a phase 2, randomized, double-blind, placebo-controlled clinical trial with adalimumab as an active comparator in 480 patients with an inadequate response to methotrexate in one branch, and in 98 patients with an inadequate response to TNF inhibitor therapy in the other. All subjects were on background methotrexate. (The study results were published April 9 in Arthritis & Rheumatology.)
In the group with a prior inadequate response to TNF inhibitors, the ACR 50 response rate at 12 weeks was 25% in the group on fenebrutinib at 200 mg twice daily, significantly better than the 12% rate in placebo. And there were favorable effects on biomarkers: The reduction in erythrocyte sedimentation rate from baseline was nearly twice as great with fenebrutinib, the drop in CRP was nearly three times greater than with placebo, and there was also a significantly greater decrease over time in DAS28-CRP.
In the methotrexate-inadequate responders, the ACR50 rates were 28% and 35% with the BTK inhibitor at 150 and 200 mg once daily, respectively, compared with 15% in controls.
The safety picture was encouraging, with similarly low adverse event rates across all treatment arms.
In contrast to the fenebrutinib experience, Dr. Genovese was lead investigator in a 250-patient, phase 2 study of another oral BTK inhibitor, poseltinib, which differs from fenebrutinib in that it is an irreversible covalent inhibitor. It was a failed study, with no significant difference between poseltinib and placebo in ACR 20 response at 12 weeks. It’s unclear whether the problem was insufficient dosing or that poseltinib is a failed molecule, perhaps because of its irreversible covalent binding to BTK, he said.
Other notable failures
The spleen tyrosine kinase (Syk) inhibitor known as GS-9876 showed no clinical efficacy in a phase 2, double-blind, randomized trial in 83 RA patients with an inadequate response to methotrexate or a biologic DMARD.
“This is like the fourth Syk inhibitor that’s failed. Syk inhibition is not sick, Syk is dead,” Dr. Fleischmann declared.
Cadherin-11 is an inflammatory cytokine expressed on fibroblasts in RA joints. In a phase 2, double-blind, randomized trial in 109 patients with RA inadequately responsive to TNF inhibitors, RG6125, a humanized monoclonal antibody directed against cadherin-11, failed to outperform placebo.
“It should have worked. It didn’t. So the question is whether this pathway is not an appropriate pathway, or the molecule was not quite the right molecule. I have a feeling it was possibly not the right molecule and the pathway may be viable,” according to Dr. Fleischmann.
He reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Genovese also reported financial relationships with more than a dozen pharmaceutical companies.
MAUI, HAWAII – Filgotinib, the oral Janus kinase (JAK) inhibitor now under Food and Drug Administration review for the treatment of RA, has a better safety profile than some of the approved oral JAK inhibitors, but that’s unlikely to save it from being saddled with a black-box safety warning label, experts agreed at the 2020 Rheumatology Winter Clinical Symposium.
“There’s probably a class label out there,” according to Mark C. Genovese, MD, professor of medicine and clinical chief of the division of immunology and rheumatology at Stanford (Calif.) University.
He cited the example of upadacitinib (Rinvoq), approved last year as the third oral JAK inhibitor for RA. Even though venous thromboembolic (VTE) events weren’t seen with any significantly increased frequency, compared with placebo, in the upadacitinib development program – unlike for the earlier-approved tofacitinib (Xeljanz) and baricitinib (Olumiant) –the FDA nevertheless required that upadacitinib’s product labeling include this black-box warning: “Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions.”
“I would fully expect that there’ll be a similar label in the filgotinib package insert saying that VTEs have been seen in other members of the class,” he predicted.
His copanelist Roy Fleischmann, MD, noted that filgotinib displayed a clean long-term safety profile in a pooled analysis of the 24-week results in the 2,088 filgotinib-treated participants in all phase 3 clinical trials for RA. For example, the incidence of herpes zoster in that large treated population was a mere 0.1%.
“Herpes zoster is almost nonexistent across the program,” observed Dr. Fleischmann, a rheumatologist at the University of Texas and medical director of the Metroplex Clinical Research Center, both in Dallas.
That’s consistent with what he’s heard from Japanese investigators about their experience. They tell him that in their studies the incidence of herpes zoster with filgotinib is five times less than with other JAK inhibitors.
The long-term pooled phase 3 filgotinib safety data also show less than a 0.1% incidence of adjudicated VTE/pulmonary embolism through 24 weeks. That’s a substantially lower rate than with tofacitinib or baricitinib, he noted.
The two rheumatologists, long-time observers of the FDA regulatory scene, stressed that they have no inside information regarding what the agency will do about filgotinib. It seems beyond doubt that the JAK inhibitor will be approved. But an open question of practical importance to clinicians is whether the agency will approve only the 100-mg dose or the 200-mg dose as well. The panelists agreed that having access to both would be advantageous since the clinical trials data indicate the higher dose is more effective and this greater efficacy doesn’t come at a cost of additional safety issues.
“If the 100 mg is sufficient, that’s great, but the reality is if you want to push to low disease activity or remission, the 200 mg seems to work better, particularly in patients who’ve already failed TNF [tumor necrosis factor] inhibitors or other biologics,” Dr. Genovese said. “If you’re not having additional safety concerns and you can get additional efficacy, I love the idea of having flexibility.”
Dr. Fleischmann is skeptical that the regulators will see things that way.
“There is a real risk that the FDA will do what it’s done before and say: ‘Well, the 200 works and the 100 works, so we’re going to approve the lower dose.’ But there doesn’t appear to be a big safety difference between 100 and 200. So I can see why they would approve the two doses, but I think that’d be unusual,” according to the rheumatologist.
The RA pipeline
The two speakers also highlighted several agents with novel mechanisms of action moving through the RA developmental pipeline, including olokizumab, otilimab, fenebrutinib, and a promising oral selective interleukin-1 receptor–associated kinase 4 inhibitor (IRAK4).
Olokizumab: This humanized monoclonal antibody targets IL-6. It has a different mechanism of action than the two commercially available IL-6 inhibitors approved for RA, tocilizumab (Actemra) and sarilumab (Kevzara), in that olokizumab uniquely targets the IL-6 ligand.
At the 2019 annual meeting of the American College of Rheumatology, Dr. Genovese presented the positive findings of a double-blind, placebo-controlled, randomized, phase 3 clinical trial of olokizumab in 428 RA patients with an inadequate response to methotrexate. The primary outcome, an ACR 20 response at 12 weeks, occurred in 25.9% of patients on placebo, 63.6% with 64 mg of olokizumab given subcutaneously every 2 weeks, and 70.4% with 64 mg every 4 weeks, with all participants on background methotrexate. An ACR 50 response at week 24 occurred in 7.7%, 42.7%, and 48.6%, respectively, with an acceptable side effect profile.
This was the first phase 3 trial to be presented from a large, ongoing phase 3 olokizumab developmental program for a variety of diseases.
“The results certainly support the idea that a 4-week regimen would probably be quite useful with this medication, although we’ll have to see what happens with the remaining phase 3 trials,” Dr. Genovese said.
Dr. Fleischmann posed a question: Do we really need a third IL-6 inhibitor?
That would make for a crowded field, Dr. Genovese agreed, adding that grabbing a reasonable market share for olokizumab may come down to cost, formulary access, and the convenience factor of once-monthly dosing. Whether the biologic’s unique mechanism of action in blocking the IL-6 ligand makes any practical difference in outcomes is unknown.
IRAK4 inhibitor: PF-06650833 is an oral selective reversible inhibitor of IRAK4, a key signaling kinase for IL-1 and toll-like receptors.
“This should be a really good drug for IL-1-mediated diseases,” according to Dr. Fleischmann.
In a phase 2b, double-blind, randomized, placebo-controlled, 12-week study featuring tofacitinib at 5 mg twice daily as an active comparator, the IRAK4 inhibitor exhibited dose-dependent efficacy for the primary endpoint of improvement from baseline in Simple Disease Activity Index score, compared with placebo. The same was true for the secondary endpoint, change over time in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). The trial results were also presented at the 2019 ACR annual meeting.
“This is a drug they should probably take forward and see how far it goes in RA,” he said.
Dr. Genovese concurred.
“We’re still trying to figure out how we can put together rational combinations in RA, and this might be something that could be considered as a combination play. In fact, Pfizer has already teed up a study looking at a JAK inhibitor/IRAK4 combination. The question will be whether this is a standalone or has an opportunity to be part of a combination approach,” the rheumatologist said.
Otilimab: This monoclonal antibody is a granulocyte-macrophage colony-stimulating factor inhibitor. In a secondary analysis of the BAROQUE trial, a phase 2b, 50-week study in RA inadequately responsive to methotrexate, otilimab demonstrated an impressive effect in terms of pain reduction. This new analysis, which was first presented at the 2019 ACR annual meeting, showed that, at week 12, a minimum clinically important difference in pain was achieved in 29% of placebo-treated controls, compared with 65%-75% of patients on low to higher doses of otilimab.
“The question is: Is this pain effect unique to this molecule, this pathway, or is it a simple reflection of the treated patient population?” Dr. Genovese commented. “It’s an interesting molecule. It’s being developed in RA, and it might have unique benefits on the pain side.”
A tale of two BTK inhibitors: Bruton tyrosine kinase (BTK) is an intracellular kinase viewed as a promising target in autoimmune disease. Fenebrutinib is an oral, noncovalent, reversible, and highly selective BTK inhibitor that performed well in a phase 2, randomized, double-blind, placebo-controlled clinical trial with adalimumab as an active comparator in 480 patients with an inadequate response to methotrexate in one branch, and in 98 patients with an inadequate response to TNF inhibitor therapy in the other. All subjects were on background methotrexate. (The study results were published April 9 in Arthritis & Rheumatology.)
In the group with a prior inadequate response to TNF inhibitors, the ACR 50 response rate at 12 weeks was 25% in the group on fenebrutinib at 200 mg twice daily, significantly better than the 12% rate in placebo. And there were favorable effects on biomarkers: The reduction in erythrocyte sedimentation rate from baseline was nearly twice as great with fenebrutinib, the drop in CRP was nearly three times greater than with placebo, and there was also a significantly greater decrease over time in DAS28-CRP.
In the methotrexate-inadequate responders, the ACR50 rates were 28% and 35% with the BTK inhibitor at 150 and 200 mg once daily, respectively, compared with 15% in controls.
The safety picture was encouraging, with similarly low adverse event rates across all treatment arms.
In contrast to the fenebrutinib experience, Dr. Genovese was lead investigator in a 250-patient, phase 2 study of another oral BTK inhibitor, poseltinib, which differs from fenebrutinib in that it is an irreversible covalent inhibitor. It was a failed study, with no significant difference between poseltinib and placebo in ACR 20 response at 12 weeks. It’s unclear whether the problem was insufficient dosing or that poseltinib is a failed molecule, perhaps because of its irreversible covalent binding to BTK, he said.
Other notable failures
The spleen tyrosine kinase (Syk) inhibitor known as GS-9876 showed no clinical efficacy in a phase 2, double-blind, randomized trial in 83 RA patients with an inadequate response to methotrexate or a biologic DMARD.
“This is like the fourth Syk inhibitor that’s failed. Syk inhibition is not sick, Syk is dead,” Dr. Fleischmann declared.
Cadherin-11 is an inflammatory cytokine expressed on fibroblasts in RA joints. In a phase 2, double-blind, randomized trial in 109 patients with RA inadequately responsive to TNF inhibitors, RG6125, a humanized monoclonal antibody directed against cadherin-11, failed to outperform placebo.
“It should have worked. It didn’t. So the question is whether this pathway is not an appropriate pathway, or the molecule was not quite the right molecule. I have a feeling it was possibly not the right molecule and the pathway may be viable,” according to Dr. Fleischmann.
He reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Genovese also reported financial relationships with more than a dozen pharmaceutical companies.
REPORTING FROM RWCS 2020