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at 31 treatment centers in North America and Europe.
Children younger than 6 years with moderate to severe AD have few options if their symptoms are uncontrolled with topical therapies, and persistent itchiness has a negative impact on quality of life for patients and families, Amy S. Paller, MD, professor and chair of dermatology, and professor of pediatrics at Northwestern University, Chicago, and colleagues wrote in the study, published in the Lancet.
The study was the basis of the Food and Drug Administration expanded approval of dupilumab in June 2022, to include children aged 6 months to 5 years with moderate to severe AD, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Regulatory submission for this age group is under review by the European Medicines Agency, and by regulatory authorities in other countries, according to the manufacturers.
Dupilumab (Dupixent), which inhibits the signaling of the interleukin-4 and IL-13 pathways, was first approved in 2017 for treating adults with moderate to severe AD.
“There has not been a biologic approved before at such a young age, and for such a common disease,” Dr. Paller said in an interview. “This is the drug that has revolutionized care of the most common inflammatory skin disease in children, and this is the pivotal study that brought it to market for the youngest children who suffer from the severe forms.”
The study also sets a precedent for a lower threshold for starting systemic medication in young children for treating moderate to severe disease given the absence of severe side effects and no need for lab monitoring, Dr. Paller noted. However, dupilumab will also be closely watched “for both impact on the developing immune system and the possibility that it will alter the long-term course of the eczema and the development of allergic comorbidities, such as lowering the risk of developing asthma, GI, allergy, and possibly other conditions.”
In the study, the researchers randomized 83 children aged 6 months up to 6 years to treatment with dupilumab, administered subcutaneously, and 79 to placebo every 4 weeks for 16 weeks; both groups also received topical corticosteroids. Dosage of dupilumab was based on body weight; those with a body weight of 5-15 kg received 200 mg, while those with a body weight of 15-30 kg received 300 mg. The primary endpoint was the proportion of patients with clear or almost clear skin at 16 weeks, defined as scores of 0 or 1 on the Investigator’s Global Assessment.
After 16 weeks, 28% of dupilumab patients met the primary endpoint versus 4% of those on placebo (P < .0001). In addition, 53% of dupilumab patients met the key secondary endpoint of a 75% improvement from baseline in Eczema Area and Severity Index, compared with 11% of patients on placebo (P < .0001). Treatment with dupilumab also resulted in significantly greater improvements in pruritus and skin pain, and sleep quality, as well as improved quality of life for patients and their caregivers, the authors reported.
Overall, adverse event rates were slightly lower in the dupilumab-treated patients, compared with patients on placebo (64% vs. 74%); there were no adverse events related to dupilumab that were serious or resulted in treatment discontinuation. Treatment-emergent adverse effects that were reported in 3% or more of patients and affected more of those on dupilumab than those on placebo included molluscum contagiosum (5% vs. 3%), viral gastroenteritis (4% vs. 0), rhinorrhea (5% vs. 1%), dental caries (5% vs. 0), and conjunctivitis (4% vs 0).
The rate of skin infections among the children on dupilumab was 12% vs. 24% among those on placebo.
Severe and treatment-related adverse events also were similar in both subgroups of body weight.
The findings were limited by the small number of patients younger than 2 years and the lack of study sites outside of North America and Europe, the researchers noted. However, the results were strengthened by the randomized, double-blind design and use of background topical therapy to provide a real-world safety and efficacy assessment in a very young population.
Overcoming injection issues
The safety profile for dupilumab, which is of the highest importance, “did not surprise me at all,” Dr. Paller said in an interview. “My only surprise is that the placebo injections actually led to more injection site reactions than [with] dupilumab, but numbers were quite low in both groups.” (Rates were 2% among those on dupilumab and 3% among those on placebo.)
The major barrier to the use of dupilumab in clinical practice is the requirement for injection, which, she explained, can be “unbearable for some young children, and thus becomes impossible for parents because of lack of cooperation and their intensified concern about giving the injection,” because of their child’s response.
“We like to administer the first dose in the office, allowing us to teach parents a few tricks related to proper technique,” including audio and visual distraction, tactile stimulation before and during the injection, use of topical anesthetic if helpful, “and making sure that the medication is at room temperature before administration,” she said. Cost is another potential barrier; however, even public insurance has been covering the medication, often after optimized use of topical medications has been unsuccessful.
Future research questions
As for additional research, the current study had a relatively small number of patients younger than 2 years, and more data are needed for this age group, said Dr. Paller. “We also need better understanding of the safety of dupilumab administration when live vaccines are administered. Finally, we certainly want to know what additional effects dupilumab may have beyond just the efficacy for treating eczema.”
In particular, these questions include whether dupilumab modifies the long-term course of the disease, possibly reducing the risk of persistence of disease with advancing age, or even cures the disease if started at a young age, she said. In addition, research has yet to show whether dupilumab might reduce the risk of other atopic disorders, such as asthma, food allergy, and allergic rhinitis.
“Ongoing studies and real-life experiences in the next several years will help us to answer these questions,” Dr. Paller said.
Data support safety, efficacy, quality of life
AD is associated with immense quality of life impairment, Raj Chovatiya, MD, of Northwestern University, Chicago, said in an interview. Most AD is initially diagnosed in early childhood, but previous treatment options for those with moderate to severe disease have been limited by safety concerns, which adds to the burden on infants and young children, and their parents and caregivers, said Dr. Chovatiya, who was not involved in the study.
“This phase 3 study showed that dupilumab, a fully human monoclonal antibody that selectively inhibits IL-4 and IL-13 mediated type 2 inflammatory signaling, provided both meaningful and statistically significant improvement in AD severity, extent of disease, and itch in patients,” he said. Dupilumab also improved children’s sleep quality and the overall quality of life in both patients and caregivers.
“These findings were quite similar to those described in older children and adults, where dupilumab is already approved for the treatment of moderate-severe AD and has demonstrated real-world safety and efficacy,” said Dr. Chovatiya. However, “the current study was limited to only a short-term analysis of 16 weeks, an ongoing open-label study should further address long-term treatment responses.”
The study was supported by Sanofi and Regeneron Pharmaceuticals. In addition to being an investigator for Regeneron, and several other pharmaceutical companies, Dr. Paller has been a consultant with honorarium for Regeneron, Sanofi, and multiple other companies. Dr. Chovatiya disclosed serving as a consultant and speaker for Regeneron and Sanofi, but was not involved in the current study.
at 31 treatment centers in North America and Europe.
Children younger than 6 years with moderate to severe AD have few options if their symptoms are uncontrolled with topical therapies, and persistent itchiness has a negative impact on quality of life for patients and families, Amy S. Paller, MD, professor and chair of dermatology, and professor of pediatrics at Northwestern University, Chicago, and colleagues wrote in the study, published in the Lancet.
The study was the basis of the Food and Drug Administration expanded approval of dupilumab in June 2022, to include children aged 6 months to 5 years with moderate to severe AD, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Regulatory submission for this age group is under review by the European Medicines Agency, and by regulatory authorities in other countries, according to the manufacturers.
Dupilumab (Dupixent), which inhibits the signaling of the interleukin-4 and IL-13 pathways, was first approved in 2017 for treating adults with moderate to severe AD.
“There has not been a biologic approved before at such a young age, and for such a common disease,” Dr. Paller said in an interview. “This is the drug that has revolutionized care of the most common inflammatory skin disease in children, and this is the pivotal study that brought it to market for the youngest children who suffer from the severe forms.”
The study also sets a precedent for a lower threshold for starting systemic medication in young children for treating moderate to severe disease given the absence of severe side effects and no need for lab monitoring, Dr. Paller noted. However, dupilumab will also be closely watched “for both impact on the developing immune system and the possibility that it will alter the long-term course of the eczema and the development of allergic comorbidities, such as lowering the risk of developing asthma, GI, allergy, and possibly other conditions.”
In the study, the researchers randomized 83 children aged 6 months up to 6 years to treatment with dupilumab, administered subcutaneously, and 79 to placebo every 4 weeks for 16 weeks; both groups also received topical corticosteroids. Dosage of dupilumab was based on body weight; those with a body weight of 5-15 kg received 200 mg, while those with a body weight of 15-30 kg received 300 mg. The primary endpoint was the proportion of patients with clear or almost clear skin at 16 weeks, defined as scores of 0 or 1 on the Investigator’s Global Assessment.
After 16 weeks, 28% of dupilumab patients met the primary endpoint versus 4% of those on placebo (P < .0001). In addition, 53% of dupilumab patients met the key secondary endpoint of a 75% improvement from baseline in Eczema Area and Severity Index, compared with 11% of patients on placebo (P < .0001). Treatment with dupilumab also resulted in significantly greater improvements in pruritus and skin pain, and sleep quality, as well as improved quality of life for patients and their caregivers, the authors reported.
Overall, adverse event rates were slightly lower in the dupilumab-treated patients, compared with patients on placebo (64% vs. 74%); there were no adverse events related to dupilumab that were serious or resulted in treatment discontinuation. Treatment-emergent adverse effects that were reported in 3% or more of patients and affected more of those on dupilumab than those on placebo included molluscum contagiosum (5% vs. 3%), viral gastroenteritis (4% vs. 0), rhinorrhea (5% vs. 1%), dental caries (5% vs. 0), and conjunctivitis (4% vs 0).
The rate of skin infections among the children on dupilumab was 12% vs. 24% among those on placebo.
Severe and treatment-related adverse events also were similar in both subgroups of body weight.
The findings were limited by the small number of patients younger than 2 years and the lack of study sites outside of North America and Europe, the researchers noted. However, the results were strengthened by the randomized, double-blind design and use of background topical therapy to provide a real-world safety and efficacy assessment in a very young population.
Overcoming injection issues
The safety profile for dupilumab, which is of the highest importance, “did not surprise me at all,” Dr. Paller said in an interview. “My only surprise is that the placebo injections actually led to more injection site reactions than [with] dupilumab, but numbers were quite low in both groups.” (Rates were 2% among those on dupilumab and 3% among those on placebo.)
The major barrier to the use of dupilumab in clinical practice is the requirement for injection, which, she explained, can be “unbearable for some young children, and thus becomes impossible for parents because of lack of cooperation and their intensified concern about giving the injection,” because of their child’s response.
“We like to administer the first dose in the office, allowing us to teach parents a few tricks related to proper technique,” including audio and visual distraction, tactile stimulation before and during the injection, use of topical anesthetic if helpful, “and making sure that the medication is at room temperature before administration,” she said. Cost is another potential barrier; however, even public insurance has been covering the medication, often after optimized use of topical medications has been unsuccessful.
Future research questions
As for additional research, the current study had a relatively small number of patients younger than 2 years, and more data are needed for this age group, said Dr. Paller. “We also need better understanding of the safety of dupilumab administration when live vaccines are administered. Finally, we certainly want to know what additional effects dupilumab may have beyond just the efficacy for treating eczema.”
In particular, these questions include whether dupilumab modifies the long-term course of the disease, possibly reducing the risk of persistence of disease with advancing age, or even cures the disease if started at a young age, she said. In addition, research has yet to show whether dupilumab might reduce the risk of other atopic disorders, such as asthma, food allergy, and allergic rhinitis.
“Ongoing studies and real-life experiences in the next several years will help us to answer these questions,” Dr. Paller said.
Data support safety, efficacy, quality of life
AD is associated with immense quality of life impairment, Raj Chovatiya, MD, of Northwestern University, Chicago, said in an interview. Most AD is initially diagnosed in early childhood, but previous treatment options for those with moderate to severe disease have been limited by safety concerns, which adds to the burden on infants and young children, and their parents and caregivers, said Dr. Chovatiya, who was not involved in the study.
“This phase 3 study showed that dupilumab, a fully human monoclonal antibody that selectively inhibits IL-4 and IL-13 mediated type 2 inflammatory signaling, provided both meaningful and statistically significant improvement in AD severity, extent of disease, and itch in patients,” he said. Dupilumab also improved children’s sleep quality and the overall quality of life in both patients and caregivers.
“These findings were quite similar to those described in older children and adults, where dupilumab is already approved for the treatment of moderate-severe AD and has demonstrated real-world safety and efficacy,” said Dr. Chovatiya. However, “the current study was limited to only a short-term analysis of 16 weeks, an ongoing open-label study should further address long-term treatment responses.”
The study was supported by Sanofi and Regeneron Pharmaceuticals. In addition to being an investigator for Regeneron, and several other pharmaceutical companies, Dr. Paller has been a consultant with honorarium for Regeneron, Sanofi, and multiple other companies. Dr. Chovatiya disclosed serving as a consultant and speaker for Regeneron and Sanofi, but was not involved in the current study.
at 31 treatment centers in North America and Europe.
Children younger than 6 years with moderate to severe AD have few options if their symptoms are uncontrolled with topical therapies, and persistent itchiness has a negative impact on quality of life for patients and families, Amy S. Paller, MD, professor and chair of dermatology, and professor of pediatrics at Northwestern University, Chicago, and colleagues wrote in the study, published in the Lancet.
The study was the basis of the Food and Drug Administration expanded approval of dupilumab in June 2022, to include children aged 6 months to 5 years with moderate to severe AD, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Regulatory submission for this age group is under review by the European Medicines Agency, and by regulatory authorities in other countries, according to the manufacturers.
Dupilumab (Dupixent), which inhibits the signaling of the interleukin-4 and IL-13 pathways, was first approved in 2017 for treating adults with moderate to severe AD.
“There has not been a biologic approved before at such a young age, and for such a common disease,” Dr. Paller said in an interview. “This is the drug that has revolutionized care of the most common inflammatory skin disease in children, and this is the pivotal study that brought it to market for the youngest children who suffer from the severe forms.”
The study also sets a precedent for a lower threshold for starting systemic medication in young children for treating moderate to severe disease given the absence of severe side effects and no need for lab monitoring, Dr. Paller noted. However, dupilumab will also be closely watched “for both impact on the developing immune system and the possibility that it will alter the long-term course of the eczema and the development of allergic comorbidities, such as lowering the risk of developing asthma, GI, allergy, and possibly other conditions.”
In the study, the researchers randomized 83 children aged 6 months up to 6 years to treatment with dupilumab, administered subcutaneously, and 79 to placebo every 4 weeks for 16 weeks; both groups also received topical corticosteroids. Dosage of dupilumab was based on body weight; those with a body weight of 5-15 kg received 200 mg, while those with a body weight of 15-30 kg received 300 mg. The primary endpoint was the proportion of patients with clear or almost clear skin at 16 weeks, defined as scores of 0 or 1 on the Investigator’s Global Assessment.
After 16 weeks, 28% of dupilumab patients met the primary endpoint versus 4% of those on placebo (P < .0001). In addition, 53% of dupilumab patients met the key secondary endpoint of a 75% improvement from baseline in Eczema Area and Severity Index, compared with 11% of patients on placebo (P < .0001). Treatment with dupilumab also resulted in significantly greater improvements in pruritus and skin pain, and sleep quality, as well as improved quality of life for patients and their caregivers, the authors reported.
Overall, adverse event rates were slightly lower in the dupilumab-treated patients, compared with patients on placebo (64% vs. 74%); there were no adverse events related to dupilumab that were serious or resulted in treatment discontinuation. Treatment-emergent adverse effects that were reported in 3% or more of patients and affected more of those on dupilumab than those on placebo included molluscum contagiosum (5% vs. 3%), viral gastroenteritis (4% vs. 0), rhinorrhea (5% vs. 1%), dental caries (5% vs. 0), and conjunctivitis (4% vs 0).
The rate of skin infections among the children on dupilumab was 12% vs. 24% among those on placebo.
Severe and treatment-related adverse events also were similar in both subgroups of body weight.
The findings were limited by the small number of patients younger than 2 years and the lack of study sites outside of North America and Europe, the researchers noted. However, the results were strengthened by the randomized, double-blind design and use of background topical therapy to provide a real-world safety and efficacy assessment in a very young population.
Overcoming injection issues
The safety profile for dupilumab, which is of the highest importance, “did not surprise me at all,” Dr. Paller said in an interview. “My only surprise is that the placebo injections actually led to more injection site reactions than [with] dupilumab, but numbers were quite low in both groups.” (Rates were 2% among those on dupilumab and 3% among those on placebo.)
The major barrier to the use of dupilumab in clinical practice is the requirement for injection, which, she explained, can be “unbearable for some young children, and thus becomes impossible for parents because of lack of cooperation and their intensified concern about giving the injection,” because of their child’s response.
“We like to administer the first dose in the office, allowing us to teach parents a few tricks related to proper technique,” including audio and visual distraction, tactile stimulation before and during the injection, use of topical anesthetic if helpful, “and making sure that the medication is at room temperature before administration,” she said. Cost is another potential barrier; however, even public insurance has been covering the medication, often after optimized use of topical medications has been unsuccessful.
Future research questions
As for additional research, the current study had a relatively small number of patients younger than 2 years, and more data are needed for this age group, said Dr. Paller. “We also need better understanding of the safety of dupilumab administration when live vaccines are administered. Finally, we certainly want to know what additional effects dupilumab may have beyond just the efficacy for treating eczema.”
In particular, these questions include whether dupilumab modifies the long-term course of the disease, possibly reducing the risk of persistence of disease with advancing age, or even cures the disease if started at a young age, she said. In addition, research has yet to show whether dupilumab might reduce the risk of other atopic disorders, such as asthma, food allergy, and allergic rhinitis.
“Ongoing studies and real-life experiences in the next several years will help us to answer these questions,” Dr. Paller said.
Data support safety, efficacy, quality of life
AD is associated with immense quality of life impairment, Raj Chovatiya, MD, of Northwestern University, Chicago, said in an interview. Most AD is initially diagnosed in early childhood, but previous treatment options for those with moderate to severe disease have been limited by safety concerns, which adds to the burden on infants and young children, and their parents and caregivers, said Dr. Chovatiya, who was not involved in the study.
“This phase 3 study showed that dupilumab, a fully human monoclonal antibody that selectively inhibits IL-4 and IL-13 mediated type 2 inflammatory signaling, provided both meaningful and statistically significant improvement in AD severity, extent of disease, and itch in patients,” he said. Dupilumab also improved children’s sleep quality and the overall quality of life in both patients and caregivers.
“These findings were quite similar to those described in older children and adults, where dupilumab is already approved for the treatment of moderate-severe AD and has demonstrated real-world safety and efficacy,” said Dr. Chovatiya. However, “the current study was limited to only a short-term analysis of 16 weeks, an ongoing open-label study should further address long-term treatment responses.”
The study was supported by Sanofi and Regeneron Pharmaceuticals. In addition to being an investigator for Regeneron, and several other pharmaceutical companies, Dr. Paller has been a consultant with honorarium for Regeneron, Sanofi, and multiple other companies. Dr. Chovatiya disclosed serving as a consultant and speaker for Regeneron and Sanofi, but was not involved in the current study.
FROM THE LANCET