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Hospitalists can make a difference in disasters
It sounds completely crazy, unless you’re a hospitalist, Mark Shapiro, MD, said during a Monday session. Or a hospitalist’s spouse.
As the Tubbs Fire raged across Northern California in October 2017, Dr. Shapiro fled with his 5-month-old son, his dog, and his wife. And then they had that conversation.
“After we got everyone settled, I said to my wife, ‘Honey, I need to go back.’ And she said, ‘Yes, of course you do.’ Having that clarity and support behind me was so important. I was able to return to the hospital and focus on my job.”
“Trust me,” said Dr. Shapiro, director of hospital medicine at Providence-St. Joseph Health Medical Group in Santa Rosa, Calif. “You will want to do your work.”
The Tubbs Fire opened a week of “extraordinary challenges” said Dr. Shapiro. His lecture, “A Survival Guide for Hospitalists: Emergency Preparedness for Hurricanes, Fires, Mass Casualties, and Other Emergencies,” drew on his personal experiences from that fire, his leadership during the emergency response, and the debriefings that inspired his colleagues and him to plan how to handle future emergencies.
“Over 1 week we struggled and suffered and learned a great deal about hospital operations and how to keep safe in an emergency situation,” he said in an interview.
The prime directive during any emergency situation is communication, on both a microcosmic and a macrocosmic scale.
“It pays to have these conversations with family and friends before a disaster happens, so that they understand you will have to go to work and that – importantly – you will want to go to work. Lay the groundwork so that when you say, ‘I love you,’ and leave, it’s not a surprise. It’s extremely important. You need to be able to do your work knowing that not only are they safe, but they’re also behind you on this.”
On a system-wide scale, emergency communications at work must be “redundant, flexible, and sustainable,” he added.
“You have to be able to communicate as a team, and that means knowing if your team is OK. Are they able to work? Are they hurt? Are they dead? We had to ask those questions at 3 a.m.”
Flexibility gives teams the option to switch communications modes on the fly – extremely important when standard modes may be endangered by natural disasters of all types.
“You don’t know how long one method will last, so your communication tools have to change. In our case, we lost cell communication but texting was intact. And we were lucky – we might not even have had that. What would you do if you lost that? Go to landlines? Pagers? It’s all very contextual.”
Another emergency preparedness must-do that Dr. Shapiro addressed in his presentation? It’s “Drill, drill, drill.”
“You have to understand what this is going to look like,” he said. Who’s going to go where, and when? What is the chain of command, and what happens when something disrupts those things, as will inevitably happen?
Cross-training is a big part of the picture, too. Not only do team members need to do their own job, they should be able to step in and at least competently do someone else’s job, as well.
“People need to be flexible, because ‘job X’ still needs to get done, no matter what.”
Dr. Shapiro’s interest in hospitalists responding to disaster extends even to his podcast, “Explore the Space,” which examines the interface between health care and society, with thought leaders from across the spectrum. Several podcasts in his series touch on disaster response and preparedness, including two from the fall of 2017, focusing specifically on the wildfire. [They can be downloaded for free at Stitcher or Apple Podcasts.]
Dr. Shapiro had no financial disclosures.
It sounds completely crazy, unless you’re a hospitalist, Mark Shapiro, MD, said during a Monday session. Or a hospitalist’s spouse.
As the Tubbs Fire raged across Northern California in October 2017, Dr. Shapiro fled with his 5-month-old son, his dog, and his wife. And then they had that conversation.
“After we got everyone settled, I said to my wife, ‘Honey, I need to go back.’ And she said, ‘Yes, of course you do.’ Having that clarity and support behind me was so important. I was able to return to the hospital and focus on my job.”
“Trust me,” said Dr. Shapiro, director of hospital medicine at Providence-St. Joseph Health Medical Group in Santa Rosa, Calif. “You will want to do your work.”
The Tubbs Fire opened a week of “extraordinary challenges” said Dr. Shapiro. His lecture, “A Survival Guide for Hospitalists: Emergency Preparedness for Hurricanes, Fires, Mass Casualties, and Other Emergencies,” drew on his personal experiences from that fire, his leadership during the emergency response, and the debriefings that inspired his colleagues and him to plan how to handle future emergencies.
“Over 1 week we struggled and suffered and learned a great deal about hospital operations and how to keep safe in an emergency situation,” he said in an interview.
The prime directive during any emergency situation is communication, on both a microcosmic and a macrocosmic scale.
“It pays to have these conversations with family and friends before a disaster happens, so that they understand you will have to go to work and that – importantly – you will want to go to work. Lay the groundwork so that when you say, ‘I love you,’ and leave, it’s not a surprise. It’s extremely important. You need to be able to do your work knowing that not only are they safe, but they’re also behind you on this.”
On a system-wide scale, emergency communications at work must be “redundant, flexible, and sustainable,” he added.
“You have to be able to communicate as a team, and that means knowing if your team is OK. Are they able to work? Are they hurt? Are they dead? We had to ask those questions at 3 a.m.”
Flexibility gives teams the option to switch communications modes on the fly – extremely important when standard modes may be endangered by natural disasters of all types.
“You don’t know how long one method will last, so your communication tools have to change. In our case, we lost cell communication but texting was intact. And we were lucky – we might not even have had that. What would you do if you lost that? Go to landlines? Pagers? It’s all very contextual.”
Another emergency preparedness must-do that Dr. Shapiro addressed in his presentation? It’s “Drill, drill, drill.”
“You have to understand what this is going to look like,” he said. Who’s going to go where, and when? What is the chain of command, and what happens when something disrupts those things, as will inevitably happen?
Cross-training is a big part of the picture, too. Not only do team members need to do their own job, they should be able to step in and at least competently do someone else’s job, as well.
“People need to be flexible, because ‘job X’ still needs to get done, no matter what.”
Dr. Shapiro’s interest in hospitalists responding to disaster extends even to his podcast, “Explore the Space,” which examines the interface between health care and society, with thought leaders from across the spectrum. Several podcasts in his series touch on disaster response and preparedness, including two from the fall of 2017, focusing specifically on the wildfire. [They can be downloaded for free at Stitcher or Apple Podcasts.]
Dr. Shapiro had no financial disclosures.
It sounds completely crazy, unless you’re a hospitalist, Mark Shapiro, MD, said during a Monday session. Or a hospitalist’s spouse.
As the Tubbs Fire raged across Northern California in October 2017, Dr. Shapiro fled with his 5-month-old son, his dog, and his wife. And then they had that conversation.
“After we got everyone settled, I said to my wife, ‘Honey, I need to go back.’ And she said, ‘Yes, of course you do.’ Having that clarity and support behind me was so important. I was able to return to the hospital and focus on my job.”
“Trust me,” said Dr. Shapiro, director of hospital medicine at Providence-St. Joseph Health Medical Group in Santa Rosa, Calif. “You will want to do your work.”
The Tubbs Fire opened a week of “extraordinary challenges” said Dr. Shapiro. His lecture, “A Survival Guide for Hospitalists: Emergency Preparedness for Hurricanes, Fires, Mass Casualties, and Other Emergencies,” drew on his personal experiences from that fire, his leadership during the emergency response, and the debriefings that inspired his colleagues and him to plan how to handle future emergencies.
“Over 1 week we struggled and suffered and learned a great deal about hospital operations and how to keep safe in an emergency situation,” he said in an interview.
The prime directive during any emergency situation is communication, on both a microcosmic and a macrocosmic scale.
“It pays to have these conversations with family and friends before a disaster happens, so that they understand you will have to go to work and that – importantly – you will want to go to work. Lay the groundwork so that when you say, ‘I love you,’ and leave, it’s not a surprise. It’s extremely important. You need to be able to do your work knowing that not only are they safe, but they’re also behind you on this.”
On a system-wide scale, emergency communications at work must be “redundant, flexible, and sustainable,” he added.
“You have to be able to communicate as a team, and that means knowing if your team is OK. Are they able to work? Are they hurt? Are they dead? We had to ask those questions at 3 a.m.”
Flexibility gives teams the option to switch communications modes on the fly – extremely important when standard modes may be endangered by natural disasters of all types.
“You don’t know how long one method will last, so your communication tools have to change. In our case, we lost cell communication but texting was intact. And we were lucky – we might not even have had that. What would you do if you lost that? Go to landlines? Pagers? It’s all very contextual.”
Another emergency preparedness must-do that Dr. Shapiro addressed in his presentation? It’s “Drill, drill, drill.”
“You have to understand what this is going to look like,” he said. Who’s going to go where, and when? What is the chain of command, and what happens when something disrupts those things, as will inevitably happen?
Cross-training is a big part of the picture, too. Not only do team members need to do their own job, they should be able to step in and at least competently do someone else’s job, as well.
“People need to be flexible, because ‘job X’ still needs to get done, no matter what.”
Dr. Shapiro’s interest in hospitalists responding to disaster extends even to his podcast, “Explore the Space,” which examines the interface between health care and society, with thought leaders from across the spectrum. Several podcasts in his series touch on disaster response and preparedness, including two from the fall of 2017, focusing specifically on the wildfire. [They can be downloaded for free at Stitcher or Apple Podcasts.]
Dr. Shapiro had no financial disclosures.
Total plasma tau correlates with dementia onset, Alzheimer’s disease
The total tau level in blood plasma appears to predict both onset and progression of dementia and could be used to help refine research cohorts.
Blood samples from two large dementia research cohorts confirmed the finding: Each standard deviation in plasma tau above the median is associated with a 29% greater risk of incident all-cause dementia and a 35%increase in the risk of incident Alzheimer’s disease, Matthew P. Pase, PhD and colleagues wrote in JAMA Neurology. It also correlated positively with some neuropathological aspects of dementia: smaller hippocampus and a higher burden of neurofibrillary tangles in the medial temporal lobe, said Dr. Pase of The Florey Institute for Neuroscience and Mental Health. Victoria, Australia.
Plasma tau isn’t the highly sought Holy Grail of a simple Alzheimer’s blood test. But the finding could benefit the research world. As a study entry criteria, it could substantially decrease the number of subjects needed to validate an outcome of either all-cause dementia or Alzheimer’s disease. Abnormal tau is also a required finding for an Alzheimer’s diagnosis in revised NIA-AA Research Framework. And, the authors noted, although plasma tau wasn’t quite as accurate a predictor as CSF tau, a needle in the arm would be much more acceptable to many more patients than a lumbar puncture.
“Whereas we do not expect plasma t-tau cutoffs to enhance diagnostic certainty for any single patient, our results suggest that plasma t-tau could be associated with improved risk stratification at a population level, targeting persons for inclusion in prevention trials, thus improving the power and precision of clinical trials and potentially accelerating therapeutic pipelines and drug discovery,” the team wrote.
The study drew on stored plasma samples from subjects enrolled in the Framingham Heart Study (1,453) and the Memento study, a multicenter cohort of persons with mild cognitive impairment or subjective cognitive complaints recruited from memory clinics across France (367).
The Framingham cohort was followed for up to 10 years between baseline examination to incident event (median 6 years).
Over that time, 134 (9.2%) cases of dementia developed; most of these (105) were due possible, probable, or definite Alzheimer’s.
Plasma tau levels rose linearly as the cohort aged. Higher plasma t-tau levels were associated with proven AD risk factors, including female sex, lower education, and higher vascular risk factors. They did not differ by apolipoprotein epsilon 4 status (APOEe4).
After adjusting for age and sex, each stand deviation unit increase in the log of tau was associated with a 29% greater risk of incident all-cause dementia, and a 35% increase in the risk of incident Alzheimer’s dementia. Subjects with tau levels above the median had a 62% increased risk of all-cause dementia and a 76% greater risk of AD. Adding APOEe4 status and vascular risk factors to the analysis didn’t alter the associations.
“Plasma t-tau level improved risk discrimination for all dementia and AD dementia beyond age and sex,” the investigators wrote. “[It] was associated with improved risk discrimination … in both APOEe4 carriers and noncarriers.”
In a hypothetical 5-year clinical trial, enrolling subjects with total plasma tau greater than the median could reduce the estimated necessary sample size by 38% for an outcome of all-cause dementia and by 50% for one of Alzheimer’s. Selecting those with both elevated plasma tau and APOEe4 carriage could reduce the required sample by 69% for all-cause dementia outcomes and by 80% for Alzheimer’s outcomes.
In the neuropathologic study, each standard deviation unit increase was associated with more neurofibrillary tangles in the medial temporal lobe, more microinfarcts, and smaller hippocampal volume. There was no association with amyloid plaque in any brain region.
Subjects in the Memento study had a meant of 4 years of follow-up. Over that time, there were 76 cases of incident dementia, 55 of which were probable Alzheimer’s.
Each standard deviation unit increase was associated with a nonsignificant 14% greater risk of all-cause dementia and a significant 54% increase in the risk of incident Alzheimer’s.
CSF was drawn on the same day as plasma in 140 of these subjects. The addition of CSF boosted the predictive value; each standard deviation increase more than doubled the risk of both Alzheimer’s (HR 2.33). Each standard deviation unit increase in CSF t-tau increased the risk by 2.14.
“Plasma t-tau was weakly correlated with CSF t-tau in our study. This finding is consistent
with previous studies showing that the associations of plasma t-tau with CSF t-tau have been weak or nonexistent,” the authors wrote. But, “Despite a weak correlation between plasma and CSF t-tau, plasma t-tau was at least as strongly associated with the development of incident AD dementia.”
“Use of plasma t-tau in this manner could be likened to the measurement of the APOEe4 allele, which is not a biomarker of AD pathology providing diagnostic certainty for AD dementia but is still routinely used to power clinical trials by selecting at-risk individuals,” they concluded.
Dr. Pase had no financial disclosures.
SOURCE: Pase, M et al JAMA Neurol 2019 doi:10.1001/jamaneurol.2018.4666
The total tau level in blood plasma appears to predict both onset and progression of dementia and could be used to help refine research cohorts.
Blood samples from two large dementia research cohorts confirmed the finding: Each standard deviation in plasma tau above the median is associated with a 29% greater risk of incident all-cause dementia and a 35%increase in the risk of incident Alzheimer’s disease, Matthew P. Pase, PhD and colleagues wrote in JAMA Neurology. It also correlated positively with some neuropathological aspects of dementia: smaller hippocampus and a higher burden of neurofibrillary tangles in the medial temporal lobe, said Dr. Pase of The Florey Institute for Neuroscience and Mental Health. Victoria, Australia.
Plasma tau isn’t the highly sought Holy Grail of a simple Alzheimer’s blood test. But the finding could benefit the research world. As a study entry criteria, it could substantially decrease the number of subjects needed to validate an outcome of either all-cause dementia or Alzheimer’s disease. Abnormal tau is also a required finding for an Alzheimer’s diagnosis in revised NIA-AA Research Framework. And, the authors noted, although plasma tau wasn’t quite as accurate a predictor as CSF tau, a needle in the arm would be much more acceptable to many more patients than a lumbar puncture.
“Whereas we do not expect plasma t-tau cutoffs to enhance diagnostic certainty for any single patient, our results suggest that plasma t-tau could be associated with improved risk stratification at a population level, targeting persons for inclusion in prevention trials, thus improving the power and precision of clinical trials and potentially accelerating therapeutic pipelines and drug discovery,” the team wrote.
The study drew on stored plasma samples from subjects enrolled in the Framingham Heart Study (1,453) and the Memento study, a multicenter cohort of persons with mild cognitive impairment or subjective cognitive complaints recruited from memory clinics across France (367).
The Framingham cohort was followed for up to 10 years between baseline examination to incident event (median 6 years).
Over that time, 134 (9.2%) cases of dementia developed; most of these (105) were due possible, probable, or definite Alzheimer’s.
Plasma tau levels rose linearly as the cohort aged. Higher plasma t-tau levels were associated with proven AD risk factors, including female sex, lower education, and higher vascular risk factors. They did not differ by apolipoprotein epsilon 4 status (APOEe4).
After adjusting for age and sex, each stand deviation unit increase in the log of tau was associated with a 29% greater risk of incident all-cause dementia, and a 35% increase in the risk of incident Alzheimer’s dementia. Subjects with tau levels above the median had a 62% increased risk of all-cause dementia and a 76% greater risk of AD. Adding APOEe4 status and vascular risk factors to the analysis didn’t alter the associations.
“Plasma t-tau level improved risk discrimination for all dementia and AD dementia beyond age and sex,” the investigators wrote. “[It] was associated with improved risk discrimination … in both APOEe4 carriers and noncarriers.”
In a hypothetical 5-year clinical trial, enrolling subjects with total plasma tau greater than the median could reduce the estimated necessary sample size by 38% for an outcome of all-cause dementia and by 50% for one of Alzheimer’s. Selecting those with both elevated plasma tau and APOEe4 carriage could reduce the required sample by 69% for all-cause dementia outcomes and by 80% for Alzheimer’s outcomes.
In the neuropathologic study, each standard deviation unit increase was associated with more neurofibrillary tangles in the medial temporal lobe, more microinfarcts, and smaller hippocampal volume. There was no association with amyloid plaque in any brain region.
Subjects in the Memento study had a meant of 4 years of follow-up. Over that time, there were 76 cases of incident dementia, 55 of which were probable Alzheimer’s.
Each standard deviation unit increase was associated with a nonsignificant 14% greater risk of all-cause dementia and a significant 54% increase in the risk of incident Alzheimer’s.
CSF was drawn on the same day as plasma in 140 of these subjects. The addition of CSF boosted the predictive value; each standard deviation increase more than doubled the risk of both Alzheimer’s (HR 2.33). Each standard deviation unit increase in CSF t-tau increased the risk by 2.14.
“Plasma t-tau was weakly correlated with CSF t-tau in our study. This finding is consistent
with previous studies showing that the associations of plasma t-tau with CSF t-tau have been weak or nonexistent,” the authors wrote. But, “Despite a weak correlation between plasma and CSF t-tau, plasma t-tau was at least as strongly associated with the development of incident AD dementia.”
“Use of plasma t-tau in this manner could be likened to the measurement of the APOEe4 allele, which is not a biomarker of AD pathology providing diagnostic certainty for AD dementia but is still routinely used to power clinical trials by selecting at-risk individuals,” they concluded.
Dr. Pase had no financial disclosures.
SOURCE: Pase, M et al JAMA Neurol 2019 doi:10.1001/jamaneurol.2018.4666
The total tau level in blood plasma appears to predict both onset and progression of dementia and could be used to help refine research cohorts.
Blood samples from two large dementia research cohorts confirmed the finding: Each standard deviation in plasma tau above the median is associated with a 29% greater risk of incident all-cause dementia and a 35%increase in the risk of incident Alzheimer’s disease, Matthew P. Pase, PhD and colleagues wrote in JAMA Neurology. It also correlated positively with some neuropathological aspects of dementia: smaller hippocampus and a higher burden of neurofibrillary tangles in the medial temporal lobe, said Dr. Pase of The Florey Institute for Neuroscience and Mental Health. Victoria, Australia.
Plasma tau isn’t the highly sought Holy Grail of a simple Alzheimer’s blood test. But the finding could benefit the research world. As a study entry criteria, it could substantially decrease the number of subjects needed to validate an outcome of either all-cause dementia or Alzheimer’s disease. Abnormal tau is also a required finding for an Alzheimer’s diagnosis in revised NIA-AA Research Framework. And, the authors noted, although plasma tau wasn’t quite as accurate a predictor as CSF tau, a needle in the arm would be much more acceptable to many more patients than a lumbar puncture.
“Whereas we do not expect plasma t-tau cutoffs to enhance diagnostic certainty for any single patient, our results suggest that plasma t-tau could be associated with improved risk stratification at a population level, targeting persons for inclusion in prevention trials, thus improving the power and precision of clinical trials and potentially accelerating therapeutic pipelines and drug discovery,” the team wrote.
The study drew on stored plasma samples from subjects enrolled in the Framingham Heart Study (1,453) and the Memento study, a multicenter cohort of persons with mild cognitive impairment or subjective cognitive complaints recruited from memory clinics across France (367).
The Framingham cohort was followed for up to 10 years between baseline examination to incident event (median 6 years).
Over that time, 134 (9.2%) cases of dementia developed; most of these (105) were due possible, probable, or definite Alzheimer’s.
Plasma tau levels rose linearly as the cohort aged. Higher plasma t-tau levels were associated with proven AD risk factors, including female sex, lower education, and higher vascular risk factors. They did not differ by apolipoprotein epsilon 4 status (APOEe4).
After adjusting for age and sex, each stand deviation unit increase in the log of tau was associated with a 29% greater risk of incident all-cause dementia, and a 35% increase in the risk of incident Alzheimer’s dementia. Subjects with tau levels above the median had a 62% increased risk of all-cause dementia and a 76% greater risk of AD. Adding APOEe4 status and vascular risk factors to the analysis didn’t alter the associations.
“Plasma t-tau level improved risk discrimination for all dementia and AD dementia beyond age and sex,” the investigators wrote. “[It] was associated with improved risk discrimination … in both APOEe4 carriers and noncarriers.”
In a hypothetical 5-year clinical trial, enrolling subjects with total plasma tau greater than the median could reduce the estimated necessary sample size by 38% for an outcome of all-cause dementia and by 50% for one of Alzheimer’s. Selecting those with both elevated plasma tau and APOEe4 carriage could reduce the required sample by 69% for all-cause dementia outcomes and by 80% for Alzheimer’s outcomes.
In the neuropathologic study, each standard deviation unit increase was associated with more neurofibrillary tangles in the medial temporal lobe, more microinfarcts, and smaller hippocampal volume. There was no association with amyloid plaque in any brain region.
Subjects in the Memento study had a meant of 4 years of follow-up. Over that time, there were 76 cases of incident dementia, 55 of which were probable Alzheimer’s.
Each standard deviation unit increase was associated with a nonsignificant 14% greater risk of all-cause dementia and a significant 54% increase in the risk of incident Alzheimer’s.
CSF was drawn on the same day as plasma in 140 of these subjects. The addition of CSF boosted the predictive value; each standard deviation increase more than doubled the risk of both Alzheimer’s (HR 2.33). Each standard deviation unit increase in CSF t-tau increased the risk by 2.14.
“Plasma t-tau was weakly correlated with CSF t-tau in our study. This finding is consistent
with previous studies showing that the associations of plasma t-tau with CSF t-tau have been weak or nonexistent,” the authors wrote. But, “Despite a weak correlation between plasma and CSF t-tau, plasma t-tau was at least as strongly associated with the development of incident AD dementia.”
“Use of plasma t-tau in this manner could be likened to the measurement of the APOEe4 allele, which is not a biomarker of AD pathology providing diagnostic certainty for AD dementia but is still routinely used to power clinical trials by selecting at-risk individuals,” they concluded.
Dr. Pase had no financial disclosures.
SOURCE: Pase, M et al JAMA Neurol 2019 doi:10.1001/jamaneurol.2018.4666
FROM JAMA NEUROLOGY
BTK inhibitor calms pemphigus vulgaris with low-dose steroids
WASHINGTON – An investigational molecule that blocks the downstream proinflammatory effects of B cells controlled disease activity and induced clinical remission in patients with pemphigus by 12 weeks.
At the end of a 24-week, open-label trial, a key driver of the sometimes-fatal blistering disease, Deedee Murrell, MD, said at the annual meeting of the American Academy of Dermatology.
The clinical efficacy plus a favorable safety profile supports the further development of the molecule, designed and manufactured by Principia Biopharma in San Francisco. The company is currently recruiting for a pivotal phase 3 trial of PRN1008 in 120 patients with moderate to severe pemphigus vulgaris.
Despite the recent approval of rituximab (Rituxan) for moderate to severe pemphigus, there remains an unmet need for a quick-acting, steroid-sparing, anti-inflammatory treatment, said Dr. Murrell, professor and head of the department of dermatology at the University of New South Wales, Sydney.
“We need something to use instead of high-dose steroids while we are waiting for rituximab to kick in, which can take 3 months,” and rituximab, which depletes B cells, puts patients at risk for infection, she said. “We need something that has rapid onset, is steroid sparing, safe for chronic administration, avoids B-cell depletion, and is convenient.”
Blocking the BTK receptor on B cells puts the brakes on the B-cell mediated inflammatory pathway, preventing activation of monocytes, macrophages, mast cells, basophils, and neutrophils. At the same time, however, it does not deplete the B-cell population, said Dr. Murrell, the lead investigator.
The BELIEVE study comprised 27 patients with mild to severe pemphigus of an average 6 years’ duration. Most (18) had relapsing disease; the remainder had newly diagnosed pemphigus. A majority (16) had severe disease, as measured by a score of 15 or more on the Pemphigus Disease Activity Index (PDAI). Almost all (23) were positive for antidesmoglein antibodies. Only one patient was negative for antibodies.
The mean corticosteroid dose at baseline was 14 mg/day, although that ranged from no steroids to 30 mg/day.
The study consisted of a 12-week treatment phase and a 12-week follow-up phase. During treatment, patients could take no more than 0.5 mg/kg of prednisone daily, although with 400 mg PRN1008 twice a day. They were allowed to undertake rescue immunosuppression if they experienced a disease flare.
The primary endpoint was disease control by day 29 as evidenced by no new lesions. Secondary endpoints were complete remission, minimization of prednisone, quality of life, antibody levels, and clinician measures including the PDAI and the Autoimmune Bullous Skin Disorder Intensity Score.
By the end of week 4, 54% of patients had achieved the primary endpoint. The benefit continued to expand, with 73% reaching that response by the end of week 12. During this period, the mean prednisone dose was 12 mg/day.
Among the 24 patients who completed the study, complete remission occurred in 17% by week 12. However, patients continued to respond through the follow-up period, even after the study medication was stopped. By week 24, 25% of these patients experienced a complete remission. At the point of remission, the mean steroid dose was 8 mg/day. The median duration of remission was 2 months after stopping PRN1008.
The PDAI fell by a median of 70% by week 12 and was maintained at that level by the end of week 24. The median level of antidesmoglein autoantibodies fell by up to 65%. Again, the improvement continued throughout the off-drug follow-up period. In subgroup analyses, PRN1008 was more effective in patients with moderate to severe disease than those with mild disease (80% response vs. 64%). It was equally effective in those with newly diagnosed disease (75% vs. 72%) and regardless of antibody level at baseline.
The adverse event profile was relatively benign. Most side effects were mild and transient, and included upper abdominal pain, headache, and nausea. There were two mild infections and one serious infection, which presented in a patient with a long-standing localized cellulitis that activated and was associated a high fever. It was culture negative and PRN1008 was restarted without issue.
There was also one serious adverse event and one death, both unrelated to the study drug. One patient developed a pancreatic cyst that was discovered on day 29. The patient dropped out of the study to have elective surgery. The death occurred in a patient who developed acute respiratory failure on day 8 of treatment, caused by an undiagnosed congenital pulmonary sequestration. The patient died of a brain embolism shortly after lung surgery.
Dr. Murrell designed the study and was an investigator. She reported a financial relationship with Principia, as well as with numerous other pharmaceutical companies.
SOURCE: Murrell D et al. AAD 2019, Session S034.
WASHINGTON – An investigational molecule that blocks the downstream proinflammatory effects of B cells controlled disease activity and induced clinical remission in patients with pemphigus by 12 weeks.
At the end of a 24-week, open-label trial, a key driver of the sometimes-fatal blistering disease, Deedee Murrell, MD, said at the annual meeting of the American Academy of Dermatology.
The clinical efficacy plus a favorable safety profile supports the further development of the molecule, designed and manufactured by Principia Biopharma in San Francisco. The company is currently recruiting for a pivotal phase 3 trial of PRN1008 in 120 patients with moderate to severe pemphigus vulgaris.
Despite the recent approval of rituximab (Rituxan) for moderate to severe pemphigus, there remains an unmet need for a quick-acting, steroid-sparing, anti-inflammatory treatment, said Dr. Murrell, professor and head of the department of dermatology at the University of New South Wales, Sydney.
“We need something to use instead of high-dose steroids while we are waiting for rituximab to kick in, which can take 3 months,” and rituximab, which depletes B cells, puts patients at risk for infection, she said. “We need something that has rapid onset, is steroid sparing, safe for chronic administration, avoids B-cell depletion, and is convenient.”
Blocking the BTK receptor on B cells puts the brakes on the B-cell mediated inflammatory pathway, preventing activation of monocytes, macrophages, mast cells, basophils, and neutrophils. At the same time, however, it does not deplete the B-cell population, said Dr. Murrell, the lead investigator.
The BELIEVE study comprised 27 patients with mild to severe pemphigus of an average 6 years’ duration. Most (18) had relapsing disease; the remainder had newly diagnosed pemphigus. A majority (16) had severe disease, as measured by a score of 15 or more on the Pemphigus Disease Activity Index (PDAI). Almost all (23) were positive for antidesmoglein antibodies. Only one patient was negative for antibodies.
The mean corticosteroid dose at baseline was 14 mg/day, although that ranged from no steroids to 30 mg/day.
The study consisted of a 12-week treatment phase and a 12-week follow-up phase. During treatment, patients could take no more than 0.5 mg/kg of prednisone daily, although with 400 mg PRN1008 twice a day. They were allowed to undertake rescue immunosuppression if they experienced a disease flare.
The primary endpoint was disease control by day 29 as evidenced by no new lesions. Secondary endpoints were complete remission, minimization of prednisone, quality of life, antibody levels, and clinician measures including the PDAI and the Autoimmune Bullous Skin Disorder Intensity Score.
By the end of week 4, 54% of patients had achieved the primary endpoint. The benefit continued to expand, with 73% reaching that response by the end of week 12. During this period, the mean prednisone dose was 12 mg/day.
Among the 24 patients who completed the study, complete remission occurred in 17% by week 12. However, patients continued to respond through the follow-up period, even after the study medication was stopped. By week 24, 25% of these patients experienced a complete remission. At the point of remission, the mean steroid dose was 8 mg/day. The median duration of remission was 2 months after stopping PRN1008.
The PDAI fell by a median of 70% by week 12 and was maintained at that level by the end of week 24. The median level of antidesmoglein autoantibodies fell by up to 65%. Again, the improvement continued throughout the off-drug follow-up period. In subgroup analyses, PRN1008 was more effective in patients with moderate to severe disease than those with mild disease (80% response vs. 64%). It was equally effective in those with newly diagnosed disease (75% vs. 72%) and regardless of antibody level at baseline.
The adverse event profile was relatively benign. Most side effects were mild and transient, and included upper abdominal pain, headache, and nausea. There were two mild infections and one serious infection, which presented in a patient with a long-standing localized cellulitis that activated and was associated a high fever. It was culture negative and PRN1008 was restarted without issue.
There was also one serious adverse event and one death, both unrelated to the study drug. One patient developed a pancreatic cyst that was discovered on day 29. The patient dropped out of the study to have elective surgery. The death occurred in a patient who developed acute respiratory failure on day 8 of treatment, caused by an undiagnosed congenital pulmonary sequestration. The patient died of a brain embolism shortly after lung surgery.
Dr. Murrell designed the study and was an investigator. She reported a financial relationship with Principia, as well as with numerous other pharmaceutical companies.
SOURCE: Murrell D et al. AAD 2019, Session S034.
WASHINGTON – An investigational molecule that blocks the downstream proinflammatory effects of B cells controlled disease activity and induced clinical remission in patients with pemphigus by 12 weeks.
At the end of a 24-week, open-label trial, a key driver of the sometimes-fatal blistering disease, Deedee Murrell, MD, said at the annual meeting of the American Academy of Dermatology.
The clinical efficacy plus a favorable safety profile supports the further development of the molecule, designed and manufactured by Principia Biopharma in San Francisco. The company is currently recruiting for a pivotal phase 3 trial of PRN1008 in 120 patients with moderate to severe pemphigus vulgaris.
Despite the recent approval of rituximab (Rituxan) for moderate to severe pemphigus, there remains an unmet need for a quick-acting, steroid-sparing, anti-inflammatory treatment, said Dr. Murrell, professor and head of the department of dermatology at the University of New South Wales, Sydney.
“We need something to use instead of high-dose steroids while we are waiting for rituximab to kick in, which can take 3 months,” and rituximab, which depletes B cells, puts patients at risk for infection, she said. “We need something that has rapid onset, is steroid sparing, safe for chronic administration, avoids B-cell depletion, and is convenient.”
Blocking the BTK receptor on B cells puts the brakes on the B-cell mediated inflammatory pathway, preventing activation of monocytes, macrophages, mast cells, basophils, and neutrophils. At the same time, however, it does not deplete the B-cell population, said Dr. Murrell, the lead investigator.
The BELIEVE study comprised 27 patients with mild to severe pemphigus of an average 6 years’ duration. Most (18) had relapsing disease; the remainder had newly diagnosed pemphigus. A majority (16) had severe disease, as measured by a score of 15 or more on the Pemphigus Disease Activity Index (PDAI). Almost all (23) were positive for antidesmoglein antibodies. Only one patient was negative for antibodies.
The mean corticosteroid dose at baseline was 14 mg/day, although that ranged from no steroids to 30 mg/day.
The study consisted of a 12-week treatment phase and a 12-week follow-up phase. During treatment, patients could take no more than 0.5 mg/kg of prednisone daily, although with 400 mg PRN1008 twice a day. They were allowed to undertake rescue immunosuppression if they experienced a disease flare.
The primary endpoint was disease control by day 29 as evidenced by no new lesions. Secondary endpoints were complete remission, minimization of prednisone, quality of life, antibody levels, and clinician measures including the PDAI and the Autoimmune Bullous Skin Disorder Intensity Score.
By the end of week 4, 54% of patients had achieved the primary endpoint. The benefit continued to expand, with 73% reaching that response by the end of week 12. During this period, the mean prednisone dose was 12 mg/day.
Among the 24 patients who completed the study, complete remission occurred in 17% by week 12. However, patients continued to respond through the follow-up period, even after the study medication was stopped. By week 24, 25% of these patients experienced a complete remission. At the point of remission, the mean steroid dose was 8 mg/day. The median duration of remission was 2 months after stopping PRN1008.
The PDAI fell by a median of 70% by week 12 and was maintained at that level by the end of week 24. The median level of antidesmoglein autoantibodies fell by up to 65%. Again, the improvement continued throughout the off-drug follow-up period. In subgroup analyses, PRN1008 was more effective in patients with moderate to severe disease than those with mild disease (80% response vs. 64%). It was equally effective in those with newly diagnosed disease (75% vs. 72%) and regardless of antibody level at baseline.
The adverse event profile was relatively benign. Most side effects were mild and transient, and included upper abdominal pain, headache, and nausea. There were two mild infections and one serious infection, which presented in a patient with a long-standing localized cellulitis that activated and was associated a high fever. It was culture negative and PRN1008 was restarted without issue.
There was also one serious adverse event and one death, both unrelated to the study drug. One patient developed a pancreatic cyst that was discovered on day 29. The patient dropped out of the study to have elective surgery. The death occurred in a patient who developed acute respiratory failure on day 8 of treatment, caused by an undiagnosed congenital pulmonary sequestration. The patient died of a brain embolism shortly after lung surgery.
Dr. Murrell designed the study and was an investigator. She reported a financial relationship with Principia, as well as with numerous other pharmaceutical companies.
SOURCE: Murrell D et al. AAD 2019, Session S034.
REPORTING FROM AAD 2019
IV ketamine, intranasal esketamine likely to ‘happily coexist’
Dr. Steven Levine offers perspective on how the FDA approval will affect patients, practice
Q: Why is this a “banner day” for psychiatry?
A: This is truly the first new option for depression in 60 years. The selective serotonin reuptake inhibitors (SSRIs) developed in the mid-’80s were not truly new, not much different from the monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants. In fact, they work much like watered-down MAOIs. Esketamine works by a truly novel mechanism.
Even though it constitutes a relatively new treatment, ketamine is a very old medicine, and we probably know more about the pharmacology and mechanisms in depression than for the SSRIs.
The idea of SSRIs working by increasing levels of neurotransmitters like serotonin has never held water. We never really believed that, but for people who respond to them – and many are helped – what is really happening weeks to months down the line is that these drugs increase the plasticity of the brain. Depression, like other mental health conditions, disrupts connections between important brain regions, reducing the number, function, and quality of the connections, and we believe SSRIs improve these.
Ketamine does these same things by a different route and much, much more quickly.
Q: What is esketamine’s method of action, and how long will a dose last?
A: Ketamine and esketamine bind to and block glutamate N-methyl-D-aspartate (NMDA) receptors. This leads to the release of several chemical messengers, the result of which increases the production of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF), that play a key role in healing damaged connections in the brain. A single dose of esketamine would only be expected to relieve depression symptoms for days, up to a week or 2. Multiple doses over the first few weeks can extend the durability of response to several weeks and sometimes months.
It is not true for every patient, but some do have improvement within 2-4 hours that correlates with physiologic changes. Others can be later responders and require up to 6 exposures.
Q: The FDA approval requires those who administer the drug to complete special training and meet licensure requirements. Is this realistic for small practices?
A: Initially, not every psychiatrist will be able to offer esketamine, and I think it might be beyond the reach of small practices, and that’s probably okay. Enough people and enough centers will be able to offer it to meet the initial demand.
Q: Is esketamine “better” than ketamine infusions? With the approved drug available, will ketamine infusion clinics still have a place?
A: There are major pros with this. The FDA approval takes out of the gray area of off-label administration. It will most likely be covered by insurance now – a huge advantage that will put this in the reach of so many patients who haven’t been able to access this treatment.
I think that, because there are advantages and disadvantages for both IV ketamine and nasal esketamine, they will happily coexist for years to come. However, because nasal esketamine will likely be restricted to prescription by psychiatrists, it may have more impact on non-psychiatrist-led practices. In this way,
Dr. Steven Levine is the founder of Actify Neurotherapies, which operates nine clinics providing ketamine treatment for depression.
Dr. Steven Levine offers perspective on how the FDA approval will affect patients, practice
Dr. Steven Levine offers perspective on how the FDA approval will affect patients, practice
Q: Why is this a “banner day” for psychiatry?
A: This is truly the first new option for depression in 60 years. The selective serotonin reuptake inhibitors (SSRIs) developed in the mid-’80s were not truly new, not much different from the monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants. In fact, they work much like watered-down MAOIs. Esketamine works by a truly novel mechanism.
Even though it constitutes a relatively new treatment, ketamine is a very old medicine, and we probably know more about the pharmacology and mechanisms in depression than for the SSRIs.
The idea of SSRIs working by increasing levels of neurotransmitters like serotonin has never held water. We never really believed that, but for people who respond to them – and many are helped – what is really happening weeks to months down the line is that these drugs increase the plasticity of the brain. Depression, like other mental health conditions, disrupts connections between important brain regions, reducing the number, function, and quality of the connections, and we believe SSRIs improve these.
Ketamine does these same things by a different route and much, much more quickly.
Q: What is esketamine’s method of action, and how long will a dose last?
A: Ketamine and esketamine bind to and block glutamate N-methyl-D-aspartate (NMDA) receptors. This leads to the release of several chemical messengers, the result of which increases the production of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF), that play a key role in healing damaged connections in the brain. A single dose of esketamine would only be expected to relieve depression symptoms for days, up to a week or 2. Multiple doses over the first few weeks can extend the durability of response to several weeks and sometimes months.
It is not true for every patient, but some do have improvement within 2-4 hours that correlates with physiologic changes. Others can be later responders and require up to 6 exposures.
Q: The FDA approval requires those who administer the drug to complete special training and meet licensure requirements. Is this realistic for small practices?
A: Initially, not every psychiatrist will be able to offer esketamine, and I think it might be beyond the reach of small practices, and that’s probably okay. Enough people and enough centers will be able to offer it to meet the initial demand.
Q: Is esketamine “better” than ketamine infusions? With the approved drug available, will ketamine infusion clinics still have a place?
A: There are major pros with this. The FDA approval takes out of the gray area of off-label administration. It will most likely be covered by insurance now – a huge advantage that will put this in the reach of so many patients who haven’t been able to access this treatment.
I think that, because there are advantages and disadvantages for both IV ketamine and nasal esketamine, they will happily coexist for years to come. However, because nasal esketamine will likely be restricted to prescription by psychiatrists, it may have more impact on non-psychiatrist-led practices. In this way,
Dr. Steven Levine is the founder of Actify Neurotherapies, which operates nine clinics providing ketamine treatment for depression.
Q: Why is this a “banner day” for psychiatry?
A: This is truly the first new option for depression in 60 years. The selective serotonin reuptake inhibitors (SSRIs) developed in the mid-’80s were not truly new, not much different from the monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants. In fact, they work much like watered-down MAOIs. Esketamine works by a truly novel mechanism.
Even though it constitutes a relatively new treatment, ketamine is a very old medicine, and we probably know more about the pharmacology and mechanisms in depression than for the SSRIs.
The idea of SSRIs working by increasing levels of neurotransmitters like serotonin has never held water. We never really believed that, but for people who respond to them – and many are helped – what is really happening weeks to months down the line is that these drugs increase the plasticity of the brain. Depression, like other mental health conditions, disrupts connections between important brain regions, reducing the number, function, and quality of the connections, and we believe SSRIs improve these.
Ketamine does these same things by a different route and much, much more quickly.
Q: What is esketamine’s method of action, and how long will a dose last?
A: Ketamine and esketamine bind to and block glutamate N-methyl-D-aspartate (NMDA) receptors. This leads to the release of several chemical messengers, the result of which increases the production of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF), that play a key role in healing damaged connections in the brain. A single dose of esketamine would only be expected to relieve depression symptoms for days, up to a week or 2. Multiple doses over the first few weeks can extend the durability of response to several weeks and sometimes months.
It is not true for every patient, but some do have improvement within 2-4 hours that correlates with physiologic changes. Others can be later responders and require up to 6 exposures.
Q: The FDA approval requires those who administer the drug to complete special training and meet licensure requirements. Is this realistic for small practices?
A: Initially, not every psychiatrist will be able to offer esketamine, and I think it might be beyond the reach of small practices, and that’s probably okay. Enough people and enough centers will be able to offer it to meet the initial demand.
Q: Is esketamine “better” than ketamine infusions? With the approved drug available, will ketamine infusion clinics still have a place?
A: There are major pros with this. The FDA approval takes out of the gray area of off-label administration. It will most likely be covered by insurance now – a huge advantage that will put this in the reach of so many patients who haven’t been able to access this treatment.
I think that, because there are advantages and disadvantages for both IV ketamine and nasal esketamine, they will happily coexist for years to come. However, because nasal esketamine will likely be restricted to prescription by psychiatrists, it may have more impact on non-psychiatrist-led practices. In this way,
Dr. Steven Levine is the founder of Actify Neurotherapies, which operates nine clinics providing ketamine treatment for depression.
FDA approves intranasal esketamine for refractory major depressive disorder
The spray (Spravato; Janssen Pharmaceuticals) will come in tamper-resistant prepackaged units of one, two, or three devices to deliver the prescribed doses of 28 mg, 56 mg, or 84 mg, respectively. To reduce the risk of diversion, misuse, or abuse, the drug will managed under an FDA Risk Evaluation and Management Strategy (REMS). It will only be available to prescribing clinicians who have undergone training on the risks of esketamine and the importance of monitoring patients after their dose is administered. Facilities licensed to dispense esketamine must have the ability to medically monitor patients for at least 2 hours after administration. Patients will self-administer the spray and will not be able to take any of it home.
The REMS will require both prescriber and the patient to both sign a Patient Enrollment Form clearly stating that patients understand the necessity of assisted transport to leave the health care facility and that there should be no driving or use of heavy machinery for the rest of the day on which they are treated.
A boxed warning on the label will note that patients are at risk for sedation and difficulty with attention, judgment, and thinking (dissociation); abuse and misuse; and suicidal thoughts and behaviors after administration of the drug.
Despite the FDA’s caveats, the approval of intranasal esketamine is seen as a substantial win for the psychiatric community, Tiffany Farchione, MD, acting director of the FDA division of psychiatry products, said in a statement. “There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition.”
“Spravato has the potential to change the treatment paradigm and offer new hope to the estimated one-third of people with major depressive disorder who have not responded to existing therapies,” said Mathai Mammen, MD, PhD, global head of Janssen Research and Development.
The company “is working quickly to educate and certify treatment centers in accordance with the REMS so that health care providers can offer Spravato to appropriate patients,” according to a statement from Janssen. “Later this month, patients can visit www.SPRAVATO.com for a locater tool and to sign up to receive alerts when new treatment centers are available.”
Intranasal esketamine was evaluated in three short-term clinical trials and one longer-term maintenance-of-effect trial. One of the studies demonstrated a clinically significant effect in depression severity, in as little as 2 days for some patients. The two other short-term trials did not show significant benefit. However, in the maintenance study, patients in stable remission or with stable response who continued treatment with esketamine plus an oral antidepressant experienced a significantly longer time to relapse of depressive symptoms than patients on placebo spray plus an oral antidepressant. The most common side effects were disassociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, and feeling drunk.
Patients with unstable or poorly controlled hypertension or pre-existing aneurysmal vascular disorders might be at increased risk for adverse cardiovascular or cerebrovascular effects. Esketamine might impair attention, judgment, thinking, reaction speed, and motor skills. It may cause fetal harm; women of childbearing age should be on reliable contraception. Breastfeeding women should not use it.
.
I’m not surprised by the FDA decision, given the strong endorsement from the advisory committees in mid-February based on the drug’s benefit-to-risk evaluation. This is an important advance for our field, and the FDA approval will allow more patients who suffer from treatment-resistant depression to gain access to this medication.
To date, ketamine (not the intranasal esketamine spray) has been offered primarily on a fee-for-service basis or in the context of a clinical trial. I anticipate this treatment to receive broad insurance coverage, but this remains to be determined.
Dr. Sanjay J. Mathew is the Marjorie Bintliff Johnson and Raleigh White Johnson Jr. Vice Chair for Research and professor in the Menninger department of psychiatry & behavioral sciences at the Baylor College of Medicine. He also is affiliated with the Michael E. Debakey VA Medical Center in Houston. Dr. Mathew has served as a consultant for and has had research funded by Janssen Pharmaceuticals.
I’m not surprised by the FDA decision, given the strong endorsement from the advisory committees in mid-February based on the drug’s benefit-to-risk evaluation. This is an important advance for our field, and the FDA approval will allow more patients who suffer from treatment-resistant depression to gain access to this medication.
To date, ketamine (not the intranasal esketamine spray) has been offered primarily on a fee-for-service basis or in the context of a clinical trial. I anticipate this treatment to receive broad insurance coverage, but this remains to be determined.
Dr. Sanjay J. Mathew is the Marjorie Bintliff Johnson and Raleigh White Johnson Jr. Vice Chair for Research and professor in the Menninger department of psychiatry & behavioral sciences at the Baylor College of Medicine. He also is affiliated with the Michael E. Debakey VA Medical Center in Houston. Dr. Mathew has served as a consultant for and has had research funded by Janssen Pharmaceuticals.
I’m not surprised by the FDA decision, given the strong endorsement from the advisory committees in mid-February based on the drug’s benefit-to-risk evaluation. This is an important advance for our field, and the FDA approval will allow more patients who suffer from treatment-resistant depression to gain access to this medication.
To date, ketamine (not the intranasal esketamine spray) has been offered primarily on a fee-for-service basis or in the context of a clinical trial. I anticipate this treatment to receive broad insurance coverage, but this remains to be determined.
Dr. Sanjay J. Mathew is the Marjorie Bintliff Johnson and Raleigh White Johnson Jr. Vice Chair for Research and professor in the Menninger department of psychiatry & behavioral sciences at the Baylor College of Medicine. He also is affiliated with the Michael E. Debakey VA Medical Center in Houston. Dr. Mathew has served as a consultant for and has had research funded by Janssen Pharmaceuticals.
The spray (Spravato; Janssen Pharmaceuticals) will come in tamper-resistant prepackaged units of one, two, or three devices to deliver the prescribed doses of 28 mg, 56 mg, or 84 mg, respectively. To reduce the risk of diversion, misuse, or abuse, the drug will managed under an FDA Risk Evaluation and Management Strategy (REMS). It will only be available to prescribing clinicians who have undergone training on the risks of esketamine and the importance of monitoring patients after their dose is administered. Facilities licensed to dispense esketamine must have the ability to medically monitor patients for at least 2 hours after administration. Patients will self-administer the spray and will not be able to take any of it home.
The REMS will require both prescriber and the patient to both sign a Patient Enrollment Form clearly stating that patients understand the necessity of assisted transport to leave the health care facility and that there should be no driving or use of heavy machinery for the rest of the day on which they are treated.
A boxed warning on the label will note that patients are at risk for sedation and difficulty with attention, judgment, and thinking (dissociation); abuse and misuse; and suicidal thoughts and behaviors after administration of the drug.
Despite the FDA’s caveats, the approval of intranasal esketamine is seen as a substantial win for the psychiatric community, Tiffany Farchione, MD, acting director of the FDA division of psychiatry products, said in a statement. “There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition.”
“Spravato has the potential to change the treatment paradigm and offer new hope to the estimated one-third of people with major depressive disorder who have not responded to existing therapies,” said Mathai Mammen, MD, PhD, global head of Janssen Research and Development.
The company “is working quickly to educate and certify treatment centers in accordance with the REMS so that health care providers can offer Spravato to appropriate patients,” according to a statement from Janssen. “Later this month, patients can visit www.SPRAVATO.com for a locater tool and to sign up to receive alerts when new treatment centers are available.”
Intranasal esketamine was evaluated in three short-term clinical trials and one longer-term maintenance-of-effect trial. One of the studies demonstrated a clinically significant effect in depression severity, in as little as 2 days for some patients. The two other short-term trials did not show significant benefit. However, in the maintenance study, patients in stable remission or with stable response who continued treatment with esketamine plus an oral antidepressant experienced a significantly longer time to relapse of depressive symptoms than patients on placebo spray plus an oral antidepressant. The most common side effects were disassociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, and feeling drunk.
Patients with unstable or poorly controlled hypertension or pre-existing aneurysmal vascular disorders might be at increased risk for adverse cardiovascular or cerebrovascular effects. Esketamine might impair attention, judgment, thinking, reaction speed, and motor skills. It may cause fetal harm; women of childbearing age should be on reliable contraception. Breastfeeding women should not use it.
.
The spray (Spravato; Janssen Pharmaceuticals) will come in tamper-resistant prepackaged units of one, two, or three devices to deliver the prescribed doses of 28 mg, 56 mg, or 84 mg, respectively. To reduce the risk of diversion, misuse, or abuse, the drug will managed under an FDA Risk Evaluation and Management Strategy (REMS). It will only be available to prescribing clinicians who have undergone training on the risks of esketamine and the importance of monitoring patients after their dose is administered. Facilities licensed to dispense esketamine must have the ability to medically monitor patients for at least 2 hours after administration. Patients will self-administer the spray and will not be able to take any of it home.
The REMS will require both prescriber and the patient to both sign a Patient Enrollment Form clearly stating that patients understand the necessity of assisted transport to leave the health care facility and that there should be no driving or use of heavy machinery for the rest of the day on which they are treated.
A boxed warning on the label will note that patients are at risk for sedation and difficulty with attention, judgment, and thinking (dissociation); abuse and misuse; and suicidal thoughts and behaviors after administration of the drug.
Despite the FDA’s caveats, the approval of intranasal esketamine is seen as a substantial win for the psychiatric community, Tiffany Farchione, MD, acting director of the FDA division of psychiatry products, said in a statement. “There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition.”
“Spravato has the potential to change the treatment paradigm and offer new hope to the estimated one-third of people with major depressive disorder who have not responded to existing therapies,” said Mathai Mammen, MD, PhD, global head of Janssen Research and Development.
The company “is working quickly to educate and certify treatment centers in accordance with the REMS so that health care providers can offer Spravato to appropriate patients,” according to a statement from Janssen. “Later this month, patients can visit www.SPRAVATO.com for a locater tool and to sign up to receive alerts when new treatment centers are available.”
Intranasal esketamine was evaluated in three short-term clinical trials and one longer-term maintenance-of-effect trial. One of the studies demonstrated a clinically significant effect in depression severity, in as little as 2 days for some patients. The two other short-term trials did not show significant benefit. However, in the maintenance study, patients in stable remission or with stable response who continued treatment with esketamine plus an oral antidepressant experienced a significantly longer time to relapse of depressive symptoms than patients on placebo spray plus an oral antidepressant. The most common side effects were disassociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, and feeling drunk.
Patients with unstable or poorly controlled hypertension or pre-existing aneurysmal vascular disorders might be at increased risk for adverse cardiovascular or cerebrovascular effects. Esketamine might impair attention, judgment, thinking, reaction speed, and motor skills. It may cause fetal harm; women of childbearing age should be on reliable contraception. Breastfeeding women should not use it.
.
Bermekimab reduces lesions, cuts pain in patients with hidradenitis suppurativa
WASHINGTON – It was nearly as effective in patients refractory to anti–tumor necrosis factor (TNF) therapy as it was to those naive to the treatment.
The antibody, which is derived directly from healthy human volunteers and then lab expanded, also improved patients’ quality of life in a “clinically meaningful way,” Alice Gottlieb, MD, PhD said at the annual meeting of the American Academy of Dermatology.
“These are sick people, and improvement of this kind is really something very important,” said Dr. Gottlieb of Mount Sinai Medical Center in New York. “I think what we see here supports the movement of bermekimab into phase 3 studies for HS [hidradenitis suppurativa].”
Bermekimab is the first inhibitor of IL-1 alpha to be investigated in HS. An overabundance of the cytokine produces several potentially problematic effects. IL-1 alpha induces inflammatory cells to migrate into the skin, drives neoangiogenesis, potentiates pain, and induces matrix metalloproteinase. The last two are particularly an issue in patients with HS. The abscesses and fistulas cause severe pain, which Dr. Gottlieb said is an undertreated and an underappreciated driver of disease disability. The tissue breakdown characteristic of the disease can also be highly disfiguring. “Many patients, especially my female patients, look as if they are basically autodigesting.”
IL-1 alpha also induces procollagen type I and III and fibroblast proliferation, contributing to the scarring many patients experience.
“Ten years ago, I thought it would be a potential target for HS,” Dr, Gottlieb said, and the idea has finally come to fruition through studies by biopharmaceutical company XBiotech in Austin, Tex. Dr. Gottlieb designed the treatment protocol and was a principal investigator on the study.
A similarly positive 2018 study employed twice-weekly intravenous infusions; this study utilized a more-concentrated form of the antibody delivered subcutaneously from prefilled syringes.
The study comprised 42 patients, 24 of whom had failed a course of anti-TNF therapy and 18 of whom were anti-TNF naive. Each group received bermekimab 400 mg subcutaneous once a week for 12 weeks. The primary endpoint was change on the Hidradenitis Suppurativa Clinical Response Score; good response was deemed at least a 50% reduction in abscesses and inflammatory nodules, with no new abscesses or draining fistulas. Secondary endpoints included pain scores, patient quality of life, and the physicians global clinical assessment.
At baseline, subjects in the anti-TNF–refractory group had a worse clinical profile than the naive patients, with more abscesses and inflammatory nodules (mean, 14 vs. 6) and worse scores on the Physicians Global Assessment. But they reported similar pain on a 10-point scale (around 8) and negative quality of life (17/30). Both groups experienced anxiety and depression.
Eight patients dropped out before finishing the trial for a variety of reasons, including family and transportation issues and comorbid illness. Only one discontinued for a reaction to the study drug (injection site redness). These patients were included in the final analysis in a last observation carried forward.
About 10% of patients began to experience improvement as soon as 2 weeks after the first injection. By week 6, 40% of the refractory patients and 10% of the naive patents had experienced a lesion reduction of at least 50%. By the end of the study, however, about 62% of patients in each group achieved that goal.
By week 12, the mean improvement in the Physicians Global Assessment was about 23% in the refractory group and 53% in the naive group. Both results were significant improvements over baseline.
The mean improvement in the pain score was about 54% in the refractory group and 65% in the naive group. In a scale that measured patients’ view of their disease severity, refractory patients reported a mean 40% improvement, and naive patients, a mean 67% improvement.
There were 57 adverse events recorded; 94% were grade 1 or 2. There were two serious adverse events requiring hospitalization – a fall and an admission for HS pain. Neither were judged related to the study drug. Two patients experienced injection site reactions and one patient experienced six bouts of nausea. There were no serious infections, no major cardiovascular events, and no neoplasms.
Dr. Gottlieb designed the study protocol and was a principal investigator. She did not receive financial compensation from the company.
WASHINGTON – It was nearly as effective in patients refractory to anti–tumor necrosis factor (TNF) therapy as it was to those naive to the treatment.
The antibody, which is derived directly from healthy human volunteers and then lab expanded, also improved patients’ quality of life in a “clinically meaningful way,” Alice Gottlieb, MD, PhD said at the annual meeting of the American Academy of Dermatology.
“These are sick people, and improvement of this kind is really something very important,” said Dr. Gottlieb of Mount Sinai Medical Center in New York. “I think what we see here supports the movement of bermekimab into phase 3 studies for HS [hidradenitis suppurativa].”
Bermekimab is the first inhibitor of IL-1 alpha to be investigated in HS. An overabundance of the cytokine produces several potentially problematic effects. IL-1 alpha induces inflammatory cells to migrate into the skin, drives neoangiogenesis, potentiates pain, and induces matrix metalloproteinase. The last two are particularly an issue in patients with HS. The abscesses and fistulas cause severe pain, which Dr. Gottlieb said is an undertreated and an underappreciated driver of disease disability. The tissue breakdown characteristic of the disease can also be highly disfiguring. “Many patients, especially my female patients, look as if they are basically autodigesting.”
IL-1 alpha also induces procollagen type I and III and fibroblast proliferation, contributing to the scarring many patients experience.
“Ten years ago, I thought it would be a potential target for HS,” Dr, Gottlieb said, and the idea has finally come to fruition through studies by biopharmaceutical company XBiotech in Austin, Tex. Dr. Gottlieb designed the treatment protocol and was a principal investigator on the study.
A similarly positive 2018 study employed twice-weekly intravenous infusions; this study utilized a more-concentrated form of the antibody delivered subcutaneously from prefilled syringes.
The study comprised 42 patients, 24 of whom had failed a course of anti-TNF therapy and 18 of whom were anti-TNF naive. Each group received bermekimab 400 mg subcutaneous once a week for 12 weeks. The primary endpoint was change on the Hidradenitis Suppurativa Clinical Response Score; good response was deemed at least a 50% reduction in abscesses and inflammatory nodules, with no new abscesses or draining fistulas. Secondary endpoints included pain scores, patient quality of life, and the physicians global clinical assessment.
At baseline, subjects in the anti-TNF–refractory group had a worse clinical profile than the naive patients, with more abscesses and inflammatory nodules (mean, 14 vs. 6) and worse scores on the Physicians Global Assessment. But they reported similar pain on a 10-point scale (around 8) and negative quality of life (17/30). Both groups experienced anxiety and depression.
Eight patients dropped out before finishing the trial for a variety of reasons, including family and transportation issues and comorbid illness. Only one discontinued for a reaction to the study drug (injection site redness). These patients were included in the final analysis in a last observation carried forward.
About 10% of patients began to experience improvement as soon as 2 weeks after the first injection. By week 6, 40% of the refractory patients and 10% of the naive patents had experienced a lesion reduction of at least 50%. By the end of the study, however, about 62% of patients in each group achieved that goal.
By week 12, the mean improvement in the Physicians Global Assessment was about 23% in the refractory group and 53% in the naive group. Both results were significant improvements over baseline.
The mean improvement in the pain score was about 54% in the refractory group and 65% in the naive group. In a scale that measured patients’ view of their disease severity, refractory patients reported a mean 40% improvement, and naive patients, a mean 67% improvement.
There were 57 adverse events recorded; 94% were grade 1 or 2. There were two serious adverse events requiring hospitalization – a fall and an admission for HS pain. Neither were judged related to the study drug. Two patients experienced injection site reactions and one patient experienced six bouts of nausea. There were no serious infections, no major cardiovascular events, and no neoplasms.
Dr. Gottlieb designed the study protocol and was a principal investigator. She did not receive financial compensation from the company.
WASHINGTON – It was nearly as effective in patients refractory to anti–tumor necrosis factor (TNF) therapy as it was to those naive to the treatment.
The antibody, which is derived directly from healthy human volunteers and then lab expanded, also improved patients’ quality of life in a “clinically meaningful way,” Alice Gottlieb, MD, PhD said at the annual meeting of the American Academy of Dermatology.
“These are sick people, and improvement of this kind is really something very important,” said Dr. Gottlieb of Mount Sinai Medical Center in New York. “I think what we see here supports the movement of bermekimab into phase 3 studies for HS [hidradenitis suppurativa].”
Bermekimab is the first inhibitor of IL-1 alpha to be investigated in HS. An overabundance of the cytokine produces several potentially problematic effects. IL-1 alpha induces inflammatory cells to migrate into the skin, drives neoangiogenesis, potentiates pain, and induces matrix metalloproteinase. The last two are particularly an issue in patients with HS. The abscesses and fistulas cause severe pain, which Dr. Gottlieb said is an undertreated and an underappreciated driver of disease disability. The tissue breakdown characteristic of the disease can also be highly disfiguring. “Many patients, especially my female patients, look as if they are basically autodigesting.”
IL-1 alpha also induces procollagen type I and III and fibroblast proliferation, contributing to the scarring many patients experience.
“Ten years ago, I thought it would be a potential target for HS,” Dr, Gottlieb said, and the idea has finally come to fruition through studies by biopharmaceutical company XBiotech in Austin, Tex. Dr. Gottlieb designed the treatment protocol and was a principal investigator on the study.
A similarly positive 2018 study employed twice-weekly intravenous infusions; this study utilized a more-concentrated form of the antibody delivered subcutaneously from prefilled syringes.
The study comprised 42 patients, 24 of whom had failed a course of anti-TNF therapy and 18 of whom were anti-TNF naive. Each group received bermekimab 400 mg subcutaneous once a week for 12 weeks. The primary endpoint was change on the Hidradenitis Suppurativa Clinical Response Score; good response was deemed at least a 50% reduction in abscesses and inflammatory nodules, with no new abscesses or draining fistulas. Secondary endpoints included pain scores, patient quality of life, and the physicians global clinical assessment.
At baseline, subjects in the anti-TNF–refractory group had a worse clinical profile than the naive patients, with more abscesses and inflammatory nodules (mean, 14 vs. 6) and worse scores on the Physicians Global Assessment. But they reported similar pain on a 10-point scale (around 8) and negative quality of life (17/30). Both groups experienced anxiety and depression.
Eight patients dropped out before finishing the trial for a variety of reasons, including family and transportation issues and comorbid illness. Only one discontinued for a reaction to the study drug (injection site redness). These patients were included in the final analysis in a last observation carried forward.
About 10% of patients began to experience improvement as soon as 2 weeks after the first injection. By week 6, 40% of the refractory patients and 10% of the naive patents had experienced a lesion reduction of at least 50%. By the end of the study, however, about 62% of patients in each group achieved that goal.
By week 12, the mean improvement in the Physicians Global Assessment was about 23% in the refractory group and 53% in the naive group. Both results were significant improvements over baseline.
The mean improvement in the pain score was about 54% in the refractory group and 65% in the naive group. In a scale that measured patients’ view of their disease severity, refractory patients reported a mean 40% improvement, and naive patients, a mean 67% improvement.
There were 57 adverse events recorded; 94% were grade 1 or 2. There were two serious adverse events requiring hospitalization – a fall and an admission for HS pain. Neither were judged related to the study drug. Two patients experienced injection site reactions and one patient experienced six bouts of nausea. There were no serious infections, no major cardiovascular events, and no neoplasms.
Dr. Gottlieb designed the study protocol and was a principal investigator. She did not receive financial compensation from the company.
REPORTING FROM AAD 2019
Many common dermatologic drugs can be safely used during pregnancy
WASHINGTON – With proper counseling and oversight, many drugs used for psoriasis, pemphigus, and atopic dermatitis are safe to use during pregnancy, Jenny Murase, MD, said at the annual meeting of the American Academy of Dermatology.
But it’s important to have an early talk about potential pregnancies, because most dermatologists don’t think about it unless a patient is taking a known teratogen, like isotretinoin, said Dr. Murase of the University of California, San Francisco. “It’s only about 10% of the time that the dermatologist brings it up. In patients with these chronic skin diseases, we need to address family planning proactively. Most women don’t discover they’re pregnant until they’re 2-5 weeks along, and by that time the development of major organs has already started.”
As part of her expertise in this topic, Dr. Murase published two comprehensive reports on the safety of dermatologic drugs in pregnancy and lactation. They were grouped according to the newest federal guidance, the Food and Drug Administration Pregnancy and Lactation Label Ruling. Issued in 2014, it requires the inclusion of any contact information for drug registries and covers reproductive risks or both males and females. Slowly being phased in as new drugs are approved, the ruling is replacing the old category A, B, and C.
The articles were published in the Journal of the American Academy of Dermatology and in the international Journal of Women’s Dermatology, an open-access journal Dr. Murase founded.
Corticosteroids
These dermatology workhorses are largely safe in pregnancy, Dr. Murase said. Some very early reports suggested that systemic cortisone might be associated with oral clefts, but that has never been borne out in prospective data. Prednisone may be the safest as it has the most limited placental transport; betamethasone and dexamethasone cross the placenta easily.
In a Cochrane review, only one study showed an increased risk of orofacial clefts. A 2013 study of about 10,000 women suggested an increased risk of low birth weight associated with a total dose of more than 300 grams during the pregnancy.
Antihistamines
First-generation antihistamines, including hydroxyzine, have been used as antiemetics in pregnant women. Hydroxyzine is generally considered safe, but should be discussed carefully, as it carries a slightly increased risk of congenital malformations (5.8% vs. 2.3% background risk).
Newborns exposed to large doses of hydroxyzine (150 mg or more daily) have also exhibited withdrawal symptoms at birth, including irritability, poor feeding, and tonic-clinic seizures.
“Antihistamines can exert oxytocin-like effects, especially in overdose or when given intravenously, so please avoid using them in the last month of pregnancy. There have also been a few reports of retrolental fibroplasia in preterm infants who were exposed to antihistamines within 2 weeks of delivery,” Dr. Murase said.
Immunosuppressants
Mycophenolate is not compatible with pregnancy. In 2007, the FDA changed the labeling of mycophenolate from category C to D, because of reports of congenital malformations arising from the U.S. National Transplantation Pregnancy Registry and other sources.
“You need to treat these patients like you do someone who is going on isotretinoin,” Dr. Murase said. “Any woman prescribed it should be on mandatory contraception at least 4 weeks before beginning the medication and for 6 weeks after completing treatment.”
Thus far there are no reported pregnancy-related safety issues with dupilumab, although data are scarce.
Pregnancy itself exerts a positive effect on psoriasis in many women, but not all. “About half the time a women will improve,” Dr. Murase said. “A quarter of the time, there’s no change and a quarter of the time, she’ll get worse. But the ones who do improve, often improve dramatically with about 80% body surface area clearance.”
She considers light therapy to be the safest treatment during pregnancy, with one caveat: Ultraviolet light can degrade some vitamins, including folic acid. “Every one of my patients of childbearing age I have on folic acid or a prenatal vitamin just in case. You have to be proactive here.”
Cyclosporine appears to be “quite safe,” she said. The possibility of intrauterine growth restriction seen in some studies is tough to tease out, because it was reported mainly in transplant populations among women with other medical comorbidities. Children from these pregnancies have been followed through toddlerhood and showed no neurodevelopmental or kidney issues.
Apremilast is a category C drug. Some animal data suggested increased spontaneous abortions and fetal demise with doses given at two to four times the human dose.
Biologics
Antibodies are an interesting lot, Dr. Murase noted. Maternal antibodies are transported to the fetus across the villi by Fc receptor; most of this transfer happens during the third trimester. The large, hydrophilic monoclonal antibodies infliximab, adalimumab, and ustekinumab travel this way as well. Cord blood can contain 50% higher serum levels than in maternal blood. Etanercept, however, is a fusion protein that diffuses across the placenta. Cord blood levels generally exceed maternal levels by less than 7%.
There is one published report of a fetal death associated with maternal infliximab for Crohn’s disease. The infant was healthy until it received a Bacillus Calmette–Guerin vaccine. It then developed widespread eczematous dermatitis, head lag, and poor weight gain and died at 4.5 months.
“This is another important counseling point,” Dr. Murase said. “Babies who have been exposed to infliximab in utero can’t have that vaccination in the first 9 months of life.”
Perhaps the safest bet for a pregnant women who needs a biologic is PEGylated certolizumab. “Certolizumab is the only PEGylated anti-TNF [tumor necrosis factor] without an Fc region; study of patients greater than 30 weeks pregnant certolizumab levels were below 0.032 mcg/mL in 13 of 14 infant samples at birth.”
Pemphigus
Pemphigus (impetigo herpetiformous) is a serious dermatologic disorder that can manifest in the third trimester, and affect the fetus as well as the mother. “You have to take even mild cases very seriously, because there’s no distinct correlation between the extent of neonatal involvement and the extent of maternal disease,” Dr. Murase said
Oral pemphigus in the mother is especially worrisome, she added. “Fetal skin shares the same desmoglein-3 profile as adult oral mucosa, and neonatal pemphigus is more likely if mother has oral disease. There’s an increased risk of fetal demise as well.”
Treatment would generally start with topical steroids, progressing to systemic low-dose corticosteroids. If more than 20 mg of prednisone a day is required, consider intravenous immunoglobulin (IVIG), azathioprine, dapsone, or rituximab.
“IVIG is very safe for pregnant women, and in fact reproductive endocrinologists use this to increase the chance of pregnancy for infertility cases,” Dr. Murase said.
She reported relationships with Regeneron, UCB, Dermira, and Genzyme/Sanofi.
WASHINGTON – With proper counseling and oversight, many drugs used for psoriasis, pemphigus, and atopic dermatitis are safe to use during pregnancy, Jenny Murase, MD, said at the annual meeting of the American Academy of Dermatology.
But it’s important to have an early talk about potential pregnancies, because most dermatologists don’t think about it unless a patient is taking a known teratogen, like isotretinoin, said Dr. Murase of the University of California, San Francisco. “It’s only about 10% of the time that the dermatologist brings it up. In patients with these chronic skin diseases, we need to address family planning proactively. Most women don’t discover they’re pregnant until they’re 2-5 weeks along, and by that time the development of major organs has already started.”
As part of her expertise in this topic, Dr. Murase published two comprehensive reports on the safety of dermatologic drugs in pregnancy and lactation. They were grouped according to the newest federal guidance, the Food and Drug Administration Pregnancy and Lactation Label Ruling. Issued in 2014, it requires the inclusion of any contact information for drug registries and covers reproductive risks or both males and females. Slowly being phased in as new drugs are approved, the ruling is replacing the old category A, B, and C.
The articles were published in the Journal of the American Academy of Dermatology and in the international Journal of Women’s Dermatology, an open-access journal Dr. Murase founded.
Corticosteroids
These dermatology workhorses are largely safe in pregnancy, Dr. Murase said. Some very early reports suggested that systemic cortisone might be associated with oral clefts, but that has never been borne out in prospective data. Prednisone may be the safest as it has the most limited placental transport; betamethasone and dexamethasone cross the placenta easily.
In a Cochrane review, only one study showed an increased risk of orofacial clefts. A 2013 study of about 10,000 women suggested an increased risk of low birth weight associated with a total dose of more than 300 grams during the pregnancy.
Antihistamines
First-generation antihistamines, including hydroxyzine, have been used as antiemetics in pregnant women. Hydroxyzine is generally considered safe, but should be discussed carefully, as it carries a slightly increased risk of congenital malformations (5.8% vs. 2.3% background risk).
Newborns exposed to large doses of hydroxyzine (150 mg or more daily) have also exhibited withdrawal symptoms at birth, including irritability, poor feeding, and tonic-clinic seizures.
“Antihistamines can exert oxytocin-like effects, especially in overdose or when given intravenously, so please avoid using them in the last month of pregnancy. There have also been a few reports of retrolental fibroplasia in preterm infants who were exposed to antihistamines within 2 weeks of delivery,” Dr. Murase said.
Immunosuppressants
Mycophenolate is not compatible with pregnancy. In 2007, the FDA changed the labeling of mycophenolate from category C to D, because of reports of congenital malformations arising from the U.S. National Transplantation Pregnancy Registry and other sources.
“You need to treat these patients like you do someone who is going on isotretinoin,” Dr. Murase said. “Any woman prescribed it should be on mandatory contraception at least 4 weeks before beginning the medication and for 6 weeks after completing treatment.”
Thus far there are no reported pregnancy-related safety issues with dupilumab, although data are scarce.
Pregnancy itself exerts a positive effect on psoriasis in many women, but not all. “About half the time a women will improve,” Dr. Murase said. “A quarter of the time, there’s no change and a quarter of the time, she’ll get worse. But the ones who do improve, often improve dramatically with about 80% body surface area clearance.”
She considers light therapy to be the safest treatment during pregnancy, with one caveat: Ultraviolet light can degrade some vitamins, including folic acid. “Every one of my patients of childbearing age I have on folic acid or a prenatal vitamin just in case. You have to be proactive here.”
Cyclosporine appears to be “quite safe,” she said. The possibility of intrauterine growth restriction seen in some studies is tough to tease out, because it was reported mainly in transplant populations among women with other medical comorbidities. Children from these pregnancies have been followed through toddlerhood and showed no neurodevelopmental or kidney issues.
Apremilast is a category C drug. Some animal data suggested increased spontaneous abortions and fetal demise with doses given at two to four times the human dose.
Biologics
Antibodies are an interesting lot, Dr. Murase noted. Maternal antibodies are transported to the fetus across the villi by Fc receptor; most of this transfer happens during the third trimester. The large, hydrophilic monoclonal antibodies infliximab, adalimumab, and ustekinumab travel this way as well. Cord blood can contain 50% higher serum levels than in maternal blood. Etanercept, however, is a fusion protein that diffuses across the placenta. Cord blood levels generally exceed maternal levels by less than 7%.
There is one published report of a fetal death associated with maternal infliximab for Crohn’s disease. The infant was healthy until it received a Bacillus Calmette–Guerin vaccine. It then developed widespread eczematous dermatitis, head lag, and poor weight gain and died at 4.5 months.
“This is another important counseling point,” Dr. Murase said. “Babies who have been exposed to infliximab in utero can’t have that vaccination in the first 9 months of life.”
Perhaps the safest bet for a pregnant women who needs a biologic is PEGylated certolizumab. “Certolizumab is the only PEGylated anti-TNF [tumor necrosis factor] without an Fc region; study of patients greater than 30 weeks pregnant certolizumab levels were below 0.032 mcg/mL in 13 of 14 infant samples at birth.”
Pemphigus
Pemphigus (impetigo herpetiformous) is a serious dermatologic disorder that can manifest in the third trimester, and affect the fetus as well as the mother. “You have to take even mild cases very seriously, because there’s no distinct correlation between the extent of neonatal involvement and the extent of maternal disease,” Dr. Murase said
Oral pemphigus in the mother is especially worrisome, she added. “Fetal skin shares the same desmoglein-3 profile as adult oral mucosa, and neonatal pemphigus is more likely if mother has oral disease. There’s an increased risk of fetal demise as well.”
Treatment would generally start with topical steroids, progressing to systemic low-dose corticosteroids. If more than 20 mg of prednisone a day is required, consider intravenous immunoglobulin (IVIG), azathioprine, dapsone, or rituximab.
“IVIG is very safe for pregnant women, and in fact reproductive endocrinologists use this to increase the chance of pregnancy for infertility cases,” Dr. Murase said.
She reported relationships with Regeneron, UCB, Dermira, and Genzyme/Sanofi.
WASHINGTON – With proper counseling and oversight, many drugs used for psoriasis, pemphigus, and atopic dermatitis are safe to use during pregnancy, Jenny Murase, MD, said at the annual meeting of the American Academy of Dermatology.
But it’s important to have an early talk about potential pregnancies, because most dermatologists don’t think about it unless a patient is taking a known teratogen, like isotretinoin, said Dr. Murase of the University of California, San Francisco. “It’s only about 10% of the time that the dermatologist brings it up. In patients with these chronic skin diseases, we need to address family planning proactively. Most women don’t discover they’re pregnant until they’re 2-5 weeks along, and by that time the development of major organs has already started.”
As part of her expertise in this topic, Dr. Murase published two comprehensive reports on the safety of dermatologic drugs in pregnancy and lactation. They were grouped according to the newest federal guidance, the Food and Drug Administration Pregnancy and Lactation Label Ruling. Issued in 2014, it requires the inclusion of any contact information for drug registries and covers reproductive risks or both males and females. Slowly being phased in as new drugs are approved, the ruling is replacing the old category A, B, and C.
The articles were published in the Journal of the American Academy of Dermatology and in the international Journal of Women’s Dermatology, an open-access journal Dr. Murase founded.
Corticosteroids
These dermatology workhorses are largely safe in pregnancy, Dr. Murase said. Some very early reports suggested that systemic cortisone might be associated with oral clefts, but that has never been borne out in prospective data. Prednisone may be the safest as it has the most limited placental transport; betamethasone and dexamethasone cross the placenta easily.
In a Cochrane review, only one study showed an increased risk of orofacial clefts. A 2013 study of about 10,000 women suggested an increased risk of low birth weight associated with a total dose of more than 300 grams during the pregnancy.
Antihistamines
First-generation antihistamines, including hydroxyzine, have been used as antiemetics in pregnant women. Hydroxyzine is generally considered safe, but should be discussed carefully, as it carries a slightly increased risk of congenital malformations (5.8% vs. 2.3% background risk).
Newborns exposed to large doses of hydroxyzine (150 mg or more daily) have also exhibited withdrawal symptoms at birth, including irritability, poor feeding, and tonic-clinic seizures.
“Antihistamines can exert oxytocin-like effects, especially in overdose or when given intravenously, so please avoid using them in the last month of pregnancy. There have also been a few reports of retrolental fibroplasia in preterm infants who were exposed to antihistamines within 2 weeks of delivery,” Dr. Murase said.
Immunosuppressants
Mycophenolate is not compatible with pregnancy. In 2007, the FDA changed the labeling of mycophenolate from category C to D, because of reports of congenital malformations arising from the U.S. National Transplantation Pregnancy Registry and other sources.
“You need to treat these patients like you do someone who is going on isotretinoin,” Dr. Murase said. “Any woman prescribed it should be on mandatory contraception at least 4 weeks before beginning the medication and for 6 weeks after completing treatment.”
Thus far there are no reported pregnancy-related safety issues with dupilumab, although data are scarce.
Pregnancy itself exerts a positive effect on psoriasis in many women, but not all. “About half the time a women will improve,” Dr. Murase said. “A quarter of the time, there’s no change and a quarter of the time, she’ll get worse. But the ones who do improve, often improve dramatically with about 80% body surface area clearance.”
She considers light therapy to be the safest treatment during pregnancy, with one caveat: Ultraviolet light can degrade some vitamins, including folic acid. “Every one of my patients of childbearing age I have on folic acid or a prenatal vitamin just in case. You have to be proactive here.”
Cyclosporine appears to be “quite safe,” she said. The possibility of intrauterine growth restriction seen in some studies is tough to tease out, because it was reported mainly in transplant populations among women with other medical comorbidities. Children from these pregnancies have been followed through toddlerhood and showed no neurodevelopmental or kidney issues.
Apremilast is a category C drug. Some animal data suggested increased spontaneous abortions and fetal demise with doses given at two to four times the human dose.
Biologics
Antibodies are an interesting lot, Dr. Murase noted. Maternal antibodies are transported to the fetus across the villi by Fc receptor; most of this transfer happens during the third trimester. The large, hydrophilic monoclonal antibodies infliximab, adalimumab, and ustekinumab travel this way as well. Cord blood can contain 50% higher serum levels than in maternal blood. Etanercept, however, is a fusion protein that diffuses across the placenta. Cord blood levels generally exceed maternal levels by less than 7%.
There is one published report of a fetal death associated with maternal infliximab for Crohn’s disease. The infant was healthy until it received a Bacillus Calmette–Guerin vaccine. It then developed widespread eczematous dermatitis, head lag, and poor weight gain and died at 4.5 months.
“This is another important counseling point,” Dr. Murase said. “Babies who have been exposed to infliximab in utero can’t have that vaccination in the first 9 months of life.”
Perhaps the safest bet for a pregnant women who needs a biologic is PEGylated certolizumab. “Certolizumab is the only PEGylated anti-TNF [tumor necrosis factor] without an Fc region; study of patients greater than 30 weeks pregnant certolizumab levels were below 0.032 mcg/mL in 13 of 14 infant samples at birth.”
Pemphigus
Pemphigus (impetigo herpetiformous) is a serious dermatologic disorder that can manifest in the third trimester, and affect the fetus as well as the mother. “You have to take even mild cases very seriously, because there’s no distinct correlation between the extent of neonatal involvement and the extent of maternal disease,” Dr. Murase said
Oral pemphigus in the mother is especially worrisome, she added. “Fetal skin shares the same desmoglein-3 profile as adult oral mucosa, and neonatal pemphigus is more likely if mother has oral disease. There’s an increased risk of fetal demise as well.”
Treatment would generally start with topical steroids, progressing to systemic low-dose corticosteroids. If more than 20 mg of prednisone a day is required, consider intravenous immunoglobulin (IVIG), azathioprine, dapsone, or rituximab.
“IVIG is very safe for pregnant women, and in fact reproductive endocrinologists use this to increase the chance of pregnancy for infertility cases,” Dr. Murase said.
She reported relationships with Regeneron, UCB, Dermira, and Genzyme/Sanofi.
EXPERT ANALYSIS FROM AAD 2019
Texting improves postpregnancy hypertension monitoring in black women
LAS VEGAS – Adi Hirshberg, MD, reported at the Pregnancy Meeting.
The text messaging system increased the compliance rate to 93%, compared with just 30% of those asked to return to the office after hospital discharge. Just as importantly, it completely erased racial disparity in compliance rates, compared with white women, with more than 90% of both groups complying, said Dr. Hirshberg of the University of Pennsylvania, Philadelphia.
“Our study shows that text-based monitoring eliminated the observed racial disparity in postpregnancy hypertension care,” she said at the meeting sponsored by the Society for Maternal-Fetal Medicine. “Using texts as a standard of care would have likely led to medication initiation or adjustment for an additional 20% or more women who missed an office visit. This is an innovative way to equally engage all women in the postpregnancy period.”
Dr. Hirshberg presented a preplanned subanalysis of the Remote Surveillance of Hypertension (TextBP) trial, published last year (BMJ Qual Saf. 2018;27:871-7). The publication gave overall data; this analysis broke results down by race.
TextBP equally randomized 206 postpartum women with pregnancy-induced hypertension to the usual practice of office-based BP monitoring, or to 2 weeks of text-based surveillance using a home BP cuff. It was open to all women with pregnancy-related hypertension who delivered in the Hospital of the University of Pennsylvania. Hypertension classes included gestational hypertension, preeclampsia, chronic hypertension with superimposed preeclampsia, and HELLP syndrome before or during the delivery admission. Women were randomized to usual care or to an office-based BP check within the first postpartum week.
The texting platform was developed through Way to Health, a web-based platform within the institution, with secure technological infrastructure. A starting introductory text message was sent by the Way to Health platform to the phone number provided on day of discharge.
Patients received reminders to text message their blood pressure twice daily for 2 weeks post partum, starting on the day after discharge. If the patient reported a systolic BP of more than 160 mm Hg or diastolic more than 110 mm Hg, the clinician received an alert.
The overall results showed that significantly more women in the texting group reported their blood pressure (92% vs. 44%), compared with the controls. Almost everyone in the texting group (84%) met the established criteria for BP measurement.
Dr. Hirshberg and her colleagues wanted to zero in on black women, to discover if the text reminders could help boost their compliance. This is important for a couple of reasons, she said. For one thing, black women face a higher baseline risk of hypertensive disorders and cardiovascular disease, both in general and during and after pregnancy. Second, “for every 100 black women who require postpartum hypertension surveillance, only about a third are likely to attended an office visit after discharge,” leaving them vulnerable to potentially preventable complications of hypertension.
Even in the original analysis, return rates for postpregnancy BP checks were low in both groups and, in fact, seemed to be declining over several years. In 2012, 56% of nonblack and 33% of black women returned for their checks. By 2014, that number had declined to 34% and 20%. The numbers parallel the increasing disparity in U.S. maternal death rate between black women and nonblack women. From 1989 to 2013, the death rate for black mothers doubled, jumping from 20 to 40 deaths per 100,000 live births. During the same period, the death rate for nonblack mothers increased from about 8 to about 11 per 10,000. Dr. Hirshberg said.
In the subanalysis, the primary outcomes were the percentage of patients in whom a blood pressure was obtained in the first 10 days following discharge. In the control office visit group, about 33% of black women had a measurement, compared with 70% of nonblack women – a significant difference. Text messaging, however, completely eliminated the disparity. In the texting group, 91% of nonblack women and 93% of black women had a BP measurement.
There were no hypertension readmissions in the texting arm; there were four in the office-visit arm, three of which occurred in black women.
“This suggests that the traditional office-based follow-up may have resulted in missed opportunities to start an antihypertensive in about 10 of the 55 women who missed their office visit,” Dr. Hirshberg said, adding that “these kinds of early interventions can reduce maternal morbidity and mortality and increase overall health in all.”
She reported no relevant financial disclosures.
SOURCE: Hirshberg A et al. Am J Obstet Gynecol. 2019 Jan;220(1):S6, Abstract 7.
LAS VEGAS – Adi Hirshberg, MD, reported at the Pregnancy Meeting.
The text messaging system increased the compliance rate to 93%, compared with just 30% of those asked to return to the office after hospital discharge. Just as importantly, it completely erased racial disparity in compliance rates, compared with white women, with more than 90% of both groups complying, said Dr. Hirshberg of the University of Pennsylvania, Philadelphia.
“Our study shows that text-based monitoring eliminated the observed racial disparity in postpregnancy hypertension care,” she said at the meeting sponsored by the Society for Maternal-Fetal Medicine. “Using texts as a standard of care would have likely led to medication initiation or adjustment for an additional 20% or more women who missed an office visit. This is an innovative way to equally engage all women in the postpregnancy period.”
Dr. Hirshberg presented a preplanned subanalysis of the Remote Surveillance of Hypertension (TextBP) trial, published last year (BMJ Qual Saf. 2018;27:871-7). The publication gave overall data; this analysis broke results down by race.
TextBP equally randomized 206 postpartum women with pregnancy-induced hypertension to the usual practice of office-based BP monitoring, or to 2 weeks of text-based surveillance using a home BP cuff. It was open to all women with pregnancy-related hypertension who delivered in the Hospital of the University of Pennsylvania. Hypertension classes included gestational hypertension, preeclampsia, chronic hypertension with superimposed preeclampsia, and HELLP syndrome before or during the delivery admission. Women were randomized to usual care or to an office-based BP check within the first postpartum week.
The texting platform was developed through Way to Health, a web-based platform within the institution, with secure technological infrastructure. A starting introductory text message was sent by the Way to Health platform to the phone number provided on day of discharge.
Patients received reminders to text message their blood pressure twice daily for 2 weeks post partum, starting on the day after discharge. If the patient reported a systolic BP of more than 160 mm Hg or diastolic more than 110 mm Hg, the clinician received an alert.
The overall results showed that significantly more women in the texting group reported their blood pressure (92% vs. 44%), compared with the controls. Almost everyone in the texting group (84%) met the established criteria for BP measurement.
Dr. Hirshberg and her colleagues wanted to zero in on black women, to discover if the text reminders could help boost their compliance. This is important for a couple of reasons, she said. For one thing, black women face a higher baseline risk of hypertensive disorders and cardiovascular disease, both in general and during and after pregnancy. Second, “for every 100 black women who require postpartum hypertension surveillance, only about a third are likely to attended an office visit after discharge,” leaving them vulnerable to potentially preventable complications of hypertension.
Even in the original analysis, return rates for postpregnancy BP checks were low in both groups and, in fact, seemed to be declining over several years. In 2012, 56% of nonblack and 33% of black women returned for their checks. By 2014, that number had declined to 34% and 20%. The numbers parallel the increasing disparity in U.S. maternal death rate between black women and nonblack women. From 1989 to 2013, the death rate for black mothers doubled, jumping from 20 to 40 deaths per 100,000 live births. During the same period, the death rate for nonblack mothers increased from about 8 to about 11 per 10,000. Dr. Hirshberg said.
In the subanalysis, the primary outcomes were the percentage of patients in whom a blood pressure was obtained in the first 10 days following discharge. In the control office visit group, about 33% of black women had a measurement, compared with 70% of nonblack women – a significant difference. Text messaging, however, completely eliminated the disparity. In the texting group, 91% of nonblack women and 93% of black women had a BP measurement.
There were no hypertension readmissions in the texting arm; there were four in the office-visit arm, three of which occurred in black women.
“This suggests that the traditional office-based follow-up may have resulted in missed opportunities to start an antihypertensive in about 10 of the 55 women who missed their office visit,” Dr. Hirshberg said, adding that “these kinds of early interventions can reduce maternal morbidity and mortality and increase overall health in all.”
She reported no relevant financial disclosures.
SOURCE: Hirshberg A et al. Am J Obstet Gynecol. 2019 Jan;220(1):S6, Abstract 7.
LAS VEGAS – Adi Hirshberg, MD, reported at the Pregnancy Meeting.
The text messaging system increased the compliance rate to 93%, compared with just 30% of those asked to return to the office after hospital discharge. Just as importantly, it completely erased racial disparity in compliance rates, compared with white women, with more than 90% of both groups complying, said Dr. Hirshberg of the University of Pennsylvania, Philadelphia.
“Our study shows that text-based monitoring eliminated the observed racial disparity in postpregnancy hypertension care,” she said at the meeting sponsored by the Society for Maternal-Fetal Medicine. “Using texts as a standard of care would have likely led to medication initiation or adjustment for an additional 20% or more women who missed an office visit. This is an innovative way to equally engage all women in the postpregnancy period.”
Dr. Hirshberg presented a preplanned subanalysis of the Remote Surveillance of Hypertension (TextBP) trial, published last year (BMJ Qual Saf. 2018;27:871-7). The publication gave overall data; this analysis broke results down by race.
TextBP equally randomized 206 postpartum women with pregnancy-induced hypertension to the usual practice of office-based BP monitoring, or to 2 weeks of text-based surveillance using a home BP cuff. It was open to all women with pregnancy-related hypertension who delivered in the Hospital of the University of Pennsylvania. Hypertension classes included gestational hypertension, preeclampsia, chronic hypertension with superimposed preeclampsia, and HELLP syndrome before or during the delivery admission. Women were randomized to usual care or to an office-based BP check within the first postpartum week.
The texting platform was developed through Way to Health, a web-based platform within the institution, with secure technological infrastructure. A starting introductory text message was sent by the Way to Health platform to the phone number provided on day of discharge.
Patients received reminders to text message their blood pressure twice daily for 2 weeks post partum, starting on the day after discharge. If the patient reported a systolic BP of more than 160 mm Hg or diastolic more than 110 mm Hg, the clinician received an alert.
The overall results showed that significantly more women in the texting group reported their blood pressure (92% vs. 44%), compared with the controls. Almost everyone in the texting group (84%) met the established criteria for BP measurement.
Dr. Hirshberg and her colleagues wanted to zero in on black women, to discover if the text reminders could help boost their compliance. This is important for a couple of reasons, she said. For one thing, black women face a higher baseline risk of hypertensive disorders and cardiovascular disease, both in general and during and after pregnancy. Second, “for every 100 black women who require postpartum hypertension surveillance, only about a third are likely to attended an office visit after discharge,” leaving them vulnerable to potentially preventable complications of hypertension.
Even in the original analysis, return rates for postpregnancy BP checks were low in both groups and, in fact, seemed to be declining over several years. In 2012, 56% of nonblack and 33% of black women returned for their checks. By 2014, that number had declined to 34% and 20%. The numbers parallel the increasing disparity in U.S. maternal death rate between black women and nonblack women. From 1989 to 2013, the death rate for black mothers doubled, jumping from 20 to 40 deaths per 100,000 live births. During the same period, the death rate for nonblack mothers increased from about 8 to about 11 per 10,000. Dr. Hirshberg said.
In the subanalysis, the primary outcomes were the percentage of patients in whom a blood pressure was obtained in the first 10 days following discharge. In the control office visit group, about 33% of black women had a measurement, compared with 70% of nonblack women – a significant difference. Text messaging, however, completely eliminated the disparity. In the texting group, 91% of nonblack women and 93% of black women had a BP measurement.
There were no hypertension readmissions in the texting arm; there were four in the office-visit arm, three of which occurred in black women.
“This suggests that the traditional office-based follow-up may have resulted in missed opportunities to start an antihypertensive in about 10 of the 55 women who missed their office visit,” Dr. Hirshberg said, adding that “these kinds of early interventions can reduce maternal morbidity and mortality and increase overall health in all.”
She reported no relevant financial disclosures.
SOURCE: Hirshberg A et al. Am J Obstet Gynecol. 2019 Jan;220(1):S6, Abstract 7.
REPORTING FROM THE PREGNANCY MEETING
Selinexor hits FDA stumbling block
Karyopharm Therapeutics must finish a randomized phase 3 trial of selinexor plus dexamethasone before the Food and Drug Administration will proceed with a safety and tolerability assessment for the first-in-class multiple myeloma drug.
By an 8-5 vote, the FDA Oncologic Drugs Advisory Committee said that data from STORM 2, Karyopharm’s single-arm phase 2b trial, didn’t sufficiently show that selinexor exerted any significant benefit over dexamethasone alone, used because the company claims it potentiates selinexor’s action.
Committee members also expressed concerns about the drug’s challenging adverse event profile. In STORM Part 2, 60% of patients experienced serious treatment-emergent adverse events and 10 died from them.
“This trial design is not adequate to assess tolerability and efficacy,” and move the drug along, said Christian S. Hinrichs, MD, of the National Cancer Institute. For that to happen, “we’d be looking for several things. We’d be looking for a subset of patients who benefited profoundly, which could be somewhat compelling despite a lower overall response rate. Next we might be looking for durable response, and here we see 4-month responses. And finally, what we look for in a single-arm trial is a really favorable side effect profile, like we see in checkpoint inhibitors. That is clearly not the case with this drug. So, on the basis of both the trial design and the results, I find it hard to conclude that these data allow for an adequate assessment that safety and efficacy are proven.”
The decision came despite the pleas of 15 patients and one patient advocate who said the drug improved clinical status and quality of life, and even extended life beyond what anyone expected. However, several committee members noted that Karyopharm paid for speakers’ travel and that patients who had negative experiences would probably be too sick to attend.
Selinexor is a completely new therapeutic option for relapsed multiple myeloma patients. It is a twice-weekly, oral tablet that inhibits nuclear export protein Exportin 1 (XPO1), which regulates the localization of tumor suppressor proteins and is associated with poor prognosis. Aberrant XPO1 expression causes tumor suppressors to locate away from their targets, allowing tumors to grow. Inhibiting it with selinexor blocks signal transduction pathways, interrupting tumor cell proliferation and inducing apoptosis while sparing normal cells.
Karyopharm is seeking approval of selinexor in combination with low-dose dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor, at least one immunomodulatory imide drug, and an anti-CD38 monoclonal antibody.
This disease is referred to as “triple-class refractory” multiple myeloma. At this stage, patients have exhausted every effective treatment option and are faced with the choice of supportive care or recycling previously successful drugs. Their median overall survival time is 3-5 months.
Karyopharm submitted its the New Drug Application using the Accelerated Approval pathway, arguing that the drug meets an unmet medical need and can be approved on surrogate endpoints – in this case, overall response rate.
The modified intent-to-treat analysis comprised 122 patients. The overall response rate was 25.4% with a median response duration of 4.4 months. Two patients had a complete response; six had a very good partial response; and 23 had a partial response.
Some committee members, however, said it would be impossible to tease out how much of the response could be due to the co-administration of 20 mg dexamethasone with each dose. In a phase 1 dose-ranging study of selinexor as monotherapy, it produced only one partial response in 56 patients. And, FDA pointed out, historical studies have shown response rates of 10%-27% for high-dose dexamethasone.
However, those in favor of the drug pointed out that the STORM patients were steroid-refractory, and that a 25% response rate would be unlikely on low-dose dexamethasone alone. This is proof of the company’s claim that the steroid works synergistically with selinexor, they said.
These members also pointed out that even a few years ago, there simply were no patients like the STORM cohort. Only recently have these patients lived long enough to develop resistance against all therapeutic lines, so it’s unrealistic to use historical data to judge what a reasonable response rate looks like in this situation.
Committee members also choked on STORM’s adverse event (AE) profile. All patients experienced at least one treatment-emergent AE, and 60% had at least one serious AE. Most (88.6%) required a dose modification due to an AE, and 28.5% discontinued due to one. The most common AEs were thrombocytopenia, anemia, nausea, fatigue, and decreased appetite. The company said these were “typically reversible and manageable with dose reductions.”
Additionally, there were 23 deaths in the trial. About half (13) were due to disease progression, but the remainder were due to a fatal treatment-emergent AE. Two of these (one pneumonia and one sepsis) were directly due to selinexor, the company said.
Despite the committee’s concerns, 16 of the 17 speakers described positive experiences with selinexor. They universally acknowledged that “it’s a hard drug to take,” and that side effects need to be managed proactively. But they also said, universally, that the drug has brought them additional months of good-quality life, decreased lengthy hospital stays, enabled them to participate in important family events, and even travel. Some also expressed the hope that selinexor would be a bridge drug, decreasing their disease burden enough that they could qualify for other clinical trials of new investigational drugs.
Only Stephanie Fox-Rawlings, PhD, of the National Center for Health Research, urged a delay. “Even if these adverse events are manageable, they harm patients’ quality of life,” she said. “This may be acceptable to some, but if the drug can’t provide a meaningful benefit then they are not worth it and in this clinical trial there was no improvement noted in quality of life. This drug has serious risks and we don’t know if it works.”
Dr. Fox said she was “very glad” that Karyopharm has completed recruitment for its phase 3 randomized study, dubbed BOSTON. BOSTON will assign active patients to once-weekly 100 mg selinexor plus weight-dosed bortezomib, plus twice-weekly 20 mg dexamethasone. The comparator group will receive weight-based bortezomib twice a week and 20 mg dexamethasone four times a week. Patients who progress can cross over to the active arm. The company hopes for even better results, saying that the proteasome inhibitor has also shown a synergistic effect with selinexor. Results are expected in 2020.
“The BOSTON study doesn’t solve anything,” retorted committee member David Harrington, PhD, emeritus professor of biostatistics at the Dana-Farber Cancer Institute. “It’s a different clinical profile, different dosing, a different combination of agents, and it doesn’t isolate the single-arm activity of selinexor.”
Karyopharm Therapeutics must finish a randomized phase 3 trial of selinexor plus dexamethasone before the Food and Drug Administration will proceed with a safety and tolerability assessment for the first-in-class multiple myeloma drug.
By an 8-5 vote, the FDA Oncologic Drugs Advisory Committee said that data from STORM 2, Karyopharm’s single-arm phase 2b trial, didn’t sufficiently show that selinexor exerted any significant benefit over dexamethasone alone, used because the company claims it potentiates selinexor’s action.
Committee members also expressed concerns about the drug’s challenging adverse event profile. In STORM Part 2, 60% of patients experienced serious treatment-emergent adverse events and 10 died from them.
“This trial design is not adequate to assess tolerability and efficacy,” and move the drug along, said Christian S. Hinrichs, MD, of the National Cancer Institute. For that to happen, “we’d be looking for several things. We’d be looking for a subset of patients who benefited profoundly, which could be somewhat compelling despite a lower overall response rate. Next we might be looking for durable response, and here we see 4-month responses. And finally, what we look for in a single-arm trial is a really favorable side effect profile, like we see in checkpoint inhibitors. That is clearly not the case with this drug. So, on the basis of both the trial design and the results, I find it hard to conclude that these data allow for an adequate assessment that safety and efficacy are proven.”
The decision came despite the pleas of 15 patients and one patient advocate who said the drug improved clinical status and quality of life, and even extended life beyond what anyone expected. However, several committee members noted that Karyopharm paid for speakers’ travel and that patients who had negative experiences would probably be too sick to attend.
Selinexor is a completely new therapeutic option for relapsed multiple myeloma patients. It is a twice-weekly, oral tablet that inhibits nuclear export protein Exportin 1 (XPO1), which regulates the localization of tumor suppressor proteins and is associated with poor prognosis. Aberrant XPO1 expression causes tumor suppressors to locate away from their targets, allowing tumors to grow. Inhibiting it with selinexor blocks signal transduction pathways, interrupting tumor cell proliferation and inducing apoptosis while sparing normal cells.
Karyopharm is seeking approval of selinexor in combination with low-dose dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor, at least one immunomodulatory imide drug, and an anti-CD38 monoclonal antibody.
This disease is referred to as “triple-class refractory” multiple myeloma. At this stage, patients have exhausted every effective treatment option and are faced with the choice of supportive care or recycling previously successful drugs. Their median overall survival time is 3-5 months.
Karyopharm submitted its the New Drug Application using the Accelerated Approval pathway, arguing that the drug meets an unmet medical need and can be approved on surrogate endpoints – in this case, overall response rate.
The modified intent-to-treat analysis comprised 122 patients. The overall response rate was 25.4% with a median response duration of 4.4 months. Two patients had a complete response; six had a very good partial response; and 23 had a partial response.
Some committee members, however, said it would be impossible to tease out how much of the response could be due to the co-administration of 20 mg dexamethasone with each dose. In a phase 1 dose-ranging study of selinexor as monotherapy, it produced only one partial response in 56 patients. And, FDA pointed out, historical studies have shown response rates of 10%-27% for high-dose dexamethasone.
However, those in favor of the drug pointed out that the STORM patients were steroid-refractory, and that a 25% response rate would be unlikely on low-dose dexamethasone alone. This is proof of the company’s claim that the steroid works synergistically with selinexor, they said.
These members also pointed out that even a few years ago, there simply were no patients like the STORM cohort. Only recently have these patients lived long enough to develop resistance against all therapeutic lines, so it’s unrealistic to use historical data to judge what a reasonable response rate looks like in this situation.
Committee members also choked on STORM’s adverse event (AE) profile. All patients experienced at least one treatment-emergent AE, and 60% had at least one serious AE. Most (88.6%) required a dose modification due to an AE, and 28.5% discontinued due to one. The most common AEs were thrombocytopenia, anemia, nausea, fatigue, and decreased appetite. The company said these were “typically reversible and manageable with dose reductions.”
Additionally, there were 23 deaths in the trial. About half (13) were due to disease progression, but the remainder were due to a fatal treatment-emergent AE. Two of these (one pneumonia and one sepsis) were directly due to selinexor, the company said.
Despite the committee’s concerns, 16 of the 17 speakers described positive experiences with selinexor. They universally acknowledged that “it’s a hard drug to take,” and that side effects need to be managed proactively. But they also said, universally, that the drug has brought them additional months of good-quality life, decreased lengthy hospital stays, enabled them to participate in important family events, and even travel. Some also expressed the hope that selinexor would be a bridge drug, decreasing their disease burden enough that they could qualify for other clinical trials of new investigational drugs.
Only Stephanie Fox-Rawlings, PhD, of the National Center for Health Research, urged a delay. “Even if these adverse events are manageable, they harm patients’ quality of life,” she said. “This may be acceptable to some, but if the drug can’t provide a meaningful benefit then they are not worth it and in this clinical trial there was no improvement noted in quality of life. This drug has serious risks and we don’t know if it works.”
Dr. Fox said she was “very glad” that Karyopharm has completed recruitment for its phase 3 randomized study, dubbed BOSTON. BOSTON will assign active patients to once-weekly 100 mg selinexor plus weight-dosed bortezomib, plus twice-weekly 20 mg dexamethasone. The comparator group will receive weight-based bortezomib twice a week and 20 mg dexamethasone four times a week. Patients who progress can cross over to the active arm. The company hopes for even better results, saying that the proteasome inhibitor has also shown a synergistic effect with selinexor. Results are expected in 2020.
“The BOSTON study doesn’t solve anything,” retorted committee member David Harrington, PhD, emeritus professor of biostatistics at the Dana-Farber Cancer Institute. “It’s a different clinical profile, different dosing, a different combination of agents, and it doesn’t isolate the single-arm activity of selinexor.”
Karyopharm Therapeutics must finish a randomized phase 3 trial of selinexor plus dexamethasone before the Food and Drug Administration will proceed with a safety and tolerability assessment for the first-in-class multiple myeloma drug.
By an 8-5 vote, the FDA Oncologic Drugs Advisory Committee said that data from STORM 2, Karyopharm’s single-arm phase 2b trial, didn’t sufficiently show that selinexor exerted any significant benefit over dexamethasone alone, used because the company claims it potentiates selinexor’s action.
Committee members also expressed concerns about the drug’s challenging adverse event profile. In STORM Part 2, 60% of patients experienced serious treatment-emergent adverse events and 10 died from them.
“This trial design is not adequate to assess tolerability and efficacy,” and move the drug along, said Christian S. Hinrichs, MD, of the National Cancer Institute. For that to happen, “we’d be looking for several things. We’d be looking for a subset of patients who benefited profoundly, which could be somewhat compelling despite a lower overall response rate. Next we might be looking for durable response, and here we see 4-month responses. And finally, what we look for in a single-arm trial is a really favorable side effect profile, like we see in checkpoint inhibitors. That is clearly not the case with this drug. So, on the basis of both the trial design and the results, I find it hard to conclude that these data allow for an adequate assessment that safety and efficacy are proven.”
The decision came despite the pleas of 15 patients and one patient advocate who said the drug improved clinical status and quality of life, and even extended life beyond what anyone expected. However, several committee members noted that Karyopharm paid for speakers’ travel and that patients who had negative experiences would probably be too sick to attend.
Selinexor is a completely new therapeutic option for relapsed multiple myeloma patients. It is a twice-weekly, oral tablet that inhibits nuclear export protein Exportin 1 (XPO1), which regulates the localization of tumor suppressor proteins and is associated with poor prognosis. Aberrant XPO1 expression causes tumor suppressors to locate away from their targets, allowing tumors to grow. Inhibiting it with selinexor blocks signal transduction pathways, interrupting tumor cell proliferation and inducing apoptosis while sparing normal cells.
Karyopharm is seeking approval of selinexor in combination with low-dose dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor, at least one immunomodulatory imide drug, and an anti-CD38 monoclonal antibody.
This disease is referred to as “triple-class refractory” multiple myeloma. At this stage, patients have exhausted every effective treatment option and are faced with the choice of supportive care or recycling previously successful drugs. Their median overall survival time is 3-5 months.
Karyopharm submitted its the New Drug Application using the Accelerated Approval pathway, arguing that the drug meets an unmet medical need and can be approved on surrogate endpoints – in this case, overall response rate.
The modified intent-to-treat analysis comprised 122 patients. The overall response rate was 25.4% with a median response duration of 4.4 months. Two patients had a complete response; six had a very good partial response; and 23 had a partial response.
Some committee members, however, said it would be impossible to tease out how much of the response could be due to the co-administration of 20 mg dexamethasone with each dose. In a phase 1 dose-ranging study of selinexor as monotherapy, it produced only one partial response in 56 patients. And, FDA pointed out, historical studies have shown response rates of 10%-27% for high-dose dexamethasone.
However, those in favor of the drug pointed out that the STORM patients were steroid-refractory, and that a 25% response rate would be unlikely on low-dose dexamethasone alone. This is proof of the company’s claim that the steroid works synergistically with selinexor, they said.
These members also pointed out that even a few years ago, there simply were no patients like the STORM cohort. Only recently have these patients lived long enough to develop resistance against all therapeutic lines, so it’s unrealistic to use historical data to judge what a reasonable response rate looks like in this situation.
Committee members also choked on STORM’s adverse event (AE) profile. All patients experienced at least one treatment-emergent AE, and 60% had at least one serious AE. Most (88.6%) required a dose modification due to an AE, and 28.5% discontinued due to one. The most common AEs were thrombocytopenia, anemia, nausea, fatigue, and decreased appetite. The company said these were “typically reversible and manageable with dose reductions.”
Additionally, there were 23 deaths in the trial. About half (13) were due to disease progression, but the remainder were due to a fatal treatment-emergent AE. Two of these (one pneumonia and one sepsis) were directly due to selinexor, the company said.
Despite the committee’s concerns, 16 of the 17 speakers described positive experiences with selinexor. They universally acknowledged that “it’s a hard drug to take,” and that side effects need to be managed proactively. But they also said, universally, that the drug has brought them additional months of good-quality life, decreased lengthy hospital stays, enabled them to participate in important family events, and even travel. Some also expressed the hope that selinexor would be a bridge drug, decreasing their disease burden enough that they could qualify for other clinical trials of new investigational drugs.
Only Stephanie Fox-Rawlings, PhD, of the National Center for Health Research, urged a delay. “Even if these adverse events are manageable, they harm patients’ quality of life,” she said. “This may be acceptable to some, but if the drug can’t provide a meaningful benefit then they are not worth it and in this clinical trial there was no improvement noted in quality of life. This drug has serious risks and we don’t know if it works.”
Dr. Fox said she was “very glad” that Karyopharm has completed recruitment for its phase 3 randomized study, dubbed BOSTON. BOSTON will assign active patients to once-weekly 100 mg selinexor plus weight-dosed bortezomib, plus twice-weekly 20 mg dexamethasone. The comparator group will receive weight-based bortezomib twice a week and 20 mg dexamethasone four times a week. Patients who progress can cross over to the active arm. The company hopes for even better results, saying that the proteasome inhibitor has also shown a synergistic effect with selinexor. Results are expected in 2020.
“The BOSTON study doesn’t solve anything,” retorted committee member David Harrington, PhD, emeritus professor of biostatistics at the Dana-Farber Cancer Institute. “It’s a different clinical profile, different dosing, a different combination of agents, and it doesn’t isolate the single-arm activity of selinexor.”
FDA: More safety data needed for 12 sunscreen active ingredients
including some of those frequently used in over-the-counter products.
The ingredients requiring additional investigation are cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone. The FDA actions were announced during a press briefing Feb. 21 held to discuss the proposed rule to update regulatory requirements for most sunscreen products marketed in the United States.
There are no urgent safety matters associated with these ingredients. The rule is part of FDA’s charge to construct an over-the-counter (OTC) monograph detailing all available data on sunscreen ingredients, as required by the Sunscreen Innovation Act.
OTC monographs establish conditions under which ingredients may be marketed without approved new drug applications because they are generally recognized as safe and effective (GRASE) “and not misbranded,” according to the FDA. The proposed rule classifies active ingredients and other conditions as Category I (proposed to be GRASE and not misbranded), Category II (proposed to be not GRASE or to be misbranded), or Category III (additional data needed).
“We are proposing that these ingredients require additional data before a positive GRASE determination can be made,” FDA press officer Sandy Walsh said in an interview, referring to the 12 ingredients. “This proposed rule does not represent a conclusion by the FDA that the sunscreen active ingredients proposed as having insufficient data are unsafe for use in sunscreens. Rather, we are requesting additional information on these ingredients so that we can evaluate their GRASE status in light of changed conditions, including substantially increased sunscreen usage and evolving information about the potential risks associated with these products since they were originally evaluated.”
Among its provisions, the proposal addresses sunscreen active-ingredient safety, dosage forms, and sun protection factor (SPF) and broad-spectrum requirements. It also proposes updates to how products are labeled to make it easier for consumers to identify key product information
Thus far, the agency says that only two active ingredients – titanium dioxide and zinc oxide – can be marketed without approved new drug applications because they are GRASE.
However, two other ingredients – PABA and trolamine salicylate – are not GRASE for use in sunscreens because of safety issues, Theresa Michele, MD, director of the Division of Nonprescription Drug Products Division of Nonprescription Drug Products in the FDA’s Center for Drug Evaluation and Research. Products that combine sunscreen and insect repellent also not fit the criteria, she said
“There are 12 ingredients for which there are insufficient safety data to make a positive GRASE determination at this time. To address these 12 ingredients, the FDA is asking industry and other interested parties for additional data. The FDA is working closely with industry and has published several guidances to make sure companies understand what data the agency believes is necessary for the FDA to evaluate safety and effectiveness for sunscreen active ingredients, including the 12 ingredients for which the FDA is seeking more data,” she said.
In addition to seeking these additional data, the rule also proposes the following:
- Dosage forms that are GRASE for use as sunscreens should include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. While powders are proposed to be eligible for inclusion in the monograph, more data are being requested before powders are included. “Wipes, towelettes, body washes, shampoos, and other dosage forms are proposed to be categorized as new drugs because the FDA has not received data showing they are eligible for inclusion in the monograph,” according to the FDA statement outlining the proposed regulation.
- The maximum proposed SPF value on sunscreen labels should be raised from SPF 50 or higher to SPF 60 or higher. “There are not enough data to suggest that consumers get any extra benefit from products with an SPF of more than 60,” Dr. Michele said.
- Sunscreens with an SPF value of 15 or higher should be required to also provide broad-spectrum protection, and for broad-spectrum products, as SPF increases, the magnitude of protection against UVA radiation should also increase. “These proposals are designed to ensure that these products provide consumers with the protections that they expect,” the statement said.
- New sunscreen product labels should be required to make it easier for consumers to identify important information, “including the addition of the active ingredients on the front of the package to bring sunscreen in line with other OTC drugs; a notification on the front label for consumers to read the skin cancer/skin aging alert for sunscreens that have not been shown to help prevent skin cancer; and revised formats for SPF, broad spectrum, and water resistance statements,” the statement said.
- Products that combine sunscreens with insect repellents are not GRASE.
In the meantime, though, consumers should continue to use sunscreens regularly as part of a comprehensive sun protection program, FDA Commissioner Scott Gottlieb, MD, said during the briefing. “Broad spectrum sunscreens with SPF values of at least 15 are critical to the arsenal of tools for preventing skin cancer and protecting the skin from damage caused by the sun’s rays,” he continued. “Given the recognized public health benefits of sunscreen use, Americans should continue to use sunscreens in conjunction with other sun protective measures (such as protective clothing) as this important rule-making effort moves forward.”
To submit comments on this proposed rule, go to https://www.regulations.gov and follow instructions for submitting comments.
including some of those frequently used in over-the-counter products.
The ingredients requiring additional investigation are cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone. The FDA actions were announced during a press briefing Feb. 21 held to discuss the proposed rule to update regulatory requirements for most sunscreen products marketed in the United States.
There are no urgent safety matters associated with these ingredients. The rule is part of FDA’s charge to construct an over-the-counter (OTC) monograph detailing all available data on sunscreen ingredients, as required by the Sunscreen Innovation Act.
OTC monographs establish conditions under which ingredients may be marketed without approved new drug applications because they are generally recognized as safe and effective (GRASE) “and not misbranded,” according to the FDA. The proposed rule classifies active ingredients and other conditions as Category I (proposed to be GRASE and not misbranded), Category II (proposed to be not GRASE or to be misbranded), or Category III (additional data needed).
“We are proposing that these ingredients require additional data before a positive GRASE determination can be made,” FDA press officer Sandy Walsh said in an interview, referring to the 12 ingredients. “This proposed rule does not represent a conclusion by the FDA that the sunscreen active ingredients proposed as having insufficient data are unsafe for use in sunscreens. Rather, we are requesting additional information on these ingredients so that we can evaluate their GRASE status in light of changed conditions, including substantially increased sunscreen usage and evolving information about the potential risks associated with these products since they were originally evaluated.”
Among its provisions, the proposal addresses sunscreen active-ingredient safety, dosage forms, and sun protection factor (SPF) and broad-spectrum requirements. It also proposes updates to how products are labeled to make it easier for consumers to identify key product information
Thus far, the agency says that only two active ingredients – titanium dioxide and zinc oxide – can be marketed without approved new drug applications because they are GRASE.
However, two other ingredients – PABA and trolamine salicylate – are not GRASE for use in sunscreens because of safety issues, Theresa Michele, MD, director of the Division of Nonprescription Drug Products Division of Nonprescription Drug Products in the FDA’s Center for Drug Evaluation and Research. Products that combine sunscreen and insect repellent also not fit the criteria, she said
“There are 12 ingredients for which there are insufficient safety data to make a positive GRASE determination at this time. To address these 12 ingredients, the FDA is asking industry and other interested parties for additional data. The FDA is working closely with industry and has published several guidances to make sure companies understand what data the agency believes is necessary for the FDA to evaluate safety and effectiveness for sunscreen active ingredients, including the 12 ingredients for which the FDA is seeking more data,” she said.
In addition to seeking these additional data, the rule also proposes the following:
- Dosage forms that are GRASE for use as sunscreens should include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. While powders are proposed to be eligible for inclusion in the monograph, more data are being requested before powders are included. “Wipes, towelettes, body washes, shampoos, and other dosage forms are proposed to be categorized as new drugs because the FDA has not received data showing they are eligible for inclusion in the monograph,” according to the FDA statement outlining the proposed regulation.
- The maximum proposed SPF value on sunscreen labels should be raised from SPF 50 or higher to SPF 60 or higher. “There are not enough data to suggest that consumers get any extra benefit from products with an SPF of more than 60,” Dr. Michele said.
- Sunscreens with an SPF value of 15 or higher should be required to also provide broad-spectrum protection, and for broad-spectrum products, as SPF increases, the magnitude of protection against UVA radiation should also increase. “These proposals are designed to ensure that these products provide consumers with the protections that they expect,” the statement said.
- New sunscreen product labels should be required to make it easier for consumers to identify important information, “including the addition of the active ingredients on the front of the package to bring sunscreen in line with other OTC drugs; a notification on the front label for consumers to read the skin cancer/skin aging alert for sunscreens that have not been shown to help prevent skin cancer; and revised formats for SPF, broad spectrum, and water resistance statements,” the statement said.
- Products that combine sunscreens with insect repellents are not GRASE.
In the meantime, though, consumers should continue to use sunscreens regularly as part of a comprehensive sun protection program, FDA Commissioner Scott Gottlieb, MD, said during the briefing. “Broad spectrum sunscreens with SPF values of at least 15 are critical to the arsenal of tools for preventing skin cancer and protecting the skin from damage caused by the sun’s rays,” he continued. “Given the recognized public health benefits of sunscreen use, Americans should continue to use sunscreens in conjunction with other sun protective measures (such as protective clothing) as this important rule-making effort moves forward.”
To submit comments on this proposed rule, go to https://www.regulations.gov and follow instructions for submitting comments.
including some of those frequently used in over-the-counter products.
The ingredients requiring additional investigation are cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone. The FDA actions were announced during a press briefing Feb. 21 held to discuss the proposed rule to update regulatory requirements for most sunscreen products marketed in the United States.
There are no urgent safety matters associated with these ingredients. The rule is part of FDA’s charge to construct an over-the-counter (OTC) monograph detailing all available data on sunscreen ingredients, as required by the Sunscreen Innovation Act.
OTC monographs establish conditions under which ingredients may be marketed without approved new drug applications because they are generally recognized as safe and effective (GRASE) “and not misbranded,” according to the FDA. The proposed rule classifies active ingredients and other conditions as Category I (proposed to be GRASE and not misbranded), Category II (proposed to be not GRASE or to be misbranded), or Category III (additional data needed).
“We are proposing that these ingredients require additional data before a positive GRASE determination can be made,” FDA press officer Sandy Walsh said in an interview, referring to the 12 ingredients. “This proposed rule does not represent a conclusion by the FDA that the sunscreen active ingredients proposed as having insufficient data are unsafe for use in sunscreens. Rather, we are requesting additional information on these ingredients so that we can evaluate their GRASE status in light of changed conditions, including substantially increased sunscreen usage and evolving information about the potential risks associated with these products since they were originally evaluated.”
Among its provisions, the proposal addresses sunscreen active-ingredient safety, dosage forms, and sun protection factor (SPF) and broad-spectrum requirements. It also proposes updates to how products are labeled to make it easier for consumers to identify key product information
Thus far, the agency says that only two active ingredients – titanium dioxide and zinc oxide – can be marketed without approved new drug applications because they are GRASE.
However, two other ingredients – PABA and trolamine salicylate – are not GRASE for use in sunscreens because of safety issues, Theresa Michele, MD, director of the Division of Nonprescription Drug Products Division of Nonprescription Drug Products in the FDA’s Center for Drug Evaluation and Research. Products that combine sunscreen and insect repellent also not fit the criteria, she said
“There are 12 ingredients for which there are insufficient safety data to make a positive GRASE determination at this time. To address these 12 ingredients, the FDA is asking industry and other interested parties for additional data. The FDA is working closely with industry and has published several guidances to make sure companies understand what data the agency believes is necessary for the FDA to evaluate safety and effectiveness for sunscreen active ingredients, including the 12 ingredients for which the FDA is seeking more data,” she said.
In addition to seeking these additional data, the rule also proposes the following:
- Dosage forms that are GRASE for use as sunscreens should include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. While powders are proposed to be eligible for inclusion in the monograph, more data are being requested before powders are included. “Wipes, towelettes, body washes, shampoos, and other dosage forms are proposed to be categorized as new drugs because the FDA has not received data showing they are eligible for inclusion in the monograph,” according to the FDA statement outlining the proposed regulation.
- The maximum proposed SPF value on sunscreen labels should be raised from SPF 50 or higher to SPF 60 or higher. “There are not enough data to suggest that consumers get any extra benefit from products with an SPF of more than 60,” Dr. Michele said.
- Sunscreens with an SPF value of 15 or higher should be required to also provide broad-spectrum protection, and for broad-spectrum products, as SPF increases, the magnitude of protection against UVA radiation should also increase. “These proposals are designed to ensure that these products provide consumers with the protections that they expect,” the statement said.
- New sunscreen product labels should be required to make it easier for consumers to identify important information, “including the addition of the active ingredients on the front of the package to bring sunscreen in line with other OTC drugs; a notification on the front label for consumers to read the skin cancer/skin aging alert for sunscreens that have not been shown to help prevent skin cancer; and revised formats for SPF, broad spectrum, and water resistance statements,” the statement said.
- Products that combine sunscreens with insect repellents are not GRASE.
In the meantime, though, consumers should continue to use sunscreens regularly as part of a comprehensive sun protection program, FDA Commissioner Scott Gottlieb, MD, said during the briefing. “Broad spectrum sunscreens with SPF values of at least 15 are critical to the arsenal of tools for preventing skin cancer and protecting the skin from damage caused by the sun’s rays,” he continued. “Given the recognized public health benefits of sunscreen use, Americans should continue to use sunscreens in conjunction with other sun protective measures (such as protective clothing) as this important rule-making effort moves forward.”
To submit comments on this proposed rule, go to https://www.regulations.gov and follow instructions for submitting comments.