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Promising data on once-weekly insulin, phase 3 study ongoing
Two new phase 2 studies show encouraging findings with the investigational once-weekly basal insulin analogue icodec (Novo Nordisk) for people with type 2 diabetes who require insulin.
Insulin icodec works by reversibly binding to albumin, which slows the release of the active insulin analogue. It has a half-life of about 1 week. The glucose-lowering effect is distributed nearly evenly over the course of that week.
Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center, Dallas, who is an author of both new articles, said: “A weekly insulin is a game changer that will decrease the treatment burden for patients while also improving compliance.”
She noted that these studies demonstrate optimal approaches to initiating treatment with icodec and serve “as the steppingstones for a large phase 3 clinical trial program that is currently ongoing ... which is designed to evaluate the efficacy of once-weekly insulin administration in patients with either type 1 or type 2 diabetes.”
Another advantage of the formulation, Dr. Lingvay pointed out in a press release from her institution, is that it could decrease the burden on caregivers of patients with diabetes who require insulin.
“For example, for patients who need help injecting, those living in long-term care facilities, and those with memory problems, a once-weekly insulin will facilitate treatment and decrease the burden on the care providers,” she explained.
Titration balances glycemic control with hypoglycemic risk reduction
The first phase 2 trial, published online April 19, 2021, in Diabetes Care, was an open-label, 16-week, treat-to-target study that involved 205 insulin-naive adults with type 2 diabetes whose hemoglobin A1c levels were 7%-10% while using oral glucose-lowering medications.
They were randomly assigned to one of three once-weekly icodec titration groups:
- Group A – Fasting glucose target of 80-130 mg/dL with adjustments ±21 units/wk
- Group B – Fasting glucose target of 80-130 mg/dL with ±28 units/wk
- Group C – Fasting glucose target of 70-108 mg/dL, adjusting by ±28 units/wk or to once-daily glargine U100 with a fasting glucose target of 80-130 mg/dL with adjustments of ±4 units/d
The percentage of time in the ideal glucose range of 70-180 mg/dL, assessed by continuous glucose monitoring during weeks 15-16, improved from baseline levels of 57.0%, 55.2%, 51.0% for groups A, B, and C, respectively, and from 55.3% for glargine to 76.6%, 83.0%, 80.9%, and 75.9%, respectively.
There were no unexpected safety problems. Hypoglycemia episodes of glucose levels <54 mg/dL occurred in 0.05, 0.15, 0.38, and 0.00 per patient-year for the four groups, respectively. None were severe (i.e., required assistance).
The titration for patients in group A (80-130 mg/dL, ±21 units/wk) yielded the best balance between glycemic control and risk for hypoglycemia, Dr. Lingvay and colleagues said.
Use of loading dose when switching to icodec improves time in range
In the other phase 2 trial, also published online April 19 in Diabetes Care, Harpreet S. Bajaj, MD, of Mount Sinai Hospital, Toronto, and colleagues, with Dr. Lingvay as a coauthor, examined two methods of switching to icodec. This multicenter, open-label, treat-to-target study included 154 patients with A1c levels of 7-10% who were already receiving basal insulin daily and at least one oral glucose-lowering medication.
Patients were randomly assigned to one of three treatment approaches: a 100% loading dose of icodec (only the first dose was doubled), no loading dose, or once-daily glargine.
The primary endpoint was time in range (70-180 mg/dL) during weeks 15 and 16. This was achieved with 72.9% of patients receiving the icodec loading dose, 66.0% of patients receiving icodec without the loading dose, and 65.0% of patients receiving daily glargine. The difference between the icodec loading-dose method and glargine was significant, Dr. Bajaj and colleagues reported.
The mean A1c level was reduced from an overall average of 7.9% at baseline to 7.1% in the icodec loading dose group and to 7.4% in both the no-loading-dose and glargine groups.
Rates of adverse events and hypoglycemic episodes did not differ significantly among the groups.
Previous phase 2 data showing that the efficacy and safety of icodec were comparable with that of once-daily insulin glargine U100 in 247 insulin-naive patients with type 2 diabetes were published in November 2020 in the New England Journal of Medicine and were presented at the European Association for the Study of Diabetes (EASD) 2020 Annual Meeting, as reported by this news organization.
Both studies were funded by Novo Nordisk. Dr. Lingvey has received research funding, advisory/consulting fees, or other support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen, Intercept, Intarcia, Target RWE, Merck, Pfizer, Novartis, GI Dynamics, Mylan, Mannkind, Valeritas, Bayer, and Zealand Pharma. Dr. Bajaj has received speaking fees from AstraZeneca, Eli Lilly, Janssen Pharmaceuticals, Merck, and Novo Nordisk and research funding paid to LMC Healthcare for serving as principal investigator on clinical trials from Amgen, AstraZeneca Boehringer Ingelheim, Ceapro Inc, Eli Lilly, Gilead Sciences, Janssen Pharmaceuticals, Kowa Pharmaceuticals, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Sanofi, and Tricida.
A version of this article first appeared on Medscape.com.
Two new phase 2 studies show encouraging findings with the investigational once-weekly basal insulin analogue icodec (Novo Nordisk) for people with type 2 diabetes who require insulin.
Insulin icodec works by reversibly binding to albumin, which slows the release of the active insulin analogue. It has a half-life of about 1 week. The glucose-lowering effect is distributed nearly evenly over the course of that week.
Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center, Dallas, who is an author of both new articles, said: “A weekly insulin is a game changer that will decrease the treatment burden for patients while also improving compliance.”
She noted that these studies demonstrate optimal approaches to initiating treatment with icodec and serve “as the steppingstones for a large phase 3 clinical trial program that is currently ongoing ... which is designed to evaluate the efficacy of once-weekly insulin administration in patients with either type 1 or type 2 diabetes.”
Another advantage of the formulation, Dr. Lingvay pointed out in a press release from her institution, is that it could decrease the burden on caregivers of patients with diabetes who require insulin.
“For example, for patients who need help injecting, those living in long-term care facilities, and those with memory problems, a once-weekly insulin will facilitate treatment and decrease the burden on the care providers,” she explained.
Titration balances glycemic control with hypoglycemic risk reduction
The first phase 2 trial, published online April 19, 2021, in Diabetes Care, was an open-label, 16-week, treat-to-target study that involved 205 insulin-naive adults with type 2 diabetes whose hemoglobin A1c levels were 7%-10% while using oral glucose-lowering medications.
They were randomly assigned to one of three once-weekly icodec titration groups:
- Group A – Fasting glucose target of 80-130 mg/dL with adjustments ±21 units/wk
- Group B – Fasting glucose target of 80-130 mg/dL with ±28 units/wk
- Group C – Fasting glucose target of 70-108 mg/dL, adjusting by ±28 units/wk or to once-daily glargine U100 with a fasting glucose target of 80-130 mg/dL with adjustments of ±4 units/d
The percentage of time in the ideal glucose range of 70-180 mg/dL, assessed by continuous glucose monitoring during weeks 15-16, improved from baseline levels of 57.0%, 55.2%, 51.0% for groups A, B, and C, respectively, and from 55.3% for glargine to 76.6%, 83.0%, 80.9%, and 75.9%, respectively.
There were no unexpected safety problems. Hypoglycemia episodes of glucose levels <54 mg/dL occurred in 0.05, 0.15, 0.38, and 0.00 per patient-year for the four groups, respectively. None were severe (i.e., required assistance).
The titration for patients in group A (80-130 mg/dL, ±21 units/wk) yielded the best balance between glycemic control and risk for hypoglycemia, Dr. Lingvay and colleagues said.
Use of loading dose when switching to icodec improves time in range
In the other phase 2 trial, also published online April 19 in Diabetes Care, Harpreet S. Bajaj, MD, of Mount Sinai Hospital, Toronto, and colleagues, with Dr. Lingvay as a coauthor, examined two methods of switching to icodec. This multicenter, open-label, treat-to-target study included 154 patients with A1c levels of 7-10% who were already receiving basal insulin daily and at least one oral glucose-lowering medication.
Patients were randomly assigned to one of three treatment approaches: a 100% loading dose of icodec (only the first dose was doubled), no loading dose, or once-daily glargine.
The primary endpoint was time in range (70-180 mg/dL) during weeks 15 and 16. This was achieved with 72.9% of patients receiving the icodec loading dose, 66.0% of patients receiving icodec without the loading dose, and 65.0% of patients receiving daily glargine. The difference between the icodec loading-dose method and glargine was significant, Dr. Bajaj and colleagues reported.
The mean A1c level was reduced from an overall average of 7.9% at baseline to 7.1% in the icodec loading dose group and to 7.4% in both the no-loading-dose and glargine groups.
Rates of adverse events and hypoglycemic episodes did not differ significantly among the groups.
Previous phase 2 data showing that the efficacy and safety of icodec were comparable with that of once-daily insulin glargine U100 in 247 insulin-naive patients with type 2 diabetes were published in November 2020 in the New England Journal of Medicine and were presented at the European Association for the Study of Diabetes (EASD) 2020 Annual Meeting, as reported by this news organization.
Both studies were funded by Novo Nordisk. Dr. Lingvey has received research funding, advisory/consulting fees, or other support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen, Intercept, Intarcia, Target RWE, Merck, Pfizer, Novartis, GI Dynamics, Mylan, Mannkind, Valeritas, Bayer, and Zealand Pharma. Dr. Bajaj has received speaking fees from AstraZeneca, Eli Lilly, Janssen Pharmaceuticals, Merck, and Novo Nordisk and research funding paid to LMC Healthcare for serving as principal investigator on clinical trials from Amgen, AstraZeneca Boehringer Ingelheim, Ceapro Inc, Eli Lilly, Gilead Sciences, Janssen Pharmaceuticals, Kowa Pharmaceuticals, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Sanofi, and Tricida.
A version of this article first appeared on Medscape.com.
Two new phase 2 studies show encouraging findings with the investigational once-weekly basal insulin analogue icodec (Novo Nordisk) for people with type 2 diabetes who require insulin.
Insulin icodec works by reversibly binding to albumin, which slows the release of the active insulin analogue. It has a half-life of about 1 week. The glucose-lowering effect is distributed nearly evenly over the course of that week.
Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center, Dallas, who is an author of both new articles, said: “A weekly insulin is a game changer that will decrease the treatment burden for patients while also improving compliance.”
She noted that these studies demonstrate optimal approaches to initiating treatment with icodec and serve “as the steppingstones for a large phase 3 clinical trial program that is currently ongoing ... which is designed to evaluate the efficacy of once-weekly insulin administration in patients with either type 1 or type 2 diabetes.”
Another advantage of the formulation, Dr. Lingvay pointed out in a press release from her institution, is that it could decrease the burden on caregivers of patients with diabetes who require insulin.
“For example, for patients who need help injecting, those living in long-term care facilities, and those with memory problems, a once-weekly insulin will facilitate treatment and decrease the burden on the care providers,” she explained.
Titration balances glycemic control with hypoglycemic risk reduction
The first phase 2 trial, published online April 19, 2021, in Diabetes Care, was an open-label, 16-week, treat-to-target study that involved 205 insulin-naive adults with type 2 diabetes whose hemoglobin A1c levels were 7%-10% while using oral glucose-lowering medications.
They were randomly assigned to one of three once-weekly icodec titration groups:
- Group A – Fasting glucose target of 80-130 mg/dL with adjustments ±21 units/wk
- Group B – Fasting glucose target of 80-130 mg/dL with ±28 units/wk
- Group C – Fasting glucose target of 70-108 mg/dL, adjusting by ±28 units/wk or to once-daily glargine U100 with a fasting glucose target of 80-130 mg/dL with adjustments of ±4 units/d
The percentage of time in the ideal glucose range of 70-180 mg/dL, assessed by continuous glucose monitoring during weeks 15-16, improved from baseline levels of 57.0%, 55.2%, 51.0% for groups A, B, and C, respectively, and from 55.3% for glargine to 76.6%, 83.0%, 80.9%, and 75.9%, respectively.
There were no unexpected safety problems. Hypoglycemia episodes of glucose levels <54 mg/dL occurred in 0.05, 0.15, 0.38, and 0.00 per patient-year for the four groups, respectively. None were severe (i.e., required assistance).
The titration for patients in group A (80-130 mg/dL, ±21 units/wk) yielded the best balance between glycemic control and risk for hypoglycemia, Dr. Lingvay and colleagues said.
Use of loading dose when switching to icodec improves time in range
In the other phase 2 trial, also published online April 19 in Diabetes Care, Harpreet S. Bajaj, MD, of Mount Sinai Hospital, Toronto, and colleagues, with Dr. Lingvay as a coauthor, examined two methods of switching to icodec. This multicenter, open-label, treat-to-target study included 154 patients with A1c levels of 7-10% who were already receiving basal insulin daily and at least one oral glucose-lowering medication.
Patients were randomly assigned to one of three treatment approaches: a 100% loading dose of icodec (only the first dose was doubled), no loading dose, or once-daily glargine.
The primary endpoint was time in range (70-180 mg/dL) during weeks 15 and 16. This was achieved with 72.9% of patients receiving the icodec loading dose, 66.0% of patients receiving icodec without the loading dose, and 65.0% of patients receiving daily glargine. The difference between the icodec loading-dose method and glargine was significant, Dr. Bajaj and colleagues reported.
The mean A1c level was reduced from an overall average of 7.9% at baseline to 7.1% in the icodec loading dose group and to 7.4% in both the no-loading-dose and glargine groups.
Rates of adverse events and hypoglycemic episodes did not differ significantly among the groups.
Previous phase 2 data showing that the efficacy and safety of icodec were comparable with that of once-daily insulin glargine U100 in 247 insulin-naive patients with type 2 diabetes were published in November 2020 in the New England Journal of Medicine and were presented at the European Association for the Study of Diabetes (EASD) 2020 Annual Meeting, as reported by this news organization.
Both studies were funded by Novo Nordisk. Dr. Lingvey has received research funding, advisory/consulting fees, or other support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen, Intercept, Intarcia, Target RWE, Merck, Pfizer, Novartis, GI Dynamics, Mylan, Mannkind, Valeritas, Bayer, and Zealand Pharma. Dr. Bajaj has received speaking fees from AstraZeneca, Eli Lilly, Janssen Pharmaceuticals, Merck, and Novo Nordisk and research funding paid to LMC Healthcare for serving as principal investigator on clinical trials from Amgen, AstraZeneca Boehringer Ingelheim, Ceapro Inc, Eli Lilly, Gilead Sciences, Janssen Pharmaceuticals, Kowa Pharmaceuticals, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Sanofi, and Tricida.
A version of this article first appeared on Medscape.com.
How does fragmented care affect IBD outcomes?
Poor continuity of care may lead to worse outcomes among patients with active inflammatory bowel disease (IBD), according to data from more than 20,000 veterans.
Even in the Veterans Health Administration health care system, which “may provide the ideal environment for care coordination,” patients with active IBD had “substantial variation” in dispersion of care, leading to more frequent surgical interventions, corticosteroid use, and hospitalizations, reported lead author Shirley Cohen-Mekelburg, MD, MS, of the University of Michigan, Ann Arbor, and colleagues.
“Health care in the United States is marked by substantial fragmentation, with patients pursuing and receiving care from multiple clinicians, often at different institutions,” the investigators wrote in JAMA Network Open. “Fragmented care has been associated with poor chronic disease outcomes, higher health care use, duplication in testing, and increased costs of care.”
In the VHA, these issues prompted creation of the Patient Aligned Care Team (PACT), a medical home model in which primary care physicians coordinate clinical teams of specialists and other health care practitioners. But coordination can be challenging with chronic medical conditions like IBD, according to Dr. Cohen-Mekelburg and colleagues.
“High-quality care for IBD includes not only disease-specific management of symptoms but also disease-specific preventive care, such as immunizations and cancer screening, to prevent associated adverse outcomes,” the investigators wrote. “Identifying which physician is responsible for managing each aspect of care requires some degree of coordination and makes patients with IBD vulnerable to care fragmentation.”
Worse outcomes tied to poor first-year continuity
To evaluate care fragmentation within the VHA, the investigators identified 20,079 veterans with IBD who had at least one outpatient encounter with the system between the beginning of 2002 and the end of 2014. Continuity of care (COC) was calculated with the Bice-Boxerman COC index, which measures how much a patient’s care is connected with a distinct physician. The investigators used the first year COC as the primary independent variable.
In the first year of care, the median COC index was 0.24 (interquartile range, 0.13-0.46). The investigators noted that this figure was lower than reported by previous studies involving patients with several other chronic conditions, including IBD.
After controlling for covariates and adjusting for facility-related clustering, the investigators found a lower COC index in the first year was associated with a higher rate of worse outcomes in the subsequent 2 years, including surgical interventions (adjusted hazard ratio, 1.72; 95% confidence interval, 1.43-2.07), hospitalizations (aHR, 1.25; 95% CI, 1.06-1.47), and outpatient flares requiring corticosteroids (aHR, 1.11; 95% CI, 1.01-1.22). Conversely, improving COC index score by 0.1 reduced risk of outpatient flare (aHR, 0.69; 95%CI, 0.58-0.82), hospitalization (aHR, 0.57; 95%CI, 0.41-0.79), and surgical intervention (aHR, 0.25; 95% CI, 0.16-0.38).
Further analyses showed that the relationship between lower COC and worse outcomes carried across measures such as baseline use of an immunomodulator or biological agent, as well as subgroups such as patients with nonsevere IBD and nonsurgical patients.
Among those treated by a VHA gastroenterologist, a lower level of COC was associated with a higher rate of surgical interventions, but not hospitalizations or outpatient flares. Physician-specific COC index scores were highest for primary care providers (0.54), followed by gastroenterologists (0.25) and surgeons (0.17). However, lower physician-specific COC scores did not translate to worse IBD outcomes.
“The level of COC among patients with IBD in the present VHA cohort was ... lower than the values described in previous studies of veterans in the VHA system, including a study of VHA-Medicare dual enrollees who were especially prone to fragmented care because of their ability to seek care both inside and outside of the VHA system,” the investigators wrote, referring to a 2018 study. “The difference in COC among patients with IBD vs. patients without IBD is likely multifactorial and may be associated with confusion about physician accountability and lack of focus on coordination in IBD multidisciplinary care. Patients with IBD require care by primary care providers, gastroenterologists, and surgeons, but the delineation of responsibility by physician is often unclear.”
‘Better care, not just more care,’ is needed
“These outcomes cannot be improved with a more robust treatment armamentarium alone,” according to Jason K. Hou, MD, MS, AGAF, FACG, interim chief of gastroenterology and hepatology at Michael E. DeBakey VA Medical Center and associate professor of medicine at Baylor College of Medicine, Houston, who cowrote a simultaneously published editorial, which was also authored by David I. Fudman, MD.
“Examples exist of improving care coordination and outcomes through patient-aligned care teams in primary care and medical specialty homes for IBD,” Dr. Hou said in an interview. “However, significant barriers to widespread implementation remain.”
Dr. Hou offered several possible approaches to overcome these barriers.
“We need improved methods to identify and follow high-risk patients most likely to have complications and health care utilization,” he said. “We need an investment by payers and health care systems on care coordination so the identified high-risk patients can receive timely testing, referral, and treatment. These changes require reevaluation of how the health care system incentivizes health care to provide better care, not just more care.”
The investigators reported grants from the U.S. Department of Veterans Affairs and the National Institutes of Health and financial relationships with AbbVie, UCB, and Takeda. Dr. Hou reported no conflicts of interest.
Poor continuity of care may lead to worse outcomes among patients with active inflammatory bowel disease (IBD), according to data from more than 20,000 veterans.
Even in the Veterans Health Administration health care system, which “may provide the ideal environment for care coordination,” patients with active IBD had “substantial variation” in dispersion of care, leading to more frequent surgical interventions, corticosteroid use, and hospitalizations, reported lead author Shirley Cohen-Mekelburg, MD, MS, of the University of Michigan, Ann Arbor, and colleagues.
“Health care in the United States is marked by substantial fragmentation, with patients pursuing and receiving care from multiple clinicians, often at different institutions,” the investigators wrote in JAMA Network Open. “Fragmented care has been associated with poor chronic disease outcomes, higher health care use, duplication in testing, and increased costs of care.”
In the VHA, these issues prompted creation of the Patient Aligned Care Team (PACT), a medical home model in which primary care physicians coordinate clinical teams of specialists and other health care practitioners. But coordination can be challenging with chronic medical conditions like IBD, according to Dr. Cohen-Mekelburg and colleagues.
“High-quality care for IBD includes not only disease-specific management of symptoms but also disease-specific preventive care, such as immunizations and cancer screening, to prevent associated adverse outcomes,” the investigators wrote. “Identifying which physician is responsible for managing each aspect of care requires some degree of coordination and makes patients with IBD vulnerable to care fragmentation.”
Worse outcomes tied to poor first-year continuity
To evaluate care fragmentation within the VHA, the investigators identified 20,079 veterans with IBD who had at least one outpatient encounter with the system between the beginning of 2002 and the end of 2014. Continuity of care (COC) was calculated with the Bice-Boxerman COC index, which measures how much a patient’s care is connected with a distinct physician. The investigators used the first year COC as the primary independent variable.
In the first year of care, the median COC index was 0.24 (interquartile range, 0.13-0.46). The investigators noted that this figure was lower than reported by previous studies involving patients with several other chronic conditions, including IBD.
After controlling for covariates and adjusting for facility-related clustering, the investigators found a lower COC index in the first year was associated with a higher rate of worse outcomes in the subsequent 2 years, including surgical interventions (adjusted hazard ratio, 1.72; 95% confidence interval, 1.43-2.07), hospitalizations (aHR, 1.25; 95% CI, 1.06-1.47), and outpatient flares requiring corticosteroids (aHR, 1.11; 95% CI, 1.01-1.22). Conversely, improving COC index score by 0.1 reduced risk of outpatient flare (aHR, 0.69; 95%CI, 0.58-0.82), hospitalization (aHR, 0.57; 95%CI, 0.41-0.79), and surgical intervention (aHR, 0.25; 95% CI, 0.16-0.38).
Further analyses showed that the relationship between lower COC and worse outcomes carried across measures such as baseline use of an immunomodulator or biological agent, as well as subgroups such as patients with nonsevere IBD and nonsurgical patients.
Among those treated by a VHA gastroenterologist, a lower level of COC was associated with a higher rate of surgical interventions, but not hospitalizations or outpatient flares. Physician-specific COC index scores were highest for primary care providers (0.54), followed by gastroenterologists (0.25) and surgeons (0.17). However, lower physician-specific COC scores did not translate to worse IBD outcomes.
“The level of COC among patients with IBD in the present VHA cohort was ... lower than the values described in previous studies of veterans in the VHA system, including a study of VHA-Medicare dual enrollees who were especially prone to fragmented care because of their ability to seek care both inside and outside of the VHA system,” the investigators wrote, referring to a 2018 study. “The difference in COC among patients with IBD vs. patients without IBD is likely multifactorial and may be associated with confusion about physician accountability and lack of focus on coordination in IBD multidisciplinary care. Patients with IBD require care by primary care providers, gastroenterologists, and surgeons, but the delineation of responsibility by physician is often unclear.”
‘Better care, not just more care,’ is needed
“These outcomes cannot be improved with a more robust treatment armamentarium alone,” according to Jason K. Hou, MD, MS, AGAF, FACG, interim chief of gastroenterology and hepatology at Michael E. DeBakey VA Medical Center and associate professor of medicine at Baylor College of Medicine, Houston, who cowrote a simultaneously published editorial, which was also authored by David I. Fudman, MD.
“Examples exist of improving care coordination and outcomes through patient-aligned care teams in primary care and medical specialty homes for IBD,” Dr. Hou said in an interview. “However, significant barriers to widespread implementation remain.”
Dr. Hou offered several possible approaches to overcome these barriers.
“We need improved methods to identify and follow high-risk patients most likely to have complications and health care utilization,” he said. “We need an investment by payers and health care systems on care coordination so the identified high-risk patients can receive timely testing, referral, and treatment. These changes require reevaluation of how the health care system incentivizes health care to provide better care, not just more care.”
The investigators reported grants from the U.S. Department of Veterans Affairs and the National Institutes of Health and financial relationships with AbbVie, UCB, and Takeda. Dr. Hou reported no conflicts of interest.
Poor continuity of care may lead to worse outcomes among patients with active inflammatory bowel disease (IBD), according to data from more than 20,000 veterans.
Even in the Veterans Health Administration health care system, which “may provide the ideal environment for care coordination,” patients with active IBD had “substantial variation” in dispersion of care, leading to more frequent surgical interventions, corticosteroid use, and hospitalizations, reported lead author Shirley Cohen-Mekelburg, MD, MS, of the University of Michigan, Ann Arbor, and colleagues.
“Health care in the United States is marked by substantial fragmentation, with patients pursuing and receiving care from multiple clinicians, often at different institutions,” the investigators wrote in JAMA Network Open. “Fragmented care has been associated with poor chronic disease outcomes, higher health care use, duplication in testing, and increased costs of care.”
In the VHA, these issues prompted creation of the Patient Aligned Care Team (PACT), a medical home model in which primary care physicians coordinate clinical teams of specialists and other health care practitioners. But coordination can be challenging with chronic medical conditions like IBD, according to Dr. Cohen-Mekelburg and colleagues.
“High-quality care for IBD includes not only disease-specific management of symptoms but also disease-specific preventive care, such as immunizations and cancer screening, to prevent associated adverse outcomes,” the investigators wrote. “Identifying which physician is responsible for managing each aspect of care requires some degree of coordination and makes patients with IBD vulnerable to care fragmentation.”
Worse outcomes tied to poor first-year continuity
To evaluate care fragmentation within the VHA, the investigators identified 20,079 veterans with IBD who had at least one outpatient encounter with the system between the beginning of 2002 and the end of 2014. Continuity of care (COC) was calculated with the Bice-Boxerman COC index, which measures how much a patient’s care is connected with a distinct physician. The investigators used the first year COC as the primary independent variable.
In the first year of care, the median COC index was 0.24 (interquartile range, 0.13-0.46). The investigators noted that this figure was lower than reported by previous studies involving patients with several other chronic conditions, including IBD.
After controlling for covariates and adjusting for facility-related clustering, the investigators found a lower COC index in the first year was associated with a higher rate of worse outcomes in the subsequent 2 years, including surgical interventions (adjusted hazard ratio, 1.72; 95% confidence interval, 1.43-2.07), hospitalizations (aHR, 1.25; 95% CI, 1.06-1.47), and outpatient flares requiring corticosteroids (aHR, 1.11; 95% CI, 1.01-1.22). Conversely, improving COC index score by 0.1 reduced risk of outpatient flare (aHR, 0.69; 95%CI, 0.58-0.82), hospitalization (aHR, 0.57; 95%CI, 0.41-0.79), and surgical intervention (aHR, 0.25; 95% CI, 0.16-0.38).
Further analyses showed that the relationship between lower COC and worse outcomes carried across measures such as baseline use of an immunomodulator or biological agent, as well as subgroups such as patients with nonsevere IBD and nonsurgical patients.
Among those treated by a VHA gastroenterologist, a lower level of COC was associated with a higher rate of surgical interventions, but not hospitalizations or outpatient flares. Physician-specific COC index scores were highest for primary care providers (0.54), followed by gastroenterologists (0.25) and surgeons (0.17). However, lower physician-specific COC scores did not translate to worse IBD outcomes.
“The level of COC among patients with IBD in the present VHA cohort was ... lower than the values described in previous studies of veterans in the VHA system, including a study of VHA-Medicare dual enrollees who were especially prone to fragmented care because of their ability to seek care both inside and outside of the VHA system,” the investigators wrote, referring to a 2018 study. “The difference in COC among patients with IBD vs. patients without IBD is likely multifactorial and may be associated with confusion about physician accountability and lack of focus on coordination in IBD multidisciplinary care. Patients with IBD require care by primary care providers, gastroenterologists, and surgeons, but the delineation of responsibility by physician is often unclear.”
‘Better care, not just more care,’ is needed
“These outcomes cannot be improved with a more robust treatment armamentarium alone,” according to Jason K. Hou, MD, MS, AGAF, FACG, interim chief of gastroenterology and hepatology at Michael E. DeBakey VA Medical Center and associate professor of medicine at Baylor College of Medicine, Houston, who cowrote a simultaneously published editorial, which was also authored by David I. Fudman, MD.
“Examples exist of improving care coordination and outcomes through patient-aligned care teams in primary care and medical specialty homes for IBD,” Dr. Hou said in an interview. “However, significant barriers to widespread implementation remain.”
Dr. Hou offered several possible approaches to overcome these barriers.
“We need improved methods to identify and follow high-risk patients most likely to have complications and health care utilization,” he said. “We need an investment by payers and health care systems on care coordination so the identified high-risk patients can receive timely testing, referral, and treatment. These changes require reevaluation of how the health care system incentivizes health care to provide better care, not just more care.”
The investigators reported grants from the U.S. Department of Veterans Affairs and the National Institutes of Health and financial relationships with AbbVie, UCB, and Takeda. Dr. Hou reported no conflicts of interest.
FROM JAMA NETWORK OPEN
COVID-19 linked to novel epileptic seizures
, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.
In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.
“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.
Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”
“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.
Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
Largest sample to date
“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.
Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.
However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.
For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.
For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).
The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
Significant adverse outcomes
Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).
In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).
In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).
Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).
Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.
Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”
He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”
Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.
The investigators have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.
In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.
“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.
Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”
“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.
Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
Largest sample to date
“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.
Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.
However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.
For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.
For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).
The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
Significant adverse outcomes
Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).
In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).
In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).
Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).
Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.
Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”
He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”
Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.
The investigators have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.
In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.
“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.
Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”
“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.
Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
Largest sample to date
“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.
Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.
However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.
For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.
For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).
The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
Significant adverse outcomes
Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).
In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).
In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).
Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).
Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.
Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”
He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”
Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.
The investigators have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From AAN 2021
Survival benefit with nivolumab extends to 5 years in NSCLC
Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m2 once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.
At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.
The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.
There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.
According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”
“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.
Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”
No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.
The optimal duration of nivolumab treatment beyond 1 year is also uncertain.
The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.
The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.
They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.
Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.
This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.
Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m2 once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.
At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.
The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.
There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.
According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”
“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.
Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”
No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.
The optimal duration of nivolumab treatment beyond 1 year is also uncertain.
The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.
The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.
They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.
Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.
This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.
Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m2 once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.
At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.
The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.
There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.
According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”
“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.
Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”
No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.
The optimal duration of nivolumab treatment beyond 1 year is also uncertain.
The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.
The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.
They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.
Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.
This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Debate: Should biologics be used for milder cases of psoriasis?
The issue was tackled in a debate at the American Academy of Dermatology Virtual Meeting Experience.
Taking the con side, Kenneth Gordon, MD, professor and chair of dermatology at the Medical College of Wisconsin, Milwaukee, argued that, with the high cost of biologics, availability of many alternatives, and other issues, “we should just say no. ... There is no good reason that we need to expand the use of biologics in patients with limited disease.”
On the pro side, Richard Langley, MD, professor of dermatology at Dalhousie University Halifax, N.S, argued for a nuanced approach. He noted that patients with smaller patches of disease can be just as miserable as patients who hit traditional benchmarks of increased severity, such as high body surface area involvement – especially if those small areas are in sensitive locations like the scalp, palms, or genitals.
The decision to use a biologic should hinge on how badly patients and their quality of life are affected, not on “some artificial and limiting definition” of severity, Dr. Langley said.
Dr. Gordon didn’t disagree, noting that current use criteria include objective measures as well as disease in sensitive areas and failure of alternative treatments.
Rather, he was concerned about “expanding the definition of who is eligible beyond these criteria ... to chase every last bit of” disease. “I don’t think we have” a good rationale for that approach, he said.
Cost is the most important issue, Dr. Gordon said.
With more biologics on the way and prices continuing to go up, “there is going to a be a huge challenge to our use of these expensive medicines over the next few years” from payers. “It is important that we use them smartly in order to make sure we are able to use them for people with severe disease” who really need them. If “we start using biologics for all our patients with psoriasis,” it will be a “cost disaster,” Dr. Gordon said.
In addition, topicals and home phototherapy can be effective as long as patients adhere to them, as can alternative systemic agents, such as methotrexate and apremilast.
Often with biologics, “the issue is mainly convenience” rather than a fundamental problem with the alternatives, and despite the good safety record in trials, “chasing the last bit” of psoriasis with a biologic “is not necessarily” without risk for the patient, Dr. Gordon said.
Still, there can be a “pretty significant disconnect” between how patients perceive their psoriasis and “what physicians are thinking and prescribing” for it based on objective measures, Dr. Langley noted. Sometimes patients who have limited disease but are in significant distress aren’t even receiving treatment or are only given another cream to add to their collection of ones that haven’t worked.
One problem with traditional severity classifications is that they don’t generally take patients’ subjective experience into account, he added. There’s also been a lack of standardization to the point that dermatologists, researchers, and payers can sometimes disagree over severity in a given patient.
There’s movement toward better incorporation of patient experience into severity considerations, but for now at least, a designation of mild psoriasis can underestimate the true severity of disease, Dr. Langley said.
Dr. Gordon and Dr. Langley reported receiving honoraria and/or research support from many pharmaceutical companies, including AbbVie, Pfizer, and Lilly.
A version of this article first appeared on Medscape.com.
The issue was tackled in a debate at the American Academy of Dermatology Virtual Meeting Experience.
Taking the con side, Kenneth Gordon, MD, professor and chair of dermatology at the Medical College of Wisconsin, Milwaukee, argued that, with the high cost of biologics, availability of many alternatives, and other issues, “we should just say no. ... There is no good reason that we need to expand the use of biologics in patients with limited disease.”
On the pro side, Richard Langley, MD, professor of dermatology at Dalhousie University Halifax, N.S, argued for a nuanced approach. He noted that patients with smaller patches of disease can be just as miserable as patients who hit traditional benchmarks of increased severity, such as high body surface area involvement – especially if those small areas are in sensitive locations like the scalp, palms, or genitals.
The decision to use a biologic should hinge on how badly patients and their quality of life are affected, not on “some artificial and limiting definition” of severity, Dr. Langley said.
Dr. Gordon didn’t disagree, noting that current use criteria include objective measures as well as disease in sensitive areas and failure of alternative treatments.
Rather, he was concerned about “expanding the definition of who is eligible beyond these criteria ... to chase every last bit of” disease. “I don’t think we have” a good rationale for that approach, he said.
Cost is the most important issue, Dr. Gordon said.
With more biologics on the way and prices continuing to go up, “there is going to a be a huge challenge to our use of these expensive medicines over the next few years” from payers. “It is important that we use them smartly in order to make sure we are able to use them for people with severe disease” who really need them. If “we start using biologics for all our patients with psoriasis,” it will be a “cost disaster,” Dr. Gordon said.
In addition, topicals and home phototherapy can be effective as long as patients adhere to them, as can alternative systemic agents, such as methotrexate and apremilast.
Often with biologics, “the issue is mainly convenience” rather than a fundamental problem with the alternatives, and despite the good safety record in trials, “chasing the last bit” of psoriasis with a biologic “is not necessarily” without risk for the patient, Dr. Gordon said.
Still, there can be a “pretty significant disconnect” between how patients perceive their psoriasis and “what physicians are thinking and prescribing” for it based on objective measures, Dr. Langley noted. Sometimes patients who have limited disease but are in significant distress aren’t even receiving treatment or are only given another cream to add to their collection of ones that haven’t worked.
One problem with traditional severity classifications is that they don’t generally take patients’ subjective experience into account, he added. There’s also been a lack of standardization to the point that dermatologists, researchers, and payers can sometimes disagree over severity in a given patient.
There’s movement toward better incorporation of patient experience into severity considerations, but for now at least, a designation of mild psoriasis can underestimate the true severity of disease, Dr. Langley said.
Dr. Gordon and Dr. Langley reported receiving honoraria and/or research support from many pharmaceutical companies, including AbbVie, Pfizer, and Lilly.
A version of this article first appeared on Medscape.com.
The issue was tackled in a debate at the American Academy of Dermatology Virtual Meeting Experience.
Taking the con side, Kenneth Gordon, MD, professor and chair of dermatology at the Medical College of Wisconsin, Milwaukee, argued that, with the high cost of biologics, availability of many alternatives, and other issues, “we should just say no. ... There is no good reason that we need to expand the use of biologics in patients with limited disease.”
On the pro side, Richard Langley, MD, professor of dermatology at Dalhousie University Halifax, N.S, argued for a nuanced approach. He noted that patients with smaller patches of disease can be just as miserable as patients who hit traditional benchmarks of increased severity, such as high body surface area involvement – especially if those small areas are in sensitive locations like the scalp, palms, or genitals.
The decision to use a biologic should hinge on how badly patients and their quality of life are affected, not on “some artificial and limiting definition” of severity, Dr. Langley said.
Dr. Gordon didn’t disagree, noting that current use criteria include objective measures as well as disease in sensitive areas and failure of alternative treatments.
Rather, he was concerned about “expanding the definition of who is eligible beyond these criteria ... to chase every last bit of” disease. “I don’t think we have” a good rationale for that approach, he said.
Cost is the most important issue, Dr. Gordon said.
With more biologics on the way and prices continuing to go up, “there is going to a be a huge challenge to our use of these expensive medicines over the next few years” from payers. “It is important that we use them smartly in order to make sure we are able to use them for people with severe disease” who really need them. If “we start using biologics for all our patients with psoriasis,” it will be a “cost disaster,” Dr. Gordon said.
In addition, topicals and home phototherapy can be effective as long as patients adhere to them, as can alternative systemic agents, such as methotrexate and apremilast.
Often with biologics, “the issue is mainly convenience” rather than a fundamental problem with the alternatives, and despite the good safety record in trials, “chasing the last bit” of psoriasis with a biologic “is not necessarily” without risk for the patient, Dr. Gordon said.
Still, there can be a “pretty significant disconnect” between how patients perceive their psoriasis and “what physicians are thinking and prescribing” for it based on objective measures, Dr. Langley noted. Sometimes patients who have limited disease but are in significant distress aren’t even receiving treatment or are only given another cream to add to their collection of ones that haven’t worked.
One problem with traditional severity classifications is that they don’t generally take patients’ subjective experience into account, he added. There’s also been a lack of standardization to the point that dermatologists, researchers, and payers can sometimes disagree over severity in a given patient.
There’s movement toward better incorporation of patient experience into severity considerations, but for now at least, a designation of mild psoriasis can underestimate the true severity of disease, Dr. Langley said.
Dr. Gordon and Dr. Langley reported receiving honoraria and/or research support from many pharmaceutical companies, including AbbVie, Pfizer, and Lilly.
A version of this article first appeared on Medscape.com.
Tofacitinib: Small study shows big cutaneous sarcoidosis response
Researchers are reporting impressive results in a small, , and all patients improved by an average of 83% via a scoring system.
“Not only did patients get better, but they were in many cases able to come off their baseline immunosuppressive regimen, including prednisone and methotrexate. They’d get off prednisone entirely or, in some cases, decrease it substantially,” study investigator William Damsky, MD, PhD, reported at the American Academy of Dermatology Virtual Meeting Experience.
Sarcoidosis is a common disease that affects an estimated 1 in 25 Black women and is believed to contribute to the deaths of about 4,000 people in the United States each year, noted Dr. Damsky of the department of dermatology, Yale University, New Haven, Conn. One famous patient is comedian Bernie Mac, who died from the condition in 2008.
“Approximately one third of patients have cutaneous involvement,” Dr. Damsky said, and skin may be the only manifestation of the disease. There is no Food and Drug Administration-approved therapy for cutaneous sarcoidosis, he added. Prednisone, the first-line therapy in skin manifestations, is approved only for pulmonary sarcoidosis.
“Oftentimes, there’s an attempt to transition either partially or fully to other therapies, including methotrexate and TNF-alpha blockers. But there’s been mixed success in doing that,” he said. This is not always possible, “so a lot of patients end up on prednisone.”
Earlier, a team at Yale prescribed 5 mg tofacitinib (Xeljanz) for several patients with severe cutaneous sarcoidosis and saw impressive results, Dr. Damsky said, including a patient with pulmonary sarcoidosis that also improved. He noted that there are case reports in the medical literature with similar findings.
Those positive results inspired the new study. Researchers recruited 10 patients with cutaneous sarcoidosis (9 with internal organ involvement) with a Cutaneous Sarcoidosis Activity and Morphology Instrument ( CSAMI ) score of 10 or higher. Nine patients were in their 50s, one was aged 63 years, and five were men. Skin colors of the patients ranged from Fitzpatrick skin types I to VI, and all had been taking at least two medications, typically methotrexate and prednisone.
The patients received 5 mg of tofacitinib twice a day for 6 months. “Everyone got better during the study, and six patients had a complete response, which we defined as a CSAMI score of zero activity,” Dr. Damsky said. “It’s really quite remarkable to see that.” Overall, the patients saw an 83% improvement in CSAMI scores.
In regard to safety, “all patients completed the study,” he said. “Tofacitinib was well tolerated, and there were no serious adverse effects or events.”
Tofacitinib is approved for treating rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis.
A month’s supply of twice-daily 5 mg tofacitinib pills would cost $4,900-$5,100 with free coupons, according to information accessed on April 24, 2021, on GoodRx.com. Generics are not available.
In an interview, Sotonye Imadojemu, MD, of the department of dermatology, Brigham and Women’s Hospital, Boston, praised the study, and said “tofacitinib is a reasonable treatment for treatment-refractory or extensive cutaneous sarcoidosis,” although it will be helpful to get results from randomized-controlled trials.
She cautioned that the drug “is a powerful immunosuppressant, so the risk of infection must be discussed with patients before prescribing. Screening for chronic infections such as viral hepatitis, tuberculosis, and HIV should be completed prior to treatment initiation. Blood counts, liver function, and lipid panels should be regularly monitored. The vaccines necessary for those who are immunosuppressed should be administered as able, and age-appropriate cancer screening must be kept up to date.”
The study was funded by Pfizer, the Dermatology Foundation, and the Yale Department of Dermatology. Dr. Damsky disclosed research support (Pfizer), consulting fees (Eli Lilly, Pfizer, TWi Biotechnology), and licensing fees (EMD Millipore/MillporeSigma). Dr. Imadojemu has no disclosures.
This article was updated 5/5/21.
Researchers are reporting impressive results in a small, , and all patients improved by an average of 83% via a scoring system.
“Not only did patients get better, but they were in many cases able to come off their baseline immunosuppressive regimen, including prednisone and methotrexate. They’d get off prednisone entirely or, in some cases, decrease it substantially,” study investigator William Damsky, MD, PhD, reported at the American Academy of Dermatology Virtual Meeting Experience.
Sarcoidosis is a common disease that affects an estimated 1 in 25 Black women and is believed to contribute to the deaths of about 4,000 people in the United States each year, noted Dr. Damsky of the department of dermatology, Yale University, New Haven, Conn. One famous patient is comedian Bernie Mac, who died from the condition in 2008.
“Approximately one third of patients have cutaneous involvement,” Dr. Damsky said, and skin may be the only manifestation of the disease. There is no Food and Drug Administration-approved therapy for cutaneous sarcoidosis, he added. Prednisone, the first-line therapy in skin manifestations, is approved only for pulmonary sarcoidosis.
“Oftentimes, there’s an attempt to transition either partially or fully to other therapies, including methotrexate and TNF-alpha blockers. But there’s been mixed success in doing that,” he said. This is not always possible, “so a lot of patients end up on prednisone.”
Earlier, a team at Yale prescribed 5 mg tofacitinib (Xeljanz) for several patients with severe cutaneous sarcoidosis and saw impressive results, Dr. Damsky said, including a patient with pulmonary sarcoidosis that also improved. He noted that there are case reports in the medical literature with similar findings.
Those positive results inspired the new study. Researchers recruited 10 patients with cutaneous sarcoidosis (9 with internal organ involvement) with a Cutaneous Sarcoidosis Activity and Morphology Instrument ( CSAMI ) score of 10 or higher. Nine patients were in their 50s, one was aged 63 years, and five were men. Skin colors of the patients ranged from Fitzpatrick skin types I to VI, and all had been taking at least two medications, typically methotrexate and prednisone.
The patients received 5 mg of tofacitinib twice a day for 6 months. “Everyone got better during the study, and six patients had a complete response, which we defined as a CSAMI score of zero activity,” Dr. Damsky said. “It’s really quite remarkable to see that.” Overall, the patients saw an 83% improvement in CSAMI scores.
In regard to safety, “all patients completed the study,” he said. “Tofacitinib was well tolerated, and there were no serious adverse effects or events.”
Tofacitinib is approved for treating rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis.
A month’s supply of twice-daily 5 mg tofacitinib pills would cost $4,900-$5,100 with free coupons, according to information accessed on April 24, 2021, on GoodRx.com. Generics are not available.
In an interview, Sotonye Imadojemu, MD, of the department of dermatology, Brigham and Women’s Hospital, Boston, praised the study, and said “tofacitinib is a reasonable treatment for treatment-refractory or extensive cutaneous sarcoidosis,” although it will be helpful to get results from randomized-controlled trials.
She cautioned that the drug “is a powerful immunosuppressant, so the risk of infection must be discussed with patients before prescribing. Screening for chronic infections such as viral hepatitis, tuberculosis, and HIV should be completed prior to treatment initiation. Blood counts, liver function, and lipid panels should be regularly monitored. The vaccines necessary for those who are immunosuppressed should be administered as able, and age-appropriate cancer screening must be kept up to date.”
The study was funded by Pfizer, the Dermatology Foundation, and the Yale Department of Dermatology. Dr. Damsky disclosed research support (Pfizer), consulting fees (Eli Lilly, Pfizer, TWi Biotechnology), and licensing fees (EMD Millipore/MillporeSigma). Dr. Imadojemu has no disclosures.
This article was updated 5/5/21.
Researchers are reporting impressive results in a small, , and all patients improved by an average of 83% via a scoring system.
“Not only did patients get better, but they were in many cases able to come off their baseline immunosuppressive regimen, including prednisone and methotrexate. They’d get off prednisone entirely or, in some cases, decrease it substantially,” study investigator William Damsky, MD, PhD, reported at the American Academy of Dermatology Virtual Meeting Experience.
Sarcoidosis is a common disease that affects an estimated 1 in 25 Black women and is believed to contribute to the deaths of about 4,000 people in the United States each year, noted Dr. Damsky of the department of dermatology, Yale University, New Haven, Conn. One famous patient is comedian Bernie Mac, who died from the condition in 2008.
“Approximately one third of patients have cutaneous involvement,” Dr. Damsky said, and skin may be the only manifestation of the disease. There is no Food and Drug Administration-approved therapy for cutaneous sarcoidosis, he added. Prednisone, the first-line therapy in skin manifestations, is approved only for pulmonary sarcoidosis.
“Oftentimes, there’s an attempt to transition either partially or fully to other therapies, including methotrexate and TNF-alpha blockers. But there’s been mixed success in doing that,” he said. This is not always possible, “so a lot of patients end up on prednisone.”
Earlier, a team at Yale prescribed 5 mg tofacitinib (Xeljanz) for several patients with severe cutaneous sarcoidosis and saw impressive results, Dr. Damsky said, including a patient with pulmonary sarcoidosis that also improved. He noted that there are case reports in the medical literature with similar findings.
Those positive results inspired the new study. Researchers recruited 10 patients with cutaneous sarcoidosis (9 with internal organ involvement) with a Cutaneous Sarcoidosis Activity and Morphology Instrument ( CSAMI ) score of 10 or higher. Nine patients were in their 50s, one was aged 63 years, and five were men. Skin colors of the patients ranged from Fitzpatrick skin types I to VI, and all had been taking at least two medications, typically methotrexate and prednisone.
The patients received 5 mg of tofacitinib twice a day for 6 months. “Everyone got better during the study, and six patients had a complete response, which we defined as a CSAMI score of zero activity,” Dr. Damsky said. “It’s really quite remarkable to see that.” Overall, the patients saw an 83% improvement in CSAMI scores.
In regard to safety, “all patients completed the study,” he said. “Tofacitinib was well tolerated, and there were no serious adverse effects or events.”
Tofacitinib is approved for treating rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis.
A month’s supply of twice-daily 5 mg tofacitinib pills would cost $4,900-$5,100 with free coupons, according to information accessed on April 24, 2021, on GoodRx.com. Generics are not available.
In an interview, Sotonye Imadojemu, MD, of the department of dermatology, Brigham and Women’s Hospital, Boston, praised the study, and said “tofacitinib is a reasonable treatment for treatment-refractory or extensive cutaneous sarcoidosis,” although it will be helpful to get results from randomized-controlled trials.
She cautioned that the drug “is a powerful immunosuppressant, so the risk of infection must be discussed with patients before prescribing. Screening for chronic infections such as viral hepatitis, tuberculosis, and HIV should be completed prior to treatment initiation. Blood counts, liver function, and lipid panels should be regularly monitored. The vaccines necessary for those who are immunosuppressed should be administered as able, and age-appropriate cancer screening must be kept up to date.”
The study was funded by Pfizer, the Dermatology Foundation, and the Yale Department of Dermatology. Dr. Damsky disclosed research support (Pfizer), consulting fees (Eli Lilly, Pfizer, TWi Biotechnology), and licensing fees (EMD Millipore/MillporeSigma). Dr. Imadojemu has no disclosures.
This article was updated 5/5/21.
REPORTING FROM AAD VMX 2021
Topical anticholinergic for axillary hyperhidrosis shows fewer side effects
according to 48-week safety and outcome data.
A structural analogue of glycopyrrolate working through the same mechanism, sofpironium bromide was developed as a retrometabolic agent. This means it is rapidly transformed into an inactive metabolite after application, reducing risk of systemic effects, study investigator Stacy Smith, MD, explained in the late-breaking research session at the American Academy of Dermatology Virtual Meeting Experience.
The anticholinergic glycopyrrolate, which currently is the most commonly used therapy for hyperhidrosis, is absorbed through the skin and excreted through the urine. The systemic exposure to the active agent after topical application explains the substantial risk of adverse effects, said Dr. Smith, a clinician and researcher affiliated with the California Dermatology and Clinical Research Institute, Encinitas.
In contrast,“sofpironium bromide is the ideal topical medication, because it has strong activity at the application site but then reduced systemic activity due to the retrometabolism,” Dr. Smith said.
The 52-week data from the open-label, phase 3 trial supports the premise. In this study of 299 patients randomized to the 5% (102 patients) or 15% (197 patients) topical sofpironium bromide gel formulations, most anticholinergic adverse events were mild or moderate and transient, with complaints concentrated in the first 3 months of the trial.
“The retrometabolic pathway seems to work,” Dr. Smith said. He acknowledged that the treatment-naive patients who entered the study “had to get used to the drug over time,” but the data “show they did.”
The phase 3 trial of sofpironium bromide, which is already approved to treat axillary hyperhidrosis in Japan, did not have a placebo control. It was focused primarily on safety, but outcomes were assessed with the Hyperhidrosis Disease Severity Measure–Axillary (HDSM-Ax).
At least a 1-point improvement in the 7-point HDSM-Ax scale, which is considered clinically meaningful, was achieved by 86.1% and 85.8% of those treated with the 5% and 15% gels, respectively. A 2-point or greater improvement at the end of the study was observed in 69.4% and 61.9%, respectively.
“The medication works well and there was improved efficacy over time. About two-thirds of the patients had at least a 2-point improvement in the HDSM-Ax score at the end of 48 weeks,” Dr. Smith reported.
While response rates climbed over the course of the study, rates of adverse events fell markedly.
After 2 weeks of treatment, the proportions of patients with a treatment-related adverse event were 6% and just under 15% for the 5% and 15% topical-gel groups, respectively. At each 2-week interval when reassessed, the rates fell. By week 12, the rates were less than 2% and about 4% in the two groups, respectively.
The discontinuation rates overall for anticholinergic side effects were 3% and 8.1% for the lower and higher doses. Blurred vision accounted for the vast majority of these discontinuations in both groups. The other discontinuations, which included those for dry mouth, urinary retention, and mydriasis, occurred in one patient each. Again, discontinuations were most common in the first few months of the study.
For the total study population, mild (10.8% vs. 24%) and moderate (10.8% vs. 20.3%) side effects accounted for almost all side effects with the lower and higher doses of the topical drug. Only one patient in the low-dose group had a severe adverse event. At 6.1%, the proportion of the high-dose group with a severe adverse event was higher, but none of the adverse events were considered serious. All were transient.
These rates of adverse events are lower than those reported historically with effective doses of glycopyrrolate, Dr. Smith said.
The data presented by Dr. Smith are part of a phase 3 pivotal trials program designed to gain FDA approval. Going forward, these trials, which are enrolling patients as young as 9 years old, are expected to focus on clinical development of the 15% gel, he added.
The gel is delivered with a metered-dose pump that has an applicator, according to Brickell Biotech, the company developing the treatment in the United States. The 5% formulation was approved in Japan in September 2020, for the treatment of primary axillary hyperhidrosis.
In an interview, David M. Pariser, MD, professor of dermatology, Eastern Virginia Medical School, Norfolk, said that he believes that this drug has could be helpful if the pivotal studies confirm efficacy with a lower risk of adverse events relative to glycopyrrolate. “If it is true that, in phase 3, placebo-controlled trials, there are fewer systemic anticholinergic effects, then this drug will be very useful,” said Dr. Pariser, cofounder of the International Hyperhidrosis Society and an investigator on a previously published dose-ranging, phase 2 study of sofpironium bromide.
The trial was sponsored by Brickell Biotech, which compensated Dr. Smith and other coauthors for their participation. Dr. Pariser has financial relationships with multiple pharmaceutical companies with dermatologic products, including Brickell Biotech.
This article was updated 4/26/21.
according to 48-week safety and outcome data.
A structural analogue of glycopyrrolate working through the same mechanism, sofpironium bromide was developed as a retrometabolic agent. This means it is rapidly transformed into an inactive metabolite after application, reducing risk of systemic effects, study investigator Stacy Smith, MD, explained in the late-breaking research session at the American Academy of Dermatology Virtual Meeting Experience.
The anticholinergic glycopyrrolate, which currently is the most commonly used therapy for hyperhidrosis, is absorbed through the skin and excreted through the urine. The systemic exposure to the active agent after topical application explains the substantial risk of adverse effects, said Dr. Smith, a clinician and researcher affiliated with the California Dermatology and Clinical Research Institute, Encinitas.
In contrast,“sofpironium bromide is the ideal topical medication, because it has strong activity at the application site but then reduced systemic activity due to the retrometabolism,” Dr. Smith said.
The 52-week data from the open-label, phase 3 trial supports the premise. In this study of 299 patients randomized to the 5% (102 patients) or 15% (197 patients) topical sofpironium bromide gel formulations, most anticholinergic adverse events were mild or moderate and transient, with complaints concentrated in the first 3 months of the trial.
“The retrometabolic pathway seems to work,” Dr. Smith said. He acknowledged that the treatment-naive patients who entered the study “had to get used to the drug over time,” but the data “show they did.”
The phase 3 trial of sofpironium bromide, which is already approved to treat axillary hyperhidrosis in Japan, did not have a placebo control. It was focused primarily on safety, but outcomes were assessed with the Hyperhidrosis Disease Severity Measure–Axillary (HDSM-Ax).
At least a 1-point improvement in the 7-point HDSM-Ax scale, which is considered clinically meaningful, was achieved by 86.1% and 85.8% of those treated with the 5% and 15% gels, respectively. A 2-point or greater improvement at the end of the study was observed in 69.4% and 61.9%, respectively.
“The medication works well and there was improved efficacy over time. About two-thirds of the patients had at least a 2-point improvement in the HDSM-Ax score at the end of 48 weeks,” Dr. Smith reported.
While response rates climbed over the course of the study, rates of adverse events fell markedly.
After 2 weeks of treatment, the proportions of patients with a treatment-related adverse event were 6% and just under 15% for the 5% and 15% topical-gel groups, respectively. At each 2-week interval when reassessed, the rates fell. By week 12, the rates were less than 2% and about 4% in the two groups, respectively.
The discontinuation rates overall for anticholinergic side effects were 3% and 8.1% for the lower and higher doses. Blurred vision accounted for the vast majority of these discontinuations in both groups. The other discontinuations, which included those for dry mouth, urinary retention, and mydriasis, occurred in one patient each. Again, discontinuations were most common in the first few months of the study.
For the total study population, mild (10.8% vs. 24%) and moderate (10.8% vs. 20.3%) side effects accounted for almost all side effects with the lower and higher doses of the topical drug. Only one patient in the low-dose group had a severe adverse event. At 6.1%, the proportion of the high-dose group with a severe adverse event was higher, but none of the adverse events were considered serious. All were transient.
These rates of adverse events are lower than those reported historically with effective doses of glycopyrrolate, Dr. Smith said.
The data presented by Dr. Smith are part of a phase 3 pivotal trials program designed to gain FDA approval. Going forward, these trials, which are enrolling patients as young as 9 years old, are expected to focus on clinical development of the 15% gel, he added.
The gel is delivered with a metered-dose pump that has an applicator, according to Brickell Biotech, the company developing the treatment in the United States. The 5% formulation was approved in Japan in September 2020, for the treatment of primary axillary hyperhidrosis.
In an interview, David M. Pariser, MD, professor of dermatology, Eastern Virginia Medical School, Norfolk, said that he believes that this drug has could be helpful if the pivotal studies confirm efficacy with a lower risk of adverse events relative to glycopyrrolate. “If it is true that, in phase 3, placebo-controlled trials, there are fewer systemic anticholinergic effects, then this drug will be very useful,” said Dr. Pariser, cofounder of the International Hyperhidrosis Society and an investigator on a previously published dose-ranging, phase 2 study of sofpironium bromide.
The trial was sponsored by Brickell Biotech, which compensated Dr. Smith and other coauthors for their participation. Dr. Pariser has financial relationships with multiple pharmaceutical companies with dermatologic products, including Brickell Biotech.
This article was updated 4/26/21.
according to 48-week safety and outcome data.
A structural analogue of glycopyrrolate working through the same mechanism, sofpironium bromide was developed as a retrometabolic agent. This means it is rapidly transformed into an inactive metabolite after application, reducing risk of systemic effects, study investigator Stacy Smith, MD, explained in the late-breaking research session at the American Academy of Dermatology Virtual Meeting Experience.
The anticholinergic glycopyrrolate, which currently is the most commonly used therapy for hyperhidrosis, is absorbed through the skin and excreted through the urine. The systemic exposure to the active agent after topical application explains the substantial risk of adverse effects, said Dr. Smith, a clinician and researcher affiliated with the California Dermatology and Clinical Research Institute, Encinitas.
In contrast,“sofpironium bromide is the ideal topical medication, because it has strong activity at the application site but then reduced systemic activity due to the retrometabolism,” Dr. Smith said.
The 52-week data from the open-label, phase 3 trial supports the premise. In this study of 299 patients randomized to the 5% (102 patients) or 15% (197 patients) topical sofpironium bromide gel formulations, most anticholinergic adverse events were mild or moderate and transient, with complaints concentrated in the first 3 months of the trial.
“The retrometabolic pathway seems to work,” Dr. Smith said. He acknowledged that the treatment-naive patients who entered the study “had to get used to the drug over time,” but the data “show they did.”
The phase 3 trial of sofpironium bromide, which is already approved to treat axillary hyperhidrosis in Japan, did not have a placebo control. It was focused primarily on safety, but outcomes were assessed with the Hyperhidrosis Disease Severity Measure–Axillary (HDSM-Ax).
At least a 1-point improvement in the 7-point HDSM-Ax scale, which is considered clinically meaningful, was achieved by 86.1% and 85.8% of those treated with the 5% and 15% gels, respectively. A 2-point or greater improvement at the end of the study was observed in 69.4% and 61.9%, respectively.
“The medication works well and there was improved efficacy over time. About two-thirds of the patients had at least a 2-point improvement in the HDSM-Ax score at the end of 48 weeks,” Dr. Smith reported.
While response rates climbed over the course of the study, rates of adverse events fell markedly.
After 2 weeks of treatment, the proportions of patients with a treatment-related adverse event were 6% and just under 15% for the 5% and 15% topical-gel groups, respectively. At each 2-week interval when reassessed, the rates fell. By week 12, the rates were less than 2% and about 4% in the two groups, respectively.
The discontinuation rates overall for anticholinergic side effects were 3% and 8.1% for the lower and higher doses. Blurred vision accounted for the vast majority of these discontinuations in both groups. The other discontinuations, which included those for dry mouth, urinary retention, and mydriasis, occurred in one patient each. Again, discontinuations were most common in the first few months of the study.
For the total study population, mild (10.8% vs. 24%) and moderate (10.8% vs. 20.3%) side effects accounted for almost all side effects with the lower and higher doses of the topical drug. Only one patient in the low-dose group had a severe adverse event. At 6.1%, the proportion of the high-dose group with a severe adverse event was higher, but none of the adverse events were considered serious. All were transient.
These rates of adverse events are lower than those reported historically with effective doses of glycopyrrolate, Dr. Smith said.
The data presented by Dr. Smith are part of a phase 3 pivotal trials program designed to gain FDA approval. Going forward, these trials, which are enrolling patients as young as 9 years old, are expected to focus on clinical development of the 15% gel, he added.
The gel is delivered with a metered-dose pump that has an applicator, according to Brickell Biotech, the company developing the treatment in the United States. The 5% formulation was approved in Japan in September 2020, for the treatment of primary axillary hyperhidrosis.
In an interview, David M. Pariser, MD, professor of dermatology, Eastern Virginia Medical School, Norfolk, said that he believes that this drug has could be helpful if the pivotal studies confirm efficacy with a lower risk of adverse events relative to glycopyrrolate. “If it is true that, in phase 3, placebo-controlled trials, there are fewer systemic anticholinergic effects, then this drug will be very useful,” said Dr. Pariser, cofounder of the International Hyperhidrosis Society and an investigator on a previously published dose-ranging, phase 2 study of sofpironium bromide.
The trial was sponsored by Brickell Biotech, which compensated Dr. Smith and other coauthors for their participation. Dr. Pariser has financial relationships with multiple pharmaceutical companies with dermatologic products, including Brickell Biotech.
This article was updated 4/26/21.
FROM AAD VMX 2021
MPL, microaggressions, and more
Dear colleagues,
Welcome to the May edition of The New Gastroenterologist, which is packed with a fantastic line-up of articles! The 1-year mark of the pandemic recently passed, and we now are gearing up for our second virtual Digestive Disease Week (DDW®). While we are all anxious to return to lives that have some semblance of normalcy, we continue to endure the ebbs and flows that characterize life in a pandemic. For over a year now, we spend our days caught in a constant battle between the risk and reward of activities we previously took for granted or considered mundane. Our moods vacillate with the continued rise and fall of COVID-19 cases, but the advent and distribution of vaccines have offered palpable hope for better outcomes.
I’m pleased to introduce this quarter’s content – beginning with our legal section. Dr. John Azizian (UCLA-Olive-View), Dr. James Tabibian (UCLA-Olive-View), Dr. Camellia Dalai (UCLA-Olive-View/University of New Mexico), and Dr. Megan Adams (University of Michigan) contribute a comprehensive piece on medical professional liability (MPL), a topic that is seldom discussed in training but has important implications in clinical practice. This article reviews basic legal concepts, recent trends and details on gastroenterology specific claims, and most importantly, advice on how to mitigate MPL risk as gastroenterologists.
Many trainees and early career gastroenterologists face microaggressions for a variety of different reasons. Dr. Oveia Aktopaire and Dr. Rachel Issaka (University of Washington) present a thought-provoking piece as they delve into structural racism in medicine and how microaggressions are a proxy for bias.
Dyssynergic defecation (DD) affects up to one-half of patients with chronic constipation. The “In Focus” feature for May provides an excellent review of DD written by international expert Dr. Satish Rao and Dr. Asad Jehangir (both, Medical College of Georgia/Augusta University). The article provides guidance on the diagnosis of DD, including high-yield features of physical and digital rectal exams, guidance on interpretation of anorectal manometry testing, and how these can dictate an effective therapeutic plan.
Meaningful mentorship is crucial for young gastroenterologists but at times the nature of the mentor-mentee relationship can be difficult to navigate. Dr. David Fessell and Bridger Rodoni (University of Michigan) explore this dynamic and discuss the notion of mentorship malpractice in a compelling addition to our ethics case series.
Abdominal wall pain is common yet often overlooked diagnosis and a great teaching point for trainees. Dr. Manish Singla (Uniformed Services University/Capital Digestive Care) and Dr. Brian Park (Naval Medical Center) discuss the diagnosis and management and how the early recognition of abdominal wall pain can save both patients and clinicians from a battery of unnecessary diagnostic testing.
The DHPA Private Practice Perspectives article this quarter, written by Dr. Aja McCutchen (Atlanta Gastroenterology Associates), addresses colorectal cancer screening, the disparities that exist, and the important role we have as gastroenterologists in reducing barriers to screening. Lastly, Dr. Bilal Asif (University of Maryland/National Institutes of Health) walks us through a fellow’s perspective on the AGA’s first virtual Advocacy Day – demonstrating that advocacy is still possible even as a trainee and in the setting of a pandemic.
If you have interest in contributing or have ideas for future TNG topics, please contact me ([email protected]) or Ryan Farrell ([email protected]), managing editor of TNG.
Stay well,
Vijaya L. Rao, MD
Editor in Chief
Assistant Professor of Medicine, University of Chicago, Section of Gastroenterology, Hepatology & Nutrition
Dear colleagues,
Welcome to the May edition of The New Gastroenterologist, which is packed with a fantastic line-up of articles! The 1-year mark of the pandemic recently passed, and we now are gearing up for our second virtual Digestive Disease Week (DDW®). While we are all anxious to return to lives that have some semblance of normalcy, we continue to endure the ebbs and flows that characterize life in a pandemic. For over a year now, we spend our days caught in a constant battle between the risk and reward of activities we previously took for granted or considered mundane. Our moods vacillate with the continued rise and fall of COVID-19 cases, but the advent and distribution of vaccines have offered palpable hope for better outcomes.
I’m pleased to introduce this quarter’s content – beginning with our legal section. Dr. John Azizian (UCLA-Olive-View), Dr. James Tabibian (UCLA-Olive-View), Dr. Camellia Dalai (UCLA-Olive-View/University of New Mexico), and Dr. Megan Adams (University of Michigan) contribute a comprehensive piece on medical professional liability (MPL), a topic that is seldom discussed in training but has important implications in clinical practice. This article reviews basic legal concepts, recent trends and details on gastroenterology specific claims, and most importantly, advice on how to mitigate MPL risk as gastroenterologists.
Many trainees and early career gastroenterologists face microaggressions for a variety of different reasons. Dr. Oveia Aktopaire and Dr. Rachel Issaka (University of Washington) present a thought-provoking piece as they delve into structural racism in medicine and how microaggressions are a proxy for bias.
Dyssynergic defecation (DD) affects up to one-half of patients with chronic constipation. The “In Focus” feature for May provides an excellent review of DD written by international expert Dr. Satish Rao and Dr. Asad Jehangir (both, Medical College of Georgia/Augusta University). The article provides guidance on the diagnosis of DD, including high-yield features of physical and digital rectal exams, guidance on interpretation of anorectal manometry testing, and how these can dictate an effective therapeutic plan.
Meaningful mentorship is crucial for young gastroenterologists but at times the nature of the mentor-mentee relationship can be difficult to navigate. Dr. David Fessell and Bridger Rodoni (University of Michigan) explore this dynamic and discuss the notion of mentorship malpractice in a compelling addition to our ethics case series.
Abdominal wall pain is common yet often overlooked diagnosis and a great teaching point for trainees. Dr. Manish Singla (Uniformed Services University/Capital Digestive Care) and Dr. Brian Park (Naval Medical Center) discuss the diagnosis and management and how the early recognition of abdominal wall pain can save both patients and clinicians from a battery of unnecessary diagnostic testing.
The DHPA Private Practice Perspectives article this quarter, written by Dr. Aja McCutchen (Atlanta Gastroenterology Associates), addresses colorectal cancer screening, the disparities that exist, and the important role we have as gastroenterologists in reducing barriers to screening. Lastly, Dr. Bilal Asif (University of Maryland/National Institutes of Health) walks us through a fellow’s perspective on the AGA’s first virtual Advocacy Day – demonstrating that advocacy is still possible even as a trainee and in the setting of a pandemic.
If you have interest in contributing or have ideas for future TNG topics, please contact me ([email protected]) or Ryan Farrell ([email protected]), managing editor of TNG.
Stay well,
Vijaya L. Rao, MD
Editor in Chief
Assistant Professor of Medicine, University of Chicago, Section of Gastroenterology, Hepatology & Nutrition
Dear colleagues,
Welcome to the May edition of The New Gastroenterologist, which is packed with a fantastic line-up of articles! The 1-year mark of the pandemic recently passed, and we now are gearing up for our second virtual Digestive Disease Week (DDW®). While we are all anxious to return to lives that have some semblance of normalcy, we continue to endure the ebbs and flows that characterize life in a pandemic. For over a year now, we spend our days caught in a constant battle between the risk and reward of activities we previously took for granted or considered mundane. Our moods vacillate with the continued rise and fall of COVID-19 cases, but the advent and distribution of vaccines have offered palpable hope for better outcomes.
I’m pleased to introduce this quarter’s content – beginning with our legal section. Dr. John Azizian (UCLA-Olive-View), Dr. James Tabibian (UCLA-Olive-View), Dr. Camellia Dalai (UCLA-Olive-View/University of New Mexico), and Dr. Megan Adams (University of Michigan) contribute a comprehensive piece on medical professional liability (MPL), a topic that is seldom discussed in training but has important implications in clinical practice. This article reviews basic legal concepts, recent trends and details on gastroenterology specific claims, and most importantly, advice on how to mitigate MPL risk as gastroenterologists.
Many trainees and early career gastroenterologists face microaggressions for a variety of different reasons. Dr. Oveia Aktopaire and Dr. Rachel Issaka (University of Washington) present a thought-provoking piece as they delve into structural racism in medicine and how microaggressions are a proxy for bias.
Dyssynergic defecation (DD) affects up to one-half of patients with chronic constipation. The “In Focus” feature for May provides an excellent review of DD written by international expert Dr. Satish Rao and Dr. Asad Jehangir (both, Medical College of Georgia/Augusta University). The article provides guidance on the diagnosis of DD, including high-yield features of physical and digital rectal exams, guidance on interpretation of anorectal manometry testing, and how these can dictate an effective therapeutic plan.
Meaningful mentorship is crucial for young gastroenterologists but at times the nature of the mentor-mentee relationship can be difficult to navigate. Dr. David Fessell and Bridger Rodoni (University of Michigan) explore this dynamic and discuss the notion of mentorship malpractice in a compelling addition to our ethics case series.
Abdominal wall pain is common yet often overlooked diagnosis and a great teaching point for trainees. Dr. Manish Singla (Uniformed Services University/Capital Digestive Care) and Dr. Brian Park (Naval Medical Center) discuss the diagnosis and management and how the early recognition of abdominal wall pain can save both patients and clinicians from a battery of unnecessary diagnostic testing.
The DHPA Private Practice Perspectives article this quarter, written by Dr. Aja McCutchen (Atlanta Gastroenterology Associates), addresses colorectal cancer screening, the disparities that exist, and the important role we have as gastroenterologists in reducing barriers to screening. Lastly, Dr. Bilal Asif (University of Maryland/National Institutes of Health) walks us through a fellow’s perspective on the AGA’s first virtual Advocacy Day – demonstrating that advocacy is still possible even as a trainee and in the setting of a pandemic.
If you have interest in contributing or have ideas for future TNG topics, please contact me ([email protected]) or Ryan Farrell ([email protected]), managing editor of TNG.
Stay well,
Vijaya L. Rao, MD
Editor in Chief
Assistant Professor of Medicine, University of Chicago, Section of Gastroenterology, Hepatology & Nutrition
Clearance rates higher with bimekizumab vs. secukinumab in phase 3 psoriasis study
Secukinumab is the latest adult plaque psoriasis treatment to be bested by a newcomer, the interleukin 17A and 17F blocker bimekizumab.
Rates of complete clearance were substantially higher with bimekizumab in a phase 3 trial with 743 patients with moderate-to-severe plaque psoriasis, but oral candidiasis (oral thrush) again emerged as a particular issue with the agent.
Clinical improvements seen with bimekizumab have exceeded those with two standard options for adult plaque psoriasis — the tumor necrosis factor blocker adalimumab and the interleukin (IL) 12/23 inhibitor ustekinumab
— in phase 3 trials from manufacturer UCB Pharma, and it›s under review for the indication by the U.S. Food and Drug Administration and the European Medicines Agency.
The biologic is also being evaluated in phase 3 trials for treating psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, and hidradenitis suppurativa.
Results of the trial comparing bimekizumab to secukinumab, dubbed BE RADIANT, were presented at the American Academy of Dermatology Virtual Meeting Experience and published online concurrently April 23 in the New England Journal of Medicine.
The results “suggest that inhibition of both interleukin-17A and interleukin-17F with bimekizumab may provide greater clinical benefit for patients with moderate-to-severe plaque psoriasis than inhibition of interleukin-17A alone,” as with secukinumab, said the investigators, led by Kristian Reich, MD, professor of dermatology at the University Medical Center Hamburg-Eppendorf in Hamburg, Germany.
The trial randomly assigned 373 adults to bimekizumab 320 mg every 4 weeks to week 16, then rerandomized them to maintenance dosing either every 4 weeks or every 8 weeks to week 48; another 370 adults were randomly assigned to secukinumab 300 mg weekly for the first 4 weeks, then every 4 weeks to week 48. Baseline Psoriasis Area and Severity Index (PASI) scores were about 20 points in both treatment groups.
At the 1-month point, 71% in the bimekizumab group, vs 47.3% on secukinumab, had a 75% or greater reduction from their baseline PASI score. At 4 months, 61.7% of those on bimekizumab but 48.9% in the secukinumab group had complete clearance with a PASI score of 100.
At 48 weeks, 67% of those on bimekizumab had a PASI 100 response — which was numerically similar between the two bimekizumab dosing regimens after week 16 — vs 46.2% of the secukinumab group (P for all < .001).
The incidence of serious adverse events was just under 6% in both groups, with adverse events leading to discontinuation in 3.5% of bimekizumab and 2.7% of secukinumab subjects. The rate of serious infections was similar in both groups.
However, as in past trials, oral candidiasis was an issue, occurring in 19.3% of bimekizumab subjects vs 3% on secukinumab. Half of the 72 bimekizumab cases were classified as mild, and all but two of the rest as moderate. Over 40% of affected subjects reported more than one case, but none led to treatment discontinuation.
More than 85% of oral candidiasis cases in the study were treated with antifungal therapy and resolved during the trial. Inflammatory bowel disease is a concern with IL-17 blockade, but this hasn’t emerged as a particular issue with bimekizumab. There was one case each of ulcerative colitis in both the bimekizumab and secukinumab groups, and just one case of ulcerative colitis in three previous phase 3 bimekizumab trials, according to the investigators.
Among the trial limitations: Patients who had been on bimekizumab or secukinumab previously were excluded, as were patients who had no response to an IL-17 biologic or more than one biologic agent of any other class within the previous 12 weeks. The limitations could reduce generalizability, the investigators said.
Patients in the trial were about 45 years old, on average, and about two thirds were men; over 90% were White.
The study was funded by UCB Pharma. The investigators had numerous disclosures, including Reich who reported grants and personal fees from companies including UCB Pharma. The full list of disclosures can be found with the New England Journal of Medicine article.
A version of this article first appeared on Medscape.com .
Secukinumab is the latest adult plaque psoriasis treatment to be bested by a newcomer, the interleukin 17A and 17F blocker bimekizumab.
Rates of complete clearance were substantially higher with bimekizumab in a phase 3 trial with 743 patients with moderate-to-severe plaque psoriasis, but oral candidiasis (oral thrush) again emerged as a particular issue with the agent.
Clinical improvements seen with bimekizumab have exceeded those with two standard options for adult plaque psoriasis — the tumor necrosis factor blocker adalimumab and the interleukin (IL) 12/23 inhibitor ustekinumab
— in phase 3 trials from manufacturer UCB Pharma, and it›s under review for the indication by the U.S. Food and Drug Administration and the European Medicines Agency.
The biologic is also being evaluated in phase 3 trials for treating psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, and hidradenitis suppurativa.
Results of the trial comparing bimekizumab to secukinumab, dubbed BE RADIANT, were presented at the American Academy of Dermatology Virtual Meeting Experience and published online concurrently April 23 in the New England Journal of Medicine.
The results “suggest that inhibition of both interleukin-17A and interleukin-17F with bimekizumab may provide greater clinical benefit for patients with moderate-to-severe plaque psoriasis than inhibition of interleukin-17A alone,” as with secukinumab, said the investigators, led by Kristian Reich, MD, professor of dermatology at the University Medical Center Hamburg-Eppendorf in Hamburg, Germany.
The trial randomly assigned 373 adults to bimekizumab 320 mg every 4 weeks to week 16, then rerandomized them to maintenance dosing either every 4 weeks or every 8 weeks to week 48; another 370 adults were randomly assigned to secukinumab 300 mg weekly for the first 4 weeks, then every 4 weeks to week 48. Baseline Psoriasis Area and Severity Index (PASI) scores were about 20 points in both treatment groups.
At the 1-month point, 71% in the bimekizumab group, vs 47.3% on secukinumab, had a 75% or greater reduction from their baseline PASI score. At 4 months, 61.7% of those on bimekizumab but 48.9% in the secukinumab group had complete clearance with a PASI score of 100.
At 48 weeks, 67% of those on bimekizumab had a PASI 100 response — which was numerically similar between the two bimekizumab dosing regimens after week 16 — vs 46.2% of the secukinumab group (P for all < .001).
The incidence of serious adverse events was just under 6% in both groups, with adverse events leading to discontinuation in 3.5% of bimekizumab and 2.7% of secukinumab subjects. The rate of serious infections was similar in both groups.
However, as in past trials, oral candidiasis was an issue, occurring in 19.3% of bimekizumab subjects vs 3% on secukinumab. Half of the 72 bimekizumab cases were classified as mild, and all but two of the rest as moderate. Over 40% of affected subjects reported more than one case, but none led to treatment discontinuation.
More than 85% of oral candidiasis cases in the study were treated with antifungal therapy and resolved during the trial. Inflammatory bowel disease is a concern with IL-17 blockade, but this hasn’t emerged as a particular issue with bimekizumab. There was one case each of ulcerative colitis in both the bimekizumab and secukinumab groups, and just one case of ulcerative colitis in three previous phase 3 bimekizumab trials, according to the investigators.
Among the trial limitations: Patients who had been on bimekizumab or secukinumab previously were excluded, as were patients who had no response to an IL-17 biologic or more than one biologic agent of any other class within the previous 12 weeks. The limitations could reduce generalizability, the investigators said.
Patients in the trial were about 45 years old, on average, and about two thirds were men; over 90% were White.
The study was funded by UCB Pharma. The investigators had numerous disclosures, including Reich who reported grants and personal fees from companies including UCB Pharma. The full list of disclosures can be found with the New England Journal of Medicine article.
A version of this article first appeared on Medscape.com .
Secukinumab is the latest adult plaque psoriasis treatment to be bested by a newcomer, the interleukin 17A and 17F blocker bimekizumab.
Rates of complete clearance were substantially higher with bimekizumab in a phase 3 trial with 743 patients with moderate-to-severe plaque psoriasis, but oral candidiasis (oral thrush) again emerged as a particular issue with the agent.
Clinical improvements seen with bimekizumab have exceeded those with two standard options for adult plaque psoriasis — the tumor necrosis factor blocker adalimumab and the interleukin (IL) 12/23 inhibitor ustekinumab
— in phase 3 trials from manufacturer UCB Pharma, and it›s under review for the indication by the U.S. Food and Drug Administration and the European Medicines Agency.
The biologic is also being evaluated in phase 3 trials for treating psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, and hidradenitis suppurativa.
Results of the trial comparing bimekizumab to secukinumab, dubbed BE RADIANT, were presented at the American Academy of Dermatology Virtual Meeting Experience and published online concurrently April 23 in the New England Journal of Medicine.
The results “suggest that inhibition of both interleukin-17A and interleukin-17F with bimekizumab may provide greater clinical benefit for patients with moderate-to-severe plaque psoriasis than inhibition of interleukin-17A alone,” as with secukinumab, said the investigators, led by Kristian Reich, MD, professor of dermatology at the University Medical Center Hamburg-Eppendorf in Hamburg, Germany.
The trial randomly assigned 373 adults to bimekizumab 320 mg every 4 weeks to week 16, then rerandomized them to maintenance dosing either every 4 weeks or every 8 weeks to week 48; another 370 adults were randomly assigned to secukinumab 300 mg weekly for the first 4 weeks, then every 4 weeks to week 48. Baseline Psoriasis Area and Severity Index (PASI) scores were about 20 points in both treatment groups.
At the 1-month point, 71% in the bimekizumab group, vs 47.3% on secukinumab, had a 75% or greater reduction from their baseline PASI score. At 4 months, 61.7% of those on bimekizumab but 48.9% in the secukinumab group had complete clearance with a PASI score of 100.
At 48 weeks, 67% of those on bimekizumab had a PASI 100 response — which was numerically similar between the two bimekizumab dosing regimens after week 16 — vs 46.2% of the secukinumab group (P for all < .001).
The incidence of serious adverse events was just under 6% in both groups, with adverse events leading to discontinuation in 3.5% of bimekizumab and 2.7% of secukinumab subjects. The rate of serious infections was similar in both groups.
However, as in past trials, oral candidiasis was an issue, occurring in 19.3% of bimekizumab subjects vs 3% on secukinumab. Half of the 72 bimekizumab cases were classified as mild, and all but two of the rest as moderate. Over 40% of affected subjects reported more than one case, but none led to treatment discontinuation.
More than 85% of oral candidiasis cases in the study were treated with antifungal therapy and resolved during the trial. Inflammatory bowel disease is a concern with IL-17 blockade, but this hasn’t emerged as a particular issue with bimekizumab. There was one case each of ulcerative colitis in both the bimekizumab and secukinumab groups, and just one case of ulcerative colitis in three previous phase 3 bimekizumab trials, according to the investigators.
Among the trial limitations: Patients who had been on bimekizumab or secukinumab previously were excluded, as were patients who had no response to an IL-17 biologic or more than one biologic agent of any other class within the previous 12 weeks. The limitations could reduce generalizability, the investigators said.
Patients in the trial were about 45 years old, on average, and about two thirds were men; over 90% were White.
The study was funded by UCB Pharma. The investigators had numerous disclosures, including Reich who reported grants and personal fees from companies including UCB Pharma. The full list of disclosures can be found with the New England Journal of Medicine article.
A version of this article first appeared on Medscape.com .
Systematic approach to pain helps avoid opioid issues for dermatologists
, according to an expert who outlined his strategies at the American Academy of Dermatology Virtual Meeting Experience.
The exceptions relate primarily to patients with issues complicating pain control, such as those with psychosocial problems exacerbating the pain response, drug-seeking behavior, or both, according to Robert G. Micheletti, MD, chief of hospital dermatology, University of Pennsylvania, Philadelphia.
To stay out of trouble, Dr. Micheletti advocated a systematic approach to the control of pain that includes documentation, clear expectations, and a sparing use of opioids only at the lowest acceptable dose for periods measured in days.
Using a case of pyoderma gangrenosum to make several points, he recognized that some patients do have a level of pain that warrants a short course of opioids, but this is not his first step. Rather, the initial focus, after administering standard therapies for this disease, is wound care, which often attenuates symptoms. He adds non-pharmacologic treatments, such as ice, heat, and rest when appropriate. The initial pharmacologic approach is alternating doses of an NSAID and acetaminophen.
“If necessary, a short course of opioids is reasonable for patients with acute pain,” he acknowledged. But he wants to avoid providing more opioids than needed to address the initial period of acute pain. In the case of pyoderma gangrenosum, he suggested a typical prescription might be 12 pills of 5 mg oxycodone taken every six hours. A followup appointment within a week provides the opportunity to reassess.
“Set clear expectations,” Dr. Micheletti said. This includes explaining that the goal is manageable pain, not complete pain relief, which is often unobtainable. For painful conditions such as pyoderma gangrenosum, hidradenitis suppurativa, or vasculitis, a short course will generally be sufficient to get past the most significant discomfort.
There are several reasons that Dr. Micheletti encourages dermatologists to take responsibility for pain related to skin diseases. One is the potential for inefficiencies and delays common to referrals, but another is the value of the dermatologist’s expertise in judging pain as a symptom of the disorder. With effective treatment, pain should self-resolve.
“If the patient is not getting better medically, then change therapies,” Dr. Micheletti said. When referred to a non-dermatologist, the pain expert might not recognize what persistent pain is revealing about the underlying condition.
Repeatedly, Dr. Micheletti made the point that dermatologists should manage pain related to skin disorders because of their ability to assess complaints in the context of the disease.
“We are the experts. We should understand when what we are seeing should or should not be painful,” he said. He added that dermatologists are also in the best position to judge “when analgesia is no longer needed.”
With this same logic, dermatologists are in a good position to distinguish nociceptive from neuropathic pain. Some conditions are likely to have both, and this should influence choice of pain relief. Citing a patient with calciphylaxis as an example, Dr. Micheletti suggested that drugs with efficacy against neuropathic pain, such as gabapentin, should be one of the options to consider before moving to opioids. In those with sufficient pain to warrant an opioid, however, Dr. Micheletti would consider tramadol, which acts on both types of pain.
Treating pain is not always straightforward, Dr. Micheletti acknowledged. For example, depression and mood disorders are known to exacerbate pain and are reasonable targets of pain control. The stress related to disruptive psychosocial problems can be another factor in risk of pain.
“Be prepared to acknowledge and address these types of issues,” Dr. Micheletti said. Although these are the types of patients some dermatologists might prefer to refer to a pain specialist, he said that the contribution of factors outside of skin disease should not be allowed to obscure a dermatologic source of pain.
“Just because a patient has psychosocial issues does not mean that there is no pain,” he said.
A systematic approach to the assessment and treatment of pain will help sort out these issues, but Dr. Micheletti also said, “Know your comfort zone.” When patients require opioids, there are several appropriate steps important or mandatory to provide adequate protection for the patient and the physician. In addition to documentation, it is reasonable to verify that the patient is not obtaining opioids from other prescribers, a step that is mandatory in some states.
When opioids are needed, Dr. Micheletti suggested a standard approach that includes short courses without refills. He recommended avoiding long-acting opioids and drugs not commonly used by non-pain specialists, such as codeine, hydrocodone, or fentanyl.
“This is not a prescribe and walk away situation,” he said.
Although the same general approach is employed by Adam Friedman, MD, professor and chair of dermatology, George Washington University, Washington, he is a little less reluctant to refer patients to pain specialists.
“For complex situations, you need complex solutions. In the case of significant pain and even itch, I will collaborate with the GW Pain Center,” he said. For severe pain, the solutions might include nerve blocks or even intravenous ketamine for in-patients.
He also made the point that dermatologists, even if they are uncomfortable prescribing opioids, “should be equipped to use relevant medications such as topical anesthetics, gabapentinoids, and SSRIs” to control pain related to skin conditions.
Dr. Micheletti reports no relevant conflicts of interest. Dr. Friedman has consulting relationships with several pharmaceutical companies, including Amgen, GlaxoSmithKline, and Valeant.
, according to an expert who outlined his strategies at the American Academy of Dermatology Virtual Meeting Experience.
The exceptions relate primarily to patients with issues complicating pain control, such as those with psychosocial problems exacerbating the pain response, drug-seeking behavior, or both, according to Robert G. Micheletti, MD, chief of hospital dermatology, University of Pennsylvania, Philadelphia.
To stay out of trouble, Dr. Micheletti advocated a systematic approach to the control of pain that includes documentation, clear expectations, and a sparing use of opioids only at the lowest acceptable dose for periods measured in days.
Using a case of pyoderma gangrenosum to make several points, he recognized that some patients do have a level of pain that warrants a short course of opioids, but this is not his first step. Rather, the initial focus, after administering standard therapies for this disease, is wound care, which often attenuates symptoms. He adds non-pharmacologic treatments, such as ice, heat, and rest when appropriate. The initial pharmacologic approach is alternating doses of an NSAID and acetaminophen.
“If necessary, a short course of opioids is reasonable for patients with acute pain,” he acknowledged. But he wants to avoid providing more opioids than needed to address the initial period of acute pain. In the case of pyoderma gangrenosum, he suggested a typical prescription might be 12 pills of 5 mg oxycodone taken every six hours. A followup appointment within a week provides the opportunity to reassess.
“Set clear expectations,” Dr. Micheletti said. This includes explaining that the goal is manageable pain, not complete pain relief, which is often unobtainable. For painful conditions such as pyoderma gangrenosum, hidradenitis suppurativa, or vasculitis, a short course will generally be sufficient to get past the most significant discomfort.
There are several reasons that Dr. Micheletti encourages dermatologists to take responsibility for pain related to skin diseases. One is the potential for inefficiencies and delays common to referrals, but another is the value of the dermatologist’s expertise in judging pain as a symptom of the disorder. With effective treatment, pain should self-resolve.
“If the patient is not getting better medically, then change therapies,” Dr. Micheletti said. When referred to a non-dermatologist, the pain expert might not recognize what persistent pain is revealing about the underlying condition.
Repeatedly, Dr. Micheletti made the point that dermatologists should manage pain related to skin disorders because of their ability to assess complaints in the context of the disease.
“We are the experts. We should understand when what we are seeing should or should not be painful,” he said. He added that dermatologists are also in the best position to judge “when analgesia is no longer needed.”
With this same logic, dermatologists are in a good position to distinguish nociceptive from neuropathic pain. Some conditions are likely to have both, and this should influence choice of pain relief. Citing a patient with calciphylaxis as an example, Dr. Micheletti suggested that drugs with efficacy against neuropathic pain, such as gabapentin, should be one of the options to consider before moving to opioids. In those with sufficient pain to warrant an opioid, however, Dr. Micheletti would consider tramadol, which acts on both types of pain.
Treating pain is not always straightforward, Dr. Micheletti acknowledged. For example, depression and mood disorders are known to exacerbate pain and are reasonable targets of pain control. The stress related to disruptive psychosocial problems can be another factor in risk of pain.
“Be prepared to acknowledge and address these types of issues,” Dr. Micheletti said. Although these are the types of patients some dermatologists might prefer to refer to a pain specialist, he said that the contribution of factors outside of skin disease should not be allowed to obscure a dermatologic source of pain.
“Just because a patient has psychosocial issues does not mean that there is no pain,” he said.
A systematic approach to the assessment and treatment of pain will help sort out these issues, but Dr. Micheletti also said, “Know your comfort zone.” When patients require opioids, there are several appropriate steps important or mandatory to provide adequate protection for the patient and the physician. In addition to documentation, it is reasonable to verify that the patient is not obtaining opioids from other prescribers, a step that is mandatory in some states.
When opioids are needed, Dr. Micheletti suggested a standard approach that includes short courses without refills. He recommended avoiding long-acting opioids and drugs not commonly used by non-pain specialists, such as codeine, hydrocodone, or fentanyl.
“This is not a prescribe and walk away situation,” he said.
Although the same general approach is employed by Adam Friedman, MD, professor and chair of dermatology, George Washington University, Washington, he is a little less reluctant to refer patients to pain specialists.
“For complex situations, you need complex solutions. In the case of significant pain and even itch, I will collaborate with the GW Pain Center,” he said. For severe pain, the solutions might include nerve blocks or even intravenous ketamine for in-patients.
He also made the point that dermatologists, even if they are uncomfortable prescribing opioids, “should be equipped to use relevant medications such as topical anesthetics, gabapentinoids, and SSRIs” to control pain related to skin conditions.
Dr. Micheletti reports no relevant conflicts of interest. Dr. Friedman has consulting relationships with several pharmaceutical companies, including Amgen, GlaxoSmithKline, and Valeant.
, according to an expert who outlined his strategies at the American Academy of Dermatology Virtual Meeting Experience.
The exceptions relate primarily to patients with issues complicating pain control, such as those with psychosocial problems exacerbating the pain response, drug-seeking behavior, or both, according to Robert G. Micheletti, MD, chief of hospital dermatology, University of Pennsylvania, Philadelphia.
To stay out of trouble, Dr. Micheletti advocated a systematic approach to the control of pain that includes documentation, clear expectations, and a sparing use of opioids only at the lowest acceptable dose for periods measured in days.
Using a case of pyoderma gangrenosum to make several points, he recognized that some patients do have a level of pain that warrants a short course of opioids, but this is not his first step. Rather, the initial focus, after administering standard therapies for this disease, is wound care, which often attenuates symptoms. He adds non-pharmacologic treatments, such as ice, heat, and rest when appropriate. The initial pharmacologic approach is alternating doses of an NSAID and acetaminophen.
“If necessary, a short course of opioids is reasonable for patients with acute pain,” he acknowledged. But he wants to avoid providing more opioids than needed to address the initial period of acute pain. In the case of pyoderma gangrenosum, he suggested a typical prescription might be 12 pills of 5 mg oxycodone taken every six hours. A followup appointment within a week provides the opportunity to reassess.
“Set clear expectations,” Dr. Micheletti said. This includes explaining that the goal is manageable pain, not complete pain relief, which is often unobtainable. For painful conditions such as pyoderma gangrenosum, hidradenitis suppurativa, or vasculitis, a short course will generally be sufficient to get past the most significant discomfort.
There are several reasons that Dr. Micheletti encourages dermatologists to take responsibility for pain related to skin diseases. One is the potential for inefficiencies and delays common to referrals, but another is the value of the dermatologist’s expertise in judging pain as a symptom of the disorder. With effective treatment, pain should self-resolve.
“If the patient is not getting better medically, then change therapies,” Dr. Micheletti said. When referred to a non-dermatologist, the pain expert might not recognize what persistent pain is revealing about the underlying condition.
Repeatedly, Dr. Micheletti made the point that dermatologists should manage pain related to skin disorders because of their ability to assess complaints in the context of the disease.
“We are the experts. We should understand when what we are seeing should or should not be painful,” he said. He added that dermatologists are also in the best position to judge “when analgesia is no longer needed.”
With this same logic, dermatologists are in a good position to distinguish nociceptive from neuropathic pain. Some conditions are likely to have both, and this should influence choice of pain relief. Citing a patient with calciphylaxis as an example, Dr. Micheletti suggested that drugs with efficacy against neuropathic pain, such as gabapentin, should be one of the options to consider before moving to opioids. In those with sufficient pain to warrant an opioid, however, Dr. Micheletti would consider tramadol, which acts on both types of pain.
Treating pain is not always straightforward, Dr. Micheletti acknowledged. For example, depression and mood disorders are known to exacerbate pain and are reasonable targets of pain control. The stress related to disruptive psychosocial problems can be another factor in risk of pain.
“Be prepared to acknowledge and address these types of issues,” Dr. Micheletti said. Although these are the types of patients some dermatologists might prefer to refer to a pain specialist, he said that the contribution of factors outside of skin disease should not be allowed to obscure a dermatologic source of pain.
“Just because a patient has psychosocial issues does not mean that there is no pain,” he said.
A systematic approach to the assessment and treatment of pain will help sort out these issues, but Dr. Micheletti also said, “Know your comfort zone.” When patients require opioids, there are several appropriate steps important or mandatory to provide adequate protection for the patient and the physician. In addition to documentation, it is reasonable to verify that the patient is not obtaining opioids from other prescribers, a step that is mandatory in some states.
When opioids are needed, Dr. Micheletti suggested a standard approach that includes short courses without refills. He recommended avoiding long-acting opioids and drugs not commonly used by non-pain specialists, such as codeine, hydrocodone, or fentanyl.
“This is not a prescribe and walk away situation,” he said.
Although the same general approach is employed by Adam Friedman, MD, professor and chair of dermatology, George Washington University, Washington, he is a little less reluctant to refer patients to pain specialists.
“For complex situations, you need complex solutions. In the case of significant pain and even itch, I will collaborate with the GW Pain Center,” he said. For severe pain, the solutions might include nerve blocks or even intravenous ketamine for in-patients.
He also made the point that dermatologists, even if they are uncomfortable prescribing opioids, “should be equipped to use relevant medications such as topical anesthetics, gabapentinoids, and SSRIs” to control pain related to skin conditions.
Dr. Micheletti reports no relevant conflicts of interest. Dr. Friedman has consulting relationships with several pharmaceutical companies, including Amgen, GlaxoSmithKline, and Valeant.
FROM AAD VMX 2021