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Mothers’ diabetes linked to ADHD in their children
Children born to women who develop diabetes either before or during their pregnancy could be at risk for developing attention-deficit/hyperactivity disorder, data from a large multinational cohort study appear to show.
Considering more than 4.5 million mother-child pairs, it was found that children whose mothers had diabetes around the time of their pregnancy were 16% more likely to have ADHD diagnosed than were those whose mothers did not.
An increased risk was seen regardless of the type of diabetes, and regardless of whether or not the diabetes was present before or appeared during the pregnancy.
“We found a small increased risk of ADHD in children born to mothers with diabetes, including pregestational diabetes and gestational diabetes,” Carolyn Cesta, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Dr. Cesta, a postdoctoral researcher in the Centre for Pharmacoepidemiology at the Karolinska Institutet in Stockholm noted that the effect sizes seen were lower than had been reported previously.
“This may be because we adjusted for a large number of covariates, including maternal ADHD and psychiatric disorders,” Dr. Cesta said.
ADHD and diabetes
“Previous studies have reported an increase in the risk of ADHD in children born to mothers with diabetes,” explained Dr. Cesta.
However, “these studies have been limited by the use of self-reported data, small sample sizes, lack of adjustment for important confounders, and they’re often limited to [White] populations,” she added. “There’s a lot of heterogeneity between these studies,” she said.
To try to iron out the differences seen in the prior studies, Dr. Cesta and associates looked at data from several databases based in Hong Kong (Clinical Data Analysis and Reporting System), four Nordic countries (Population Health Registers for Finland, Iceland, Norway, and Sweden), and Taiwan (National Health Insurance Database).
To create the matched mother-child pairs, the databases were searched to find women who had children born between 2001 and 2018, and who had follow-up data available up to 2020 on not only their diabetes status and child’s ADHD status, but also other parameters, such as other maternal diagnoses, maternal medications, and a host of sociodemographic factors.
More than 24 potentially confounding or covariates were considered in the analysis, which used Cox proportional hazard regression modeling and propensity score analysis to calculate hazard ratios with 95% confidence intervals.
“We looked at whether [mothers] had a diagnosis of ADHD themselves, or other psychiatric disorders, because there is high heritability for these disorders,” Dr. Cesta said, indicating that all bases had endeavored to be covered.
Main findings
Results showed some differences in the prevalence of diabetes and ADHD between the three cohorts used in the analysis. The prevalence of any maternal diabetes ranged from 8.8% in the Hong Kong cohort to 3.3% in the Taiwan cohort, with a prevalence of 6.8% for the Nordic cohort.
Rates of pregestational diabetes were lowest in the Taiwan and Hong Kong cohorts, at 0.2% and 0.5%, respectively, and 2.2% in the Nordic cohort. Gestational diabetes rates were a respective 3.1%, 7.8%, and 4.6%.
The highest rate of ADHD in children was seen in the Taiwan cohort, at 9.6%, followed by 4.2% for the Hong Kong cohort, and 2.6% for the Nordic cohort.
The hazard ratio for having childhood ADHD was 1.16 when comparing any maternal diabetes to no maternal diabetes, 1.40 comparing mothers with and without pregestational diabetes, and a respective 1.36 and 1.37 comparing those with and without type 1 diabetes, and those with and without type 2 diabetes.
The HR for childhood ADHD comparing mothers with and without gestational diabetes was 1.13.
“Within the analysis for gestational diabetes, we had enough numbers to look at siblings that are discordant for maternal gestational diabetes,” Dr. Cesta said. Essentially “we’re comparing two siblings from the same mother, one that was exposed to gestational diabetes, one that wasn’t,” she explained.
Interestingly there was no association between ADHD and maternal gestational diabetes in the sibling analysis (HR, 1.0).
“When it comes to gestational diabetes, the evidence from our sibling analysis indicate that the association may actually be confounded by shared genetics and environmental factors,” said Dr. Cesta.
“So, future studies should explore the role of specific genetic factors in glycemic control during pregnancy and the relationship between maternal diabetes and ADHD.”
Answering long-standing questions
These data will help a lot in answering questions that clinicians have been asking themselves a long time, commented Jardena Puder, MD, who chaired the session.
“It still remains a bit puzzling that genetic and environmental factors could be responsible, if you see the same effect in type 1 [diabetes], and in type 2 [diabetes], and gestational diabetes,” said Dr. Puder, who is an endocrinologist and diabetologist at the woman-mother-child department at the Vaud University Hospital Center, Lausanne, Switzerland.
Type 1 and type 2 are “very distinct” in terms of the genetic and environmental factors involved, “so, the fact that you see [the effect] in both remains a bit puzzling,” said Dr. Puder.
“I wish we had the numbers to be able to do the sibling analysis for type 1 and type 2, just to see if we could tease anything out,” said Dr. Cesta.
“I do think this is part of the bigger question of what the relationship is between, like, metabolic disorders and psychiatric disorders, because even outside of pregnancy, we see that there’s often a comorbidity with them. So, it’s a good point.”
The next step is to look at the role of treatment and what effects glycemic control might have on the small, but still apparent, association between maternal diabetes and ADHD.
The study had multiple funders including the Hong Kong Research Grant Council, NordForsk, the Research Council of Norway, the Norwegian ADHD Research Network, the Hong Kong Innovation and Technology Commission, and European Horizon 2020.
Dr. Cesta had no conflicts of interest to disclose. Dr. Puder chaired the session in which the findings were presented and made no specific disclosures.
Children born to women who develop diabetes either before or during their pregnancy could be at risk for developing attention-deficit/hyperactivity disorder, data from a large multinational cohort study appear to show.
Considering more than 4.5 million mother-child pairs, it was found that children whose mothers had diabetes around the time of their pregnancy were 16% more likely to have ADHD diagnosed than were those whose mothers did not.
An increased risk was seen regardless of the type of diabetes, and regardless of whether or not the diabetes was present before or appeared during the pregnancy.
“We found a small increased risk of ADHD in children born to mothers with diabetes, including pregestational diabetes and gestational diabetes,” Carolyn Cesta, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Dr. Cesta, a postdoctoral researcher in the Centre for Pharmacoepidemiology at the Karolinska Institutet in Stockholm noted that the effect sizes seen were lower than had been reported previously.
“This may be because we adjusted for a large number of covariates, including maternal ADHD and psychiatric disorders,” Dr. Cesta said.
ADHD and diabetes
“Previous studies have reported an increase in the risk of ADHD in children born to mothers with diabetes,” explained Dr. Cesta.
However, “these studies have been limited by the use of self-reported data, small sample sizes, lack of adjustment for important confounders, and they’re often limited to [White] populations,” she added. “There’s a lot of heterogeneity between these studies,” she said.
To try to iron out the differences seen in the prior studies, Dr. Cesta and associates looked at data from several databases based in Hong Kong (Clinical Data Analysis and Reporting System), four Nordic countries (Population Health Registers for Finland, Iceland, Norway, and Sweden), and Taiwan (National Health Insurance Database).
To create the matched mother-child pairs, the databases were searched to find women who had children born between 2001 and 2018, and who had follow-up data available up to 2020 on not only their diabetes status and child’s ADHD status, but also other parameters, such as other maternal diagnoses, maternal medications, and a host of sociodemographic factors.
More than 24 potentially confounding or covariates were considered in the analysis, which used Cox proportional hazard regression modeling and propensity score analysis to calculate hazard ratios with 95% confidence intervals.
“We looked at whether [mothers] had a diagnosis of ADHD themselves, or other psychiatric disorders, because there is high heritability for these disorders,” Dr. Cesta said, indicating that all bases had endeavored to be covered.
Main findings
Results showed some differences in the prevalence of diabetes and ADHD between the three cohorts used in the analysis. The prevalence of any maternal diabetes ranged from 8.8% in the Hong Kong cohort to 3.3% in the Taiwan cohort, with a prevalence of 6.8% for the Nordic cohort.
Rates of pregestational diabetes were lowest in the Taiwan and Hong Kong cohorts, at 0.2% and 0.5%, respectively, and 2.2% in the Nordic cohort. Gestational diabetes rates were a respective 3.1%, 7.8%, and 4.6%.
The highest rate of ADHD in children was seen in the Taiwan cohort, at 9.6%, followed by 4.2% for the Hong Kong cohort, and 2.6% for the Nordic cohort.
The hazard ratio for having childhood ADHD was 1.16 when comparing any maternal diabetes to no maternal diabetes, 1.40 comparing mothers with and without pregestational diabetes, and a respective 1.36 and 1.37 comparing those with and without type 1 diabetes, and those with and without type 2 diabetes.
The HR for childhood ADHD comparing mothers with and without gestational diabetes was 1.13.
“Within the analysis for gestational diabetes, we had enough numbers to look at siblings that are discordant for maternal gestational diabetes,” Dr. Cesta said. Essentially “we’re comparing two siblings from the same mother, one that was exposed to gestational diabetes, one that wasn’t,” she explained.
Interestingly there was no association between ADHD and maternal gestational diabetes in the sibling analysis (HR, 1.0).
“When it comes to gestational diabetes, the evidence from our sibling analysis indicate that the association may actually be confounded by shared genetics and environmental factors,” said Dr. Cesta.
“So, future studies should explore the role of specific genetic factors in glycemic control during pregnancy and the relationship between maternal diabetes and ADHD.”
Answering long-standing questions
These data will help a lot in answering questions that clinicians have been asking themselves a long time, commented Jardena Puder, MD, who chaired the session.
“It still remains a bit puzzling that genetic and environmental factors could be responsible, if you see the same effect in type 1 [diabetes], and in type 2 [diabetes], and gestational diabetes,” said Dr. Puder, who is an endocrinologist and diabetologist at the woman-mother-child department at the Vaud University Hospital Center, Lausanne, Switzerland.
Type 1 and type 2 are “very distinct” in terms of the genetic and environmental factors involved, “so, the fact that you see [the effect] in both remains a bit puzzling,” said Dr. Puder.
“I wish we had the numbers to be able to do the sibling analysis for type 1 and type 2, just to see if we could tease anything out,” said Dr. Cesta.
“I do think this is part of the bigger question of what the relationship is between, like, metabolic disorders and psychiatric disorders, because even outside of pregnancy, we see that there’s often a comorbidity with them. So, it’s a good point.”
The next step is to look at the role of treatment and what effects glycemic control might have on the small, but still apparent, association between maternal diabetes and ADHD.
The study had multiple funders including the Hong Kong Research Grant Council, NordForsk, the Research Council of Norway, the Norwegian ADHD Research Network, the Hong Kong Innovation and Technology Commission, and European Horizon 2020.
Dr. Cesta had no conflicts of interest to disclose. Dr. Puder chaired the session in which the findings were presented and made no specific disclosures.
Children born to women who develop diabetes either before or during their pregnancy could be at risk for developing attention-deficit/hyperactivity disorder, data from a large multinational cohort study appear to show.
Considering more than 4.5 million mother-child pairs, it was found that children whose mothers had diabetes around the time of their pregnancy were 16% more likely to have ADHD diagnosed than were those whose mothers did not.
An increased risk was seen regardless of the type of diabetes, and regardless of whether or not the diabetes was present before or appeared during the pregnancy.
“We found a small increased risk of ADHD in children born to mothers with diabetes, including pregestational diabetes and gestational diabetes,” Carolyn Cesta, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Dr. Cesta, a postdoctoral researcher in the Centre for Pharmacoepidemiology at the Karolinska Institutet in Stockholm noted that the effect sizes seen were lower than had been reported previously.
“This may be because we adjusted for a large number of covariates, including maternal ADHD and psychiatric disorders,” Dr. Cesta said.
ADHD and diabetes
“Previous studies have reported an increase in the risk of ADHD in children born to mothers with diabetes,” explained Dr. Cesta.
However, “these studies have been limited by the use of self-reported data, small sample sizes, lack of adjustment for important confounders, and they’re often limited to [White] populations,” she added. “There’s a lot of heterogeneity between these studies,” she said.
To try to iron out the differences seen in the prior studies, Dr. Cesta and associates looked at data from several databases based in Hong Kong (Clinical Data Analysis and Reporting System), four Nordic countries (Population Health Registers for Finland, Iceland, Norway, and Sweden), and Taiwan (National Health Insurance Database).
To create the matched mother-child pairs, the databases were searched to find women who had children born between 2001 and 2018, and who had follow-up data available up to 2020 on not only their diabetes status and child’s ADHD status, but also other parameters, such as other maternal diagnoses, maternal medications, and a host of sociodemographic factors.
More than 24 potentially confounding or covariates were considered in the analysis, which used Cox proportional hazard regression modeling and propensity score analysis to calculate hazard ratios with 95% confidence intervals.
“We looked at whether [mothers] had a diagnosis of ADHD themselves, or other psychiatric disorders, because there is high heritability for these disorders,” Dr. Cesta said, indicating that all bases had endeavored to be covered.
Main findings
Results showed some differences in the prevalence of diabetes and ADHD between the three cohorts used in the analysis. The prevalence of any maternal diabetes ranged from 8.8% in the Hong Kong cohort to 3.3% in the Taiwan cohort, with a prevalence of 6.8% for the Nordic cohort.
Rates of pregestational diabetes were lowest in the Taiwan and Hong Kong cohorts, at 0.2% and 0.5%, respectively, and 2.2% in the Nordic cohort. Gestational diabetes rates were a respective 3.1%, 7.8%, and 4.6%.
The highest rate of ADHD in children was seen in the Taiwan cohort, at 9.6%, followed by 4.2% for the Hong Kong cohort, and 2.6% for the Nordic cohort.
The hazard ratio for having childhood ADHD was 1.16 when comparing any maternal diabetes to no maternal diabetes, 1.40 comparing mothers with and without pregestational diabetes, and a respective 1.36 and 1.37 comparing those with and without type 1 diabetes, and those with and without type 2 diabetes.
The HR for childhood ADHD comparing mothers with and without gestational diabetes was 1.13.
“Within the analysis for gestational diabetes, we had enough numbers to look at siblings that are discordant for maternal gestational diabetes,” Dr. Cesta said. Essentially “we’re comparing two siblings from the same mother, one that was exposed to gestational diabetes, one that wasn’t,” she explained.
Interestingly there was no association between ADHD and maternal gestational diabetes in the sibling analysis (HR, 1.0).
“When it comes to gestational diabetes, the evidence from our sibling analysis indicate that the association may actually be confounded by shared genetics and environmental factors,” said Dr. Cesta.
“So, future studies should explore the role of specific genetic factors in glycemic control during pregnancy and the relationship between maternal diabetes and ADHD.”
Answering long-standing questions
These data will help a lot in answering questions that clinicians have been asking themselves a long time, commented Jardena Puder, MD, who chaired the session.
“It still remains a bit puzzling that genetic and environmental factors could be responsible, if you see the same effect in type 1 [diabetes], and in type 2 [diabetes], and gestational diabetes,” said Dr. Puder, who is an endocrinologist and diabetologist at the woman-mother-child department at the Vaud University Hospital Center, Lausanne, Switzerland.
Type 1 and type 2 are “very distinct” in terms of the genetic and environmental factors involved, “so, the fact that you see [the effect] in both remains a bit puzzling,” said Dr. Puder.
“I wish we had the numbers to be able to do the sibling analysis for type 1 and type 2, just to see if we could tease anything out,” said Dr. Cesta.
“I do think this is part of the bigger question of what the relationship is between, like, metabolic disorders and psychiatric disorders, because even outside of pregnancy, we see that there’s often a comorbidity with them. So, it’s a good point.”
The next step is to look at the role of treatment and what effects glycemic control might have on the small, but still apparent, association between maternal diabetes and ADHD.
The study had multiple funders including the Hong Kong Research Grant Council, NordForsk, the Research Council of Norway, the Norwegian ADHD Research Network, the Hong Kong Innovation and Technology Commission, and European Horizon 2020.
Dr. Cesta had no conflicts of interest to disclose. Dr. Puder chaired the session in which the findings were presented and made no specific disclosures.
FROM EASD 2022
Apremilast alleviates severe psoriasis in some children, data show
not controlled by topical therapy, according to the results of a phase 3 trial.
“Unfortunately, there are limited treatment options for pediatric patients with moderate to severe plaque psoriasis” who do not respond to or cannot use topical therapy, said study investigator Anna Belloni Fortina, MD, speaking at the annual meeting of the European Academy of Dermatology and Venereology.
“In this randomized, placebo-controlled trial, oral apremilast demonstrated effectiveness and was well tolerated,” added Dr. Belloni Fortina, of Azienda Ospedale Università Padova (Italy). “I underline oral because for children, oral administration is better than the injection treatment.”
Key findings
Dubbed the SPROUT study, the trial set a primary endpoint of the percentage of children with a Physician’s Global Assessment (sPGA) response after 16 weeks of treatment or placebo. The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe). The study enrolled children with an sPGA greater than or equal to 3. Response was defined as a sPGA score of 0 or 1, indicating clear or almost clear skin, with at least a 2-point reduction from baseline values.
At week 16, the primary endpoint was met by 33% of 163 children treated with apremilast versus 11% of 82 children who had been given a placebo, a treatment difference of 21.7% (95% confidence interval, 11.2%-32.1%).
A greater proportion of children treated with apremilast also achieved a major secondary endpoint, a 75% or greater reduction in the Psoriasis Area and Severity Index (PASI-75) (45.4% vs. 16.1%), a treatment difference of 29.4% (95% CI, 17.8%-40.9%).
Results unaffected by weight and age
Regarding apremilast, “it’s important to underline that patients were dosed according to their weight,” Dr. Belloni Fortina said.
A dose of 20 mg twice daily was given to children who weighed between 20 kg and less than 50 kg, and a 30-mg twice-daily dose was given to those who weighed greater than or equal to 50 kg.
When the data were analyzed according to weight, proportionately more children on apremilast saw a sPGA response: 47.4% versus 21.8% in the lower weight and dose range and 19.2% versus 1.6% in the higher weight and dose range.
As for PASI-75, a greater proportion of children on apremilast also responded in both the lower and upper weight ranges, a respective 52.4% and 38.7% of patients, compared with 21.4% and 11% of those treated with placebo.
Data were also evaluated according to age, with a younger (aged 6-11 years) and older (age 12-17 years) group. The mean age of children was 12 years overall. Results showed a similar pattern for weight: The psoriasis of more children treated with apremilast was reduced by both measures, sPGA response, and PASI-75.
Safety of apremilast in children
“The overall safety profile during the placebo-controlled phase was comparable with the known safety profile of apremilast,” Dr. Belloni Fontina reported. “No new safety signals were identified.”
The rate of any adverse event was substantially higher in children given the active treatment, however, at 65% versus 41.3% for placebo.
Rates of severe and serious adverse events were low, at around 1.3%, and similar between the groups.
There was also a low rate of withdrawal because of side effects, although this was higher in the apremilast group (3.1% vs. 1.3%).
The primary reason for withdrawal of apremilast treatment were the most commonly reported adverse events: gastrointestinal disorders, including diarrhea, nausea, upper and lower abdominal pain, and vomiting. Headache, pyrexia, and nasopharyngitis were also reported.
Despite being common, most treatment-related adverse effects resolved within 3 days, Dr. Belloni Fontina said.
Expect further data
Further data from the trial are to be expected, because only the 16-week primary endpoint results have been released so far. The trial also included a 36-week extension phase, during which all children who had originally been randomly assigned to placebo were now eligible to be treated with apremilast, and all those who were originally given the active treatment were able to continue. This extension treatment period means that data will be available for a full year of treatment, and there will also be a further 2-week observational follow-up at the end of the trial.
The study was funded by Amgen. Dr. Belloni Fontina reported acting as an investigator and advisory board member for and receiving honoraria from Amgen, Galderma, Leo Pharma, and Pfizer. She also reported speaking on behalf of Pierre-Fabre and Galderma.
A version of this article first appeared on Medscape.com.
not controlled by topical therapy, according to the results of a phase 3 trial.
“Unfortunately, there are limited treatment options for pediatric patients with moderate to severe plaque psoriasis” who do not respond to or cannot use topical therapy, said study investigator Anna Belloni Fortina, MD, speaking at the annual meeting of the European Academy of Dermatology and Venereology.
“In this randomized, placebo-controlled trial, oral apremilast demonstrated effectiveness and was well tolerated,” added Dr. Belloni Fortina, of Azienda Ospedale Università Padova (Italy). “I underline oral because for children, oral administration is better than the injection treatment.”
Key findings
Dubbed the SPROUT study, the trial set a primary endpoint of the percentage of children with a Physician’s Global Assessment (sPGA) response after 16 weeks of treatment or placebo. The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe). The study enrolled children with an sPGA greater than or equal to 3. Response was defined as a sPGA score of 0 or 1, indicating clear or almost clear skin, with at least a 2-point reduction from baseline values.
At week 16, the primary endpoint was met by 33% of 163 children treated with apremilast versus 11% of 82 children who had been given a placebo, a treatment difference of 21.7% (95% confidence interval, 11.2%-32.1%).
A greater proportion of children treated with apremilast also achieved a major secondary endpoint, a 75% or greater reduction in the Psoriasis Area and Severity Index (PASI-75) (45.4% vs. 16.1%), a treatment difference of 29.4% (95% CI, 17.8%-40.9%).
Results unaffected by weight and age
Regarding apremilast, “it’s important to underline that patients were dosed according to their weight,” Dr. Belloni Fortina said.
A dose of 20 mg twice daily was given to children who weighed between 20 kg and less than 50 kg, and a 30-mg twice-daily dose was given to those who weighed greater than or equal to 50 kg.
When the data were analyzed according to weight, proportionately more children on apremilast saw a sPGA response: 47.4% versus 21.8% in the lower weight and dose range and 19.2% versus 1.6% in the higher weight and dose range.
As for PASI-75, a greater proportion of children on apremilast also responded in both the lower and upper weight ranges, a respective 52.4% and 38.7% of patients, compared with 21.4% and 11% of those treated with placebo.
Data were also evaluated according to age, with a younger (aged 6-11 years) and older (age 12-17 years) group. The mean age of children was 12 years overall. Results showed a similar pattern for weight: The psoriasis of more children treated with apremilast was reduced by both measures, sPGA response, and PASI-75.
Safety of apremilast in children
“The overall safety profile during the placebo-controlled phase was comparable with the known safety profile of apremilast,” Dr. Belloni Fontina reported. “No new safety signals were identified.”
The rate of any adverse event was substantially higher in children given the active treatment, however, at 65% versus 41.3% for placebo.
Rates of severe and serious adverse events were low, at around 1.3%, and similar between the groups.
There was also a low rate of withdrawal because of side effects, although this was higher in the apremilast group (3.1% vs. 1.3%).
The primary reason for withdrawal of apremilast treatment were the most commonly reported adverse events: gastrointestinal disorders, including diarrhea, nausea, upper and lower abdominal pain, and vomiting. Headache, pyrexia, and nasopharyngitis were also reported.
Despite being common, most treatment-related adverse effects resolved within 3 days, Dr. Belloni Fontina said.
Expect further data
Further data from the trial are to be expected, because only the 16-week primary endpoint results have been released so far. The trial also included a 36-week extension phase, during which all children who had originally been randomly assigned to placebo were now eligible to be treated with apremilast, and all those who were originally given the active treatment were able to continue. This extension treatment period means that data will be available for a full year of treatment, and there will also be a further 2-week observational follow-up at the end of the trial.
The study was funded by Amgen. Dr. Belloni Fontina reported acting as an investigator and advisory board member for and receiving honoraria from Amgen, Galderma, Leo Pharma, and Pfizer. She also reported speaking on behalf of Pierre-Fabre and Galderma.
A version of this article first appeared on Medscape.com.
not controlled by topical therapy, according to the results of a phase 3 trial.
“Unfortunately, there are limited treatment options for pediatric patients with moderate to severe plaque psoriasis” who do not respond to or cannot use topical therapy, said study investigator Anna Belloni Fortina, MD, speaking at the annual meeting of the European Academy of Dermatology and Venereology.
“In this randomized, placebo-controlled trial, oral apremilast demonstrated effectiveness and was well tolerated,” added Dr. Belloni Fortina, of Azienda Ospedale Università Padova (Italy). “I underline oral because for children, oral administration is better than the injection treatment.”
Key findings
Dubbed the SPROUT study, the trial set a primary endpoint of the percentage of children with a Physician’s Global Assessment (sPGA) response after 16 weeks of treatment or placebo. The sPGA is a 5-point scale ranging from 0 (clear) to 4 (severe). The study enrolled children with an sPGA greater than or equal to 3. Response was defined as a sPGA score of 0 or 1, indicating clear or almost clear skin, with at least a 2-point reduction from baseline values.
At week 16, the primary endpoint was met by 33% of 163 children treated with apremilast versus 11% of 82 children who had been given a placebo, a treatment difference of 21.7% (95% confidence interval, 11.2%-32.1%).
A greater proportion of children treated with apremilast also achieved a major secondary endpoint, a 75% or greater reduction in the Psoriasis Area and Severity Index (PASI-75) (45.4% vs. 16.1%), a treatment difference of 29.4% (95% CI, 17.8%-40.9%).
Results unaffected by weight and age
Regarding apremilast, “it’s important to underline that patients were dosed according to their weight,” Dr. Belloni Fortina said.
A dose of 20 mg twice daily was given to children who weighed between 20 kg and less than 50 kg, and a 30-mg twice-daily dose was given to those who weighed greater than or equal to 50 kg.
When the data were analyzed according to weight, proportionately more children on apremilast saw a sPGA response: 47.4% versus 21.8% in the lower weight and dose range and 19.2% versus 1.6% in the higher weight and dose range.
As for PASI-75, a greater proportion of children on apremilast also responded in both the lower and upper weight ranges, a respective 52.4% and 38.7% of patients, compared with 21.4% and 11% of those treated with placebo.
Data were also evaluated according to age, with a younger (aged 6-11 years) and older (age 12-17 years) group. The mean age of children was 12 years overall. Results showed a similar pattern for weight: The psoriasis of more children treated with apremilast was reduced by both measures, sPGA response, and PASI-75.
Safety of apremilast in children
“The overall safety profile during the placebo-controlled phase was comparable with the known safety profile of apremilast,” Dr. Belloni Fontina reported. “No new safety signals were identified.”
The rate of any adverse event was substantially higher in children given the active treatment, however, at 65% versus 41.3% for placebo.
Rates of severe and serious adverse events were low, at around 1.3%, and similar between the groups.
There was also a low rate of withdrawal because of side effects, although this was higher in the apremilast group (3.1% vs. 1.3%).
The primary reason for withdrawal of apremilast treatment were the most commonly reported adverse events: gastrointestinal disorders, including diarrhea, nausea, upper and lower abdominal pain, and vomiting. Headache, pyrexia, and nasopharyngitis were also reported.
Despite being common, most treatment-related adverse effects resolved within 3 days, Dr. Belloni Fontina said.
Expect further data
Further data from the trial are to be expected, because only the 16-week primary endpoint results have been released so far. The trial also included a 36-week extension phase, during which all children who had originally been randomly assigned to placebo were now eligible to be treated with apremilast, and all those who were originally given the active treatment were able to continue. This extension treatment period means that data will be available for a full year of treatment, and there will also be a further 2-week observational follow-up at the end of the trial.
The study was funded by Amgen. Dr. Belloni Fontina reported acting as an investigator and advisory board member for and receiving honoraria from Amgen, Galderma, Leo Pharma, and Pfizer. She also reported speaking on behalf of Pierre-Fabre and Galderma.
A version of this article first appeared on Medscape.com.
FROM EADV 2022
Hope shines bright for hidradenitis suppurativa treatments
in separate trials.
Around 40%-50% of patients exhibited a clinical response to these agents at 16 weeks, a leading HS expert reported at the annual congress of the European Academy of Dermatology and Venereology.
Time in the spotlight for HS
Research into HS is “an incredibly active field at this moment,” said Alexa B. Kimball, MD, MPH, professor of dermatology, Harvard Medical School, and president and chief executive officer of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, Boston.
It’s “been great for advancing our understanding of the biology and the treatments that we will be able to use,” she said.
During the late-breaking sessions at the annual EADV Congress, Dr. Kimball presented data from two trials – SUNSHINE and SUNRISE – that investigated the efficacy, safety and tolerability of the interleukin (IL) 17A inhibitor secukinumab (Cosentyx) versus placebo in the treatment of moderate to severe HS.
“This is only the second phase 3 program we have ever seen in HS and the first one since 2016,” Dr. Kimball said of the trials. It’s also the largest trial program in HS conducted to date, she added, “so it really is a milestone.”
The last big development was when adalimumab, a tumor necrosis factor (TNF) blocker, gained regulatory approval for HS in 2016, observed Neil Patel, PhD, MRCP, who leads the HS service at Imperial College Healthcare NHS Trust in London.
“Adalimumab has been very helpful for many patients, but not all patients respond, and others may respond initially but then the treatment starts to fail after a year or 2,” Dr. Patel said in an interview with this news organization.
“There is definitely a huge need for alternative medication for this condition, which still has a lack of effective treatment options,” added Dr. Patel, who was not involved in either of the studies.
“One major upside for secukinumab is that its safety profile is generally very good and familiarity in the dermatologic community is already well established,” Christopher Sayed, MD, said in a separate interview.
“This will make most providers very comfortable offering it as a potential treatment option sooner rather than later given that its efficacy has now been demonstrated in phase 3 trials,” added Dr. Sayed, associate professor of dermatology at the University of North Carolina at Chapel Hill.
Two identically designed trials
Altogether, SUNSHINE and SUNRISE enrolled just over 1,000 patients at 219 sites in 33 countries. Both trials were identical in their design: A 4-week run-in phase before a randomized, double-blind treatment phase that tested two dosing regimens of secukinumab (300 mg administered subcutaneously) every 2 or 4 weeks vs. placebo for 16 weeks. The trial continued after this time, with patients in the placebo arm re–randomly assigned to treatment with one of the two secukinumab regimens out to a year.
The primary endpoint was the percentage of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR) after 16 weeks of treatment, with key secondary endpoints, which were abscess and inflammatory nodule (AN) count, occurrence of flares, and at least a 30% reduction in Patient’s Global Assessment of Skin Pain assessed using a numeric rating scale (NPRS30).
Secukinumab superior to placebo
The HiSCR is defined as at least a 50% decrease in AN count with no increase in the number of abscesses or in the number of draining fistulas relative to baseline. This was achieved by about 42%-45% of patients who received secukinumab every 2 weeks, about 42%-46% of those who received secukinumab every 4 weeks, and about 31%-33% of those on placebo in both studies.
Of note, fewer patients treated with secukinumab (about 15%-20% among those treated every 2 weeks, and about 15% to 23% among those treated every 4 weeks) than those on placebo (27%-29%) experienced flares, defined as at least a 25% increase in AN count and at least a two-point increase relative to baseline values.
Improvement in HS pain can be a difficult parameter to meet, Dr. Kimball noted. “Pain is such an important feature of this disease as it so debilitating for the patients.” More than one-third (almost 36%-39%) of patients given secukinumab vs. just over a quarter (26.9%) given placebo achieved at least a 30% reduction in NPRS30 ratings, she reported. The difference between active and placebo treatment was significant only when secukinumab was given every 2 weeks, however.
“The placebo rates that we see in these studies are exactly parallel to what we saw in other studies, and other disease states when we had a 50% bar of improvement,” Dr. Kimball said when questioned about these results.
“HS is a highly variable disease; it’s maybe not so much the placebo rate or the scoring system used but maybe the 50% bar set for improvement is too low. It’s likely, as data start to mature and a 75% HiSCR can be calculated, that the placebo rates will drop,” she said.
There were no surprises when it came to the safety of secukinumab, being an old player in a new game, she noted. It was “well tolerated” and tolerability was “consistent with the known safety profile,” Dr. Kimball said, “so we expect it to be a new, safe, and effective add to our armamentarium in treating this disease.”
This research involves “basically borrowing drugs from other areas and trying them in HS to see what effect they may have,” Dr. Patel said, noting that drugs such as adalimumab and secukinumab already had a proven track record in other diseases, such as psoriasis. “These early data for secukinumab definitely are very exciting, but we would need to see real-life results” in patients with HS who are not enrolled in trials to see the benefits, he added.
‘Tipping point’ for HS research
“I think we will look back on this meeting and realize that it was an incredibly important tipping point for the treatment of this incredibly debilitating disease,” Dr. Kimball said.
Elsewhere at the meeting, she had presented findings from a phase 2a study that pitted three different kinase inhibitors with different modes of action against each other and compared them with placebo.
The three agents evaluated are an IL-1 receptor–associated kinase 4 inhibitor known as PF-06650833, a tyrosine kinase 2 (TYK2) JAK1 inhibitor brepocitinib, and the TYK2 inhibitor PF-06826647.
“This technique has been used in oncology,” Dr. Kimball said, noting that the ability to test multiple drugs at the same time “means we can really much more efficiently test two different things at the same time, and also put fewer patients at risk for potential problems if drugs don’t work.”
Positive signs for brepocitinib, not the other kinases tested
The results showed that though brepocitinib worked in HS, the other two novel compounds did not appear to have beneficial effects. Just over half (52%) of the 52 patients treated with brepocitinib achieved an HiSCR at 16 weeks, compared with around one-third of those given placebo, PF-06650833, or PF-06826647.
A similar benefit was seen in terms of reduction in flares for brepocitinib but not the other agents, although there was no difference between them all in terms of NPRS30 pain reduction.
“We’ve been able to test three different modalities. This tells us some things about the pathophysiology for HS, which is a very profoundly intensive inflammatory process,” which, Dr. Kimball said, “may require multiple modalities of action to get it under control.” In addition, these “general modalities seem to safe and well tolerated,” she added.
Take-homes for practice and future research
“While it is disappointing that two of the drugs tested did not clearly demonstrate efficacy, it is very possible that these mechanisms of action may be successful targets in the future as new dosing strategies and drugs targeting these pathways are developed,” Dr. Sayed said.
A case in point, he added, was that “adalimumab did not meet treatment endpoints at a dose of 40 mg every other week, but clearly has made a major impact at 40 mg weekly.”
The bottom line is that “both secukinumab and beprocitinib demonstrated efficacy over placebo and are likely to be helpful for a significant number of patients with HS,” Dr. Sayed said. “Hopefully, we’ll see head-to-head trials and more data regarding proportions of patients with deeper responses using criteria such as HiSCR75 and HiSCR90.”
Moreover, “having a larger number of drugs with a range of mechanisms of action is extraordinarily helpful given how difficult the disease can be to manage. We will hopefully continue to see creative approaches and further successes in the current wave of phase 1, 2, and 3 trials that are already underway.”
The SUNSHINE and SUNRISE studies were funded by Novartis Pharma AG, Basel, Switzerland. The phase 2A study Dr. Kimball presented was sponsored by Pfizer.
Dr. Kimball disclosed ties to both Novartis and Pfizer and acts as a consultant and investigator to AbbVie, Bristol-Myers Squibb, Janssen, Eli Lilly, Novartis, and UCB. She is an investigator for Incyte and AnaptysBio; acts as a consultant to Bayer, Boehringer Ingelheim, Ventyz, Moonlake, Lily, Concert, EvoImmune, Sonoma Bio, and Sanofi; receives fellowship funding from Janssen, and serves on the Board of Directors for Almirall.
Dr. Patel had no conflicts of interest to disclose. Dr. Sayed is the director of the HS Foundation, a nonprofit organization, and has acted as an adviser or consultant to, speaker for, and received research funding from multiple drug companies including AbbVie, ChemoCentryx, Incyte, InflaRx, Novartis, and UCB.
A version of this article first appeared on Medscape.com.
in separate trials.
Around 40%-50% of patients exhibited a clinical response to these agents at 16 weeks, a leading HS expert reported at the annual congress of the European Academy of Dermatology and Venereology.
Time in the spotlight for HS
Research into HS is “an incredibly active field at this moment,” said Alexa B. Kimball, MD, MPH, professor of dermatology, Harvard Medical School, and president and chief executive officer of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, Boston.
It’s “been great for advancing our understanding of the biology and the treatments that we will be able to use,” she said.
During the late-breaking sessions at the annual EADV Congress, Dr. Kimball presented data from two trials – SUNSHINE and SUNRISE – that investigated the efficacy, safety and tolerability of the interleukin (IL) 17A inhibitor secukinumab (Cosentyx) versus placebo in the treatment of moderate to severe HS.
“This is only the second phase 3 program we have ever seen in HS and the first one since 2016,” Dr. Kimball said of the trials. It’s also the largest trial program in HS conducted to date, she added, “so it really is a milestone.”
The last big development was when adalimumab, a tumor necrosis factor (TNF) blocker, gained regulatory approval for HS in 2016, observed Neil Patel, PhD, MRCP, who leads the HS service at Imperial College Healthcare NHS Trust in London.
“Adalimumab has been very helpful for many patients, but not all patients respond, and others may respond initially but then the treatment starts to fail after a year or 2,” Dr. Patel said in an interview with this news organization.
“There is definitely a huge need for alternative medication for this condition, which still has a lack of effective treatment options,” added Dr. Patel, who was not involved in either of the studies.
“One major upside for secukinumab is that its safety profile is generally very good and familiarity in the dermatologic community is already well established,” Christopher Sayed, MD, said in a separate interview.
“This will make most providers very comfortable offering it as a potential treatment option sooner rather than later given that its efficacy has now been demonstrated in phase 3 trials,” added Dr. Sayed, associate professor of dermatology at the University of North Carolina at Chapel Hill.
Two identically designed trials
Altogether, SUNSHINE and SUNRISE enrolled just over 1,000 patients at 219 sites in 33 countries. Both trials were identical in their design: A 4-week run-in phase before a randomized, double-blind treatment phase that tested two dosing regimens of secukinumab (300 mg administered subcutaneously) every 2 or 4 weeks vs. placebo for 16 weeks. The trial continued after this time, with patients in the placebo arm re–randomly assigned to treatment with one of the two secukinumab regimens out to a year.
The primary endpoint was the percentage of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR) after 16 weeks of treatment, with key secondary endpoints, which were abscess and inflammatory nodule (AN) count, occurrence of flares, and at least a 30% reduction in Patient’s Global Assessment of Skin Pain assessed using a numeric rating scale (NPRS30).
Secukinumab superior to placebo
The HiSCR is defined as at least a 50% decrease in AN count with no increase in the number of abscesses or in the number of draining fistulas relative to baseline. This was achieved by about 42%-45% of patients who received secukinumab every 2 weeks, about 42%-46% of those who received secukinumab every 4 weeks, and about 31%-33% of those on placebo in both studies.
Of note, fewer patients treated with secukinumab (about 15%-20% among those treated every 2 weeks, and about 15% to 23% among those treated every 4 weeks) than those on placebo (27%-29%) experienced flares, defined as at least a 25% increase in AN count and at least a two-point increase relative to baseline values.
Improvement in HS pain can be a difficult parameter to meet, Dr. Kimball noted. “Pain is such an important feature of this disease as it so debilitating for the patients.” More than one-third (almost 36%-39%) of patients given secukinumab vs. just over a quarter (26.9%) given placebo achieved at least a 30% reduction in NPRS30 ratings, she reported. The difference between active and placebo treatment was significant only when secukinumab was given every 2 weeks, however.
“The placebo rates that we see in these studies are exactly parallel to what we saw in other studies, and other disease states when we had a 50% bar of improvement,” Dr. Kimball said when questioned about these results.
“HS is a highly variable disease; it’s maybe not so much the placebo rate or the scoring system used but maybe the 50% bar set for improvement is too low. It’s likely, as data start to mature and a 75% HiSCR can be calculated, that the placebo rates will drop,” she said.
There were no surprises when it came to the safety of secukinumab, being an old player in a new game, she noted. It was “well tolerated” and tolerability was “consistent with the known safety profile,” Dr. Kimball said, “so we expect it to be a new, safe, and effective add to our armamentarium in treating this disease.”
This research involves “basically borrowing drugs from other areas and trying them in HS to see what effect they may have,” Dr. Patel said, noting that drugs such as adalimumab and secukinumab already had a proven track record in other diseases, such as psoriasis. “These early data for secukinumab definitely are very exciting, but we would need to see real-life results” in patients with HS who are not enrolled in trials to see the benefits, he added.
‘Tipping point’ for HS research
“I think we will look back on this meeting and realize that it was an incredibly important tipping point for the treatment of this incredibly debilitating disease,” Dr. Kimball said.
Elsewhere at the meeting, she had presented findings from a phase 2a study that pitted three different kinase inhibitors with different modes of action against each other and compared them with placebo.
The three agents evaluated are an IL-1 receptor–associated kinase 4 inhibitor known as PF-06650833, a tyrosine kinase 2 (TYK2) JAK1 inhibitor brepocitinib, and the TYK2 inhibitor PF-06826647.
“This technique has been used in oncology,” Dr. Kimball said, noting that the ability to test multiple drugs at the same time “means we can really much more efficiently test two different things at the same time, and also put fewer patients at risk for potential problems if drugs don’t work.”
Positive signs for brepocitinib, not the other kinases tested
The results showed that though brepocitinib worked in HS, the other two novel compounds did not appear to have beneficial effects. Just over half (52%) of the 52 patients treated with brepocitinib achieved an HiSCR at 16 weeks, compared with around one-third of those given placebo, PF-06650833, or PF-06826647.
A similar benefit was seen in terms of reduction in flares for brepocitinib but not the other agents, although there was no difference between them all in terms of NPRS30 pain reduction.
“We’ve been able to test three different modalities. This tells us some things about the pathophysiology for HS, which is a very profoundly intensive inflammatory process,” which, Dr. Kimball said, “may require multiple modalities of action to get it under control.” In addition, these “general modalities seem to safe and well tolerated,” she added.
Take-homes for practice and future research
“While it is disappointing that two of the drugs tested did not clearly demonstrate efficacy, it is very possible that these mechanisms of action may be successful targets in the future as new dosing strategies and drugs targeting these pathways are developed,” Dr. Sayed said.
A case in point, he added, was that “adalimumab did not meet treatment endpoints at a dose of 40 mg every other week, but clearly has made a major impact at 40 mg weekly.”
The bottom line is that “both secukinumab and beprocitinib demonstrated efficacy over placebo and are likely to be helpful for a significant number of patients with HS,” Dr. Sayed said. “Hopefully, we’ll see head-to-head trials and more data regarding proportions of patients with deeper responses using criteria such as HiSCR75 and HiSCR90.”
Moreover, “having a larger number of drugs with a range of mechanisms of action is extraordinarily helpful given how difficult the disease can be to manage. We will hopefully continue to see creative approaches and further successes in the current wave of phase 1, 2, and 3 trials that are already underway.”
The SUNSHINE and SUNRISE studies were funded by Novartis Pharma AG, Basel, Switzerland. The phase 2A study Dr. Kimball presented was sponsored by Pfizer.
Dr. Kimball disclosed ties to both Novartis and Pfizer and acts as a consultant and investigator to AbbVie, Bristol-Myers Squibb, Janssen, Eli Lilly, Novartis, and UCB. She is an investigator for Incyte and AnaptysBio; acts as a consultant to Bayer, Boehringer Ingelheim, Ventyz, Moonlake, Lily, Concert, EvoImmune, Sonoma Bio, and Sanofi; receives fellowship funding from Janssen, and serves on the Board of Directors for Almirall.
Dr. Patel had no conflicts of interest to disclose. Dr. Sayed is the director of the HS Foundation, a nonprofit organization, and has acted as an adviser or consultant to, speaker for, and received research funding from multiple drug companies including AbbVie, ChemoCentryx, Incyte, InflaRx, Novartis, and UCB.
A version of this article first appeared on Medscape.com.
in separate trials.
Around 40%-50% of patients exhibited a clinical response to these agents at 16 weeks, a leading HS expert reported at the annual congress of the European Academy of Dermatology and Venereology.
Time in the spotlight for HS
Research into HS is “an incredibly active field at this moment,” said Alexa B. Kimball, MD, MPH, professor of dermatology, Harvard Medical School, and president and chief executive officer of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, Boston.
It’s “been great for advancing our understanding of the biology and the treatments that we will be able to use,” she said.
During the late-breaking sessions at the annual EADV Congress, Dr. Kimball presented data from two trials – SUNSHINE and SUNRISE – that investigated the efficacy, safety and tolerability of the interleukin (IL) 17A inhibitor secukinumab (Cosentyx) versus placebo in the treatment of moderate to severe HS.
“This is only the second phase 3 program we have ever seen in HS and the first one since 2016,” Dr. Kimball said of the trials. It’s also the largest trial program in HS conducted to date, she added, “so it really is a milestone.”
The last big development was when adalimumab, a tumor necrosis factor (TNF) blocker, gained regulatory approval for HS in 2016, observed Neil Patel, PhD, MRCP, who leads the HS service at Imperial College Healthcare NHS Trust in London.
“Adalimumab has been very helpful for many patients, but not all patients respond, and others may respond initially but then the treatment starts to fail after a year or 2,” Dr. Patel said in an interview with this news organization.
“There is definitely a huge need for alternative medication for this condition, which still has a lack of effective treatment options,” added Dr. Patel, who was not involved in either of the studies.
“One major upside for secukinumab is that its safety profile is generally very good and familiarity in the dermatologic community is already well established,” Christopher Sayed, MD, said in a separate interview.
“This will make most providers very comfortable offering it as a potential treatment option sooner rather than later given that its efficacy has now been demonstrated in phase 3 trials,” added Dr. Sayed, associate professor of dermatology at the University of North Carolina at Chapel Hill.
Two identically designed trials
Altogether, SUNSHINE and SUNRISE enrolled just over 1,000 patients at 219 sites in 33 countries. Both trials were identical in their design: A 4-week run-in phase before a randomized, double-blind treatment phase that tested two dosing regimens of secukinumab (300 mg administered subcutaneously) every 2 or 4 weeks vs. placebo for 16 weeks. The trial continued after this time, with patients in the placebo arm re–randomly assigned to treatment with one of the two secukinumab regimens out to a year.
The primary endpoint was the percentage of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR) after 16 weeks of treatment, with key secondary endpoints, which were abscess and inflammatory nodule (AN) count, occurrence of flares, and at least a 30% reduction in Patient’s Global Assessment of Skin Pain assessed using a numeric rating scale (NPRS30).
Secukinumab superior to placebo
The HiSCR is defined as at least a 50% decrease in AN count with no increase in the number of abscesses or in the number of draining fistulas relative to baseline. This was achieved by about 42%-45% of patients who received secukinumab every 2 weeks, about 42%-46% of those who received secukinumab every 4 weeks, and about 31%-33% of those on placebo in both studies.
Of note, fewer patients treated with secukinumab (about 15%-20% among those treated every 2 weeks, and about 15% to 23% among those treated every 4 weeks) than those on placebo (27%-29%) experienced flares, defined as at least a 25% increase in AN count and at least a two-point increase relative to baseline values.
Improvement in HS pain can be a difficult parameter to meet, Dr. Kimball noted. “Pain is such an important feature of this disease as it so debilitating for the patients.” More than one-third (almost 36%-39%) of patients given secukinumab vs. just over a quarter (26.9%) given placebo achieved at least a 30% reduction in NPRS30 ratings, she reported. The difference between active and placebo treatment was significant only when secukinumab was given every 2 weeks, however.
“The placebo rates that we see in these studies are exactly parallel to what we saw in other studies, and other disease states when we had a 50% bar of improvement,” Dr. Kimball said when questioned about these results.
“HS is a highly variable disease; it’s maybe not so much the placebo rate or the scoring system used but maybe the 50% bar set for improvement is too low. It’s likely, as data start to mature and a 75% HiSCR can be calculated, that the placebo rates will drop,” she said.
There were no surprises when it came to the safety of secukinumab, being an old player in a new game, she noted. It was “well tolerated” and tolerability was “consistent with the known safety profile,” Dr. Kimball said, “so we expect it to be a new, safe, and effective add to our armamentarium in treating this disease.”
This research involves “basically borrowing drugs from other areas and trying them in HS to see what effect they may have,” Dr. Patel said, noting that drugs such as adalimumab and secukinumab already had a proven track record in other diseases, such as psoriasis. “These early data for secukinumab definitely are very exciting, but we would need to see real-life results” in patients with HS who are not enrolled in trials to see the benefits, he added.
‘Tipping point’ for HS research
“I think we will look back on this meeting and realize that it was an incredibly important tipping point for the treatment of this incredibly debilitating disease,” Dr. Kimball said.
Elsewhere at the meeting, she had presented findings from a phase 2a study that pitted three different kinase inhibitors with different modes of action against each other and compared them with placebo.
The three agents evaluated are an IL-1 receptor–associated kinase 4 inhibitor known as PF-06650833, a tyrosine kinase 2 (TYK2) JAK1 inhibitor brepocitinib, and the TYK2 inhibitor PF-06826647.
“This technique has been used in oncology,” Dr. Kimball said, noting that the ability to test multiple drugs at the same time “means we can really much more efficiently test two different things at the same time, and also put fewer patients at risk for potential problems if drugs don’t work.”
Positive signs for brepocitinib, not the other kinases tested
The results showed that though brepocitinib worked in HS, the other two novel compounds did not appear to have beneficial effects. Just over half (52%) of the 52 patients treated with brepocitinib achieved an HiSCR at 16 weeks, compared with around one-third of those given placebo, PF-06650833, or PF-06826647.
A similar benefit was seen in terms of reduction in flares for brepocitinib but not the other agents, although there was no difference between them all in terms of NPRS30 pain reduction.
“We’ve been able to test three different modalities. This tells us some things about the pathophysiology for HS, which is a very profoundly intensive inflammatory process,” which, Dr. Kimball said, “may require multiple modalities of action to get it under control.” In addition, these “general modalities seem to safe and well tolerated,” she added.
Take-homes for practice and future research
“While it is disappointing that two of the drugs tested did not clearly demonstrate efficacy, it is very possible that these mechanisms of action may be successful targets in the future as new dosing strategies and drugs targeting these pathways are developed,” Dr. Sayed said.
A case in point, he added, was that “adalimumab did not meet treatment endpoints at a dose of 40 mg every other week, but clearly has made a major impact at 40 mg weekly.”
The bottom line is that “both secukinumab and beprocitinib demonstrated efficacy over placebo and are likely to be helpful for a significant number of patients with HS,” Dr. Sayed said. “Hopefully, we’ll see head-to-head trials and more data regarding proportions of patients with deeper responses using criteria such as HiSCR75 and HiSCR90.”
Moreover, “having a larger number of drugs with a range of mechanisms of action is extraordinarily helpful given how difficult the disease can be to manage. We will hopefully continue to see creative approaches and further successes in the current wave of phase 1, 2, and 3 trials that are already underway.”
The SUNSHINE and SUNRISE studies were funded by Novartis Pharma AG, Basel, Switzerland. The phase 2A study Dr. Kimball presented was sponsored by Pfizer.
Dr. Kimball disclosed ties to both Novartis and Pfizer and acts as a consultant and investigator to AbbVie, Bristol-Myers Squibb, Janssen, Eli Lilly, Novartis, and UCB. She is an investigator for Incyte and AnaptysBio; acts as a consultant to Bayer, Boehringer Ingelheim, Ventyz, Moonlake, Lily, Concert, EvoImmune, Sonoma Bio, and Sanofi; receives fellowship funding from Janssen, and serves on the Board of Directors for Almirall.
Dr. Patel had no conflicts of interest to disclose. Dr. Sayed is the director of the HS Foundation, a nonprofit organization, and has acted as an adviser or consultant to, speaker for, and received research funding from multiple drug companies including AbbVie, ChemoCentryx, Incyte, InflaRx, Novartis, and UCB.
A version of this article first appeared on Medscape.com.
FROM THE EADV CONGRESS
Experts express caution over type 2 diabetes/tea-drinking claim
type 2 diabetes/tea-drinking claim
A claim that drinking tea might protect people against developing type 2 diabetes has been met with caution from multiple experts ahead of the annual meeting of the European Association for the Study of Diabetes.
The claim is that people who drink four or more cups of tea every day – specifically green, Oolong, or black tea – are 17% less likely to develop type 2 diabetes than those who do not drink tea. Drinking fewer cups of tea per day was not found to confer any benefit.
“Our results are exciting because they suggest that people can do something as simple as drinking four cups of tea a day to potentially lessen their risk of developing type 2 diabetes,” Xiaying Li of Wuhan (China) University of Science and Technology is quoted as saying in an official EASD press release.
“It is possible that particular components in tea, such as polyphenols, may reduce blood glucose levels, but a sufficient amount of these bioactive compounds may be needed to be effective,” Dr. Li added.
“The words ‘suggest’ and ‘potentially’ are crucial here,” said Kevin McConway, PhD, MSc, MBA, emeritus professor of applied statistics at The Open University, said in a separate statement to the press that reeled in Dr. Li’s enthusiasm.
“Tea drinking would only be useful for reducing diabetes risk if the tea drinking causes reductions in risk, that is, if the risk is reduced if you drink the tea and not if you don’t – and this study simply can’t show whether it does this or not,” Dr. Conway stressed.
Naveed Sattar, FMedSci FRCPath FRCPGlas FRSE, professor of metabolic medicine at the University of Glasgow, was also cautiously critical. “There is no good trial evidence whatsoever that the chemicals in tea prevent diabetes,” he observed separately.
“So, I suspect its more about tea being healthier (less calorific) than many alternative drinks or tea drinkers leading healthier lives more generally.”
Dr. Sattar added that it could be that people who drink tea might also be avoiding drinking more harmful sugary drinks and have other health behaviors that might lead them to have a lower risk for type 2 diabetes.
Time for tea?
Dr. Li will present the findings of two analyses on Sept. 21 at the EASD meeting: the first a large observational cohort study and the second an updated systematic review and meta-analysis.
For the cohort study, Dr. Li and her coauthors took data on more than 5,100 adults who had participated in the long-running and ongoing China Health and Nutrition Survey (CHNS). Information on tea drinking behavior was extracted from questionnaires that had been filled out at two time points – 1997 and 2009 – and they determined whether people had developed type 2 diabetes according to American Diabetes Association criteria.
Nearly half, 45.8%, were found to be tea drinkers, and 10% of the population they sampled had developed type 2 diabetes. No association between tea drinking and type 2 diabetes development was found, however, with the hazard ratio comparing tea drinkers and non–tea drinkers sitting firmly at 1.02. Moreover, a sensitivity analysis that excluded participants who had developed type 2 diabetes in the first 3 years of follow-up did not change the result.
Things were slightly different when Dr. Li and associates performed their meta-analysis that involved analyzing data on more than 1 million participants in 19 studies conducted in eight countries that had been published up to September 2021.
Here, they found there was a significant (P < .003) linear association between tea consumption and having type 2 diabetes, with the relative risk of developing type 2 diabetes decreasing by 0.986 for every additional cup of tea that was drunk.
HRs for the development of type 2 diabetes in tea drinkers versus non–tea drinkers were 1.00 for those who drank less than one cup per day, 0.96 for those who had one to two cups, and 0.84 for those who drank four or more cups.
“While more research needs to be done to determine the exact dosage and mechanisms behind these observations, our findings suggest that drinking tea is beneficial in reducing the risk of type 2 diabetes, but only at high doses (at least 4 cups a day)”, said Dr. Li.
Perhaps, “we did not find an association between tea drinking and type 2 diabetes in our cohort study because we did not look at higher tea consumption,” she added.
Tempest in a teacup
“This is large, observational data. It’s not a randomized controlled trial so there’s plenty of room for data to be misunderstood,” warned Matt Sydes, MSc, professor of clinical trials & methodology at the MRC Clinical Trials Unit, University College London.
“Everyone drinks fluids. If there is an effect here (and that’s a big if), it might be not about the tea they drink, but about what they don’t drink. One can’t tell at the moment. It seems unlikely that a large randomized controlled trial could be done to disambiguate” added Dr. Sydes
“Being only a conference abstract, it is difficult to assess the quality of this research,” Baptiste Leurent, PhD, a medical statistician also working at University College London, said. Not only was the cohort study observational, so were all the other studies included in the meta-analysis, he pointed out.
“Therefore, no cause-effect conclusions can be drawn. The association could simply be due to other factors, such as those drinking more tea having a healthier lifestyle. It does not seem that the authors tried to control for confounders, which is usually difficult in meta-analysis,” Dr. Leurent said.
“There is reason to be a bit skeptical at this point; we really need to have the full details to assess it properly,” said Jonathan Cook of the Centre for Statistics in Medicine at the University of Oxford (England). “It’s a fair attempt to look at this, but not cutting edge, [using] fairly standard approaches.”
Similar studies have shown a reduced risk associated with coffee drinking, noted Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University in Birmingham.
“The important take-home message is that lifestyle is important in managing risk of developing type 2 diabetes,” Dr. Mellor said.
“That includes choosing low-calorie drinks including mainly water as well as unsweetened tea and coffee as your drinks of choice as part of a healthy lifestyle.”
The study was funded by the Young Talents Project of Hubei Provincial Health Commission, the Science and Technology Research Key Project of Education Department of Hubei Province, the Sanuo Diabetes Charity Foundation, and the Xiangyang Science and Technology Plan Project, all based in China. Dr. Li had no conflicts of interest to disclose. Dr. McConway is a Trustee and on the advisory committee of The Science Media Centre. Dr. Sattar has consulted for many companies that make diabetes and cardiovascular drugs and has been involved in multiple trials of lifestyle approaches for the prevention and remission of diabetes. Dr. Sydes, Dr. Leurent, Dr. Cook, and Dr. Mellor had no conflicts of interest to report.
A claim that drinking tea might protect people against developing type 2 diabetes has been met with caution from multiple experts ahead of the annual meeting of the European Association for the Study of Diabetes.
The claim is that people who drink four or more cups of tea every day – specifically green, Oolong, or black tea – are 17% less likely to develop type 2 diabetes than those who do not drink tea. Drinking fewer cups of tea per day was not found to confer any benefit.
“Our results are exciting because they suggest that people can do something as simple as drinking four cups of tea a day to potentially lessen their risk of developing type 2 diabetes,” Xiaying Li of Wuhan (China) University of Science and Technology is quoted as saying in an official EASD press release.
“It is possible that particular components in tea, such as polyphenols, may reduce blood glucose levels, but a sufficient amount of these bioactive compounds may be needed to be effective,” Dr. Li added.
“The words ‘suggest’ and ‘potentially’ are crucial here,” said Kevin McConway, PhD, MSc, MBA, emeritus professor of applied statistics at The Open University, said in a separate statement to the press that reeled in Dr. Li’s enthusiasm.
“Tea drinking would only be useful for reducing diabetes risk if the tea drinking causes reductions in risk, that is, if the risk is reduced if you drink the tea and not if you don’t – and this study simply can’t show whether it does this or not,” Dr. Conway stressed.
Naveed Sattar, FMedSci FRCPath FRCPGlas FRSE, professor of metabolic medicine at the University of Glasgow, was also cautiously critical. “There is no good trial evidence whatsoever that the chemicals in tea prevent diabetes,” he observed separately.
“So, I suspect its more about tea being healthier (less calorific) than many alternative drinks or tea drinkers leading healthier lives more generally.”
Dr. Sattar added that it could be that people who drink tea might also be avoiding drinking more harmful sugary drinks and have other health behaviors that might lead them to have a lower risk for type 2 diabetes.
Time for tea?
Dr. Li will present the findings of two analyses on Sept. 21 at the EASD meeting: the first a large observational cohort study and the second an updated systematic review and meta-analysis.
For the cohort study, Dr. Li and her coauthors took data on more than 5,100 adults who had participated in the long-running and ongoing China Health and Nutrition Survey (CHNS). Information on tea drinking behavior was extracted from questionnaires that had been filled out at two time points – 1997 and 2009 – and they determined whether people had developed type 2 diabetes according to American Diabetes Association criteria.
Nearly half, 45.8%, were found to be tea drinkers, and 10% of the population they sampled had developed type 2 diabetes. No association between tea drinking and type 2 diabetes development was found, however, with the hazard ratio comparing tea drinkers and non–tea drinkers sitting firmly at 1.02. Moreover, a sensitivity analysis that excluded participants who had developed type 2 diabetes in the first 3 years of follow-up did not change the result.
Things were slightly different when Dr. Li and associates performed their meta-analysis that involved analyzing data on more than 1 million participants in 19 studies conducted in eight countries that had been published up to September 2021.
Here, they found there was a significant (P < .003) linear association between tea consumption and having type 2 diabetes, with the relative risk of developing type 2 diabetes decreasing by 0.986 for every additional cup of tea that was drunk.
HRs for the development of type 2 diabetes in tea drinkers versus non–tea drinkers were 1.00 for those who drank less than one cup per day, 0.96 for those who had one to two cups, and 0.84 for those who drank four or more cups.
“While more research needs to be done to determine the exact dosage and mechanisms behind these observations, our findings suggest that drinking tea is beneficial in reducing the risk of type 2 diabetes, but only at high doses (at least 4 cups a day)”, said Dr. Li.
Perhaps, “we did not find an association between tea drinking and type 2 diabetes in our cohort study because we did not look at higher tea consumption,” she added.
Tempest in a teacup
“This is large, observational data. It’s not a randomized controlled trial so there’s plenty of room for data to be misunderstood,” warned Matt Sydes, MSc, professor of clinical trials & methodology at the MRC Clinical Trials Unit, University College London.
“Everyone drinks fluids. If there is an effect here (and that’s a big if), it might be not about the tea they drink, but about what they don’t drink. One can’t tell at the moment. It seems unlikely that a large randomized controlled trial could be done to disambiguate” added Dr. Sydes
“Being only a conference abstract, it is difficult to assess the quality of this research,” Baptiste Leurent, PhD, a medical statistician also working at University College London, said. Not only was the cohort study observational, so were all the other studies included in the meta-analysis, he pointed out.
“Therefore, no cause-effect conclusions can be drawn. The association could simply be due to other factors, such as those drinking more tea having a healthier lifestyle. It does not seem that the authors tried to control for confounders, which is usually difficult in meta-analysis,” Dr. Leurent said.
“There is reason to be a bit skeptical at this point; we really need to have the full details to assess it properly,” said Jonathan Cook of the Centre for Statistics in Medicine at the University of Oxford (England). “It’s a fair attempt to look at this, but not cutting edge, [using] fairly standard approaches.”
Similar studies have shown a reduced risk associated with coffee drinking, noted Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University in Birmingham.
“The important take-home message is that lifestyle is important in managing risk of developing type 2 diabetes,” Dr. Mellor said.
“That includes choosing low-calorie drinks including mainly water as well as unsweetened tea and coffee as your drinks of choice as part of a healthy lifestyle.”
The study was funded by the Young Talents Project of Hubei Provincial Health Commission, the Science and Technology Research Key Project of Education Department of Hubei Province, the Sanuo Diabetes Charity Foundation, and the Xiangyang Science and Technology Plan Project, all based in China. Dr. Li had no conflicts of interest to disclose. Dr. McConway is a Trustee and on the advisory committee of The Science Media Centre. Dr. Sattar has consulted for many companies that make diabetes and cardiovascular drugs and has been involved in multiple trials of lifestyle approaches for the prevention and remission of diabetes. Dr. Sydes, Dr. Leurent, Dr. Cook, and Dr. Mellor had no conflicts of interest to report.
A claim that drinking tea might protect people against developing type 2 diabetes has been met with caution from multiple experts ahead of the annual meeting of the European Association for the Study of Diabetes.
The claim is that people who drink four or more cups of tea every day – specifically green, Oolong, or black tea – are 17% less likely to develop type 2 diabetes than those who do not drink tea. Drinking fewer cups of tea per day was not found to confer any benefit.
“Our results are exciting because they suggest that people can do something as simple as drinking four cups of tea a day to potentially lessen their risk of developing type 2 diabetes,” Xiaying Li of Wuhan (China) University of Science and Technology is quoted as saying in an official EASD press release.
“It is possible that particular components in tea, such as polyphenols, may reduce blood glucose levels, but a sufficient amount of these bioactive compounds may be needed to be effective,” Dr. Li added.
“The words ‘suggest’ and ‘potentially’ are crucial here,” said Kevin McConway, PhD, MSc, MBA, emeritus professor of applied statistics at The Open University, said in a separate statement to the press that reeled in Dr. Li’s enthusiasm.
“Tea drinking would only be useful for reducing diabetes risk if the tea drinking causes reductions in risk, that is, if the risk is reduced if you drink the tea and not if you don’t – and this study simply can’t show whether it does this or not,” Dr. Conway stressed.
Naveed Sattar, FMedSci FRCPath FRCPGlas FRSE, professor of metabolic medicine at the University of Glasgow, was also cautiously critical. “There is no good trial evidence whatsoever that the chemicals in tea prevent diabetes,” he observed separately.
“So, I suspect its more about tea being healthier (less calorific) than many alternative drinks or tea drinkers leading healthier lives more generally.”
Dr. Sattar added that it could be that people who drink tea might also be avoiding drinking more harmful sugary drinks and have other health behaviors that might lead them to have a lower risk for type 2 diabetes.
Time for tea?
Dr. Li will present the findings of two analyses on Sept. 21 at the EASD meeting: the first a large observational cohort study and the second an updated systematic review and meta-analysis.
For the cohort study, Dr. Li and her coauthors took data on more than 5,100 adults who had participated in the long-running and ongoing China Health and Nutrition Survey (CHNS). Information on tea drinking behavior was extracted from questionnaires that had been filled out at two time points – 1997 and 2009 – and they determined whether people had developed type 2 diabetes according to American Diabetes Association criteria.
Nearly half, 45.8%, were found to be tea drinkers, and 10% of the population they sampled had developed type 2 diabetes. No association between tea drinking and type 2 diabetes development was found, however, with the hazard ratio comparing tea drinkers and non–tea drinkers sitting firmly at 1.02. Moreover, a sensitivity analysis that excluded participants who had developed type 2 diabetes in the first 3 years of follow-up did not change the result.
Things were slightly different when Dr. Li and associates performed their meta-analysis that involved analyzing data on more than 1 million participants in 19 studies conducted in eight countries that had been published up to September 2021.
Here, they found there was a significant (P < .003) linear association between tea consumption and having type 2 diabetes, with the relative risk of developing type 2 diabetes decreasing by 0.986 for every additional cup of tea that was drunk.
HRs for the development of type 2 diabetes in tea drinkers versus non–tea drinkers were 1.00 for those who drank less than one cup per day, 0.96 for those who had one to two cups, and 0.84 for those who drank four or more cups.
“While more research needs to be done to determine the exact dosage and mechanisms behind these observations, our findings suggest that drinking tea is beneficial in reducing the risk of type 2 diabetes, but only at high doses (at least 4 cups a day)”, said Dr. Li.
Perhaps, “we did not find an association between tea drinking and type 2 diabetes in our cohort study because we did not look at higher tea consumption,” she added.
Tempest in a teacup
“This is large, observational data. It’s not a randomized controlled trial so there’s plenty of room for data to be misunderstood,” warned Matt Sydes, MSc, professor of clinical trials & methodology at the MRC Clinical Trials Unit, University College London.
“Everyone drinks fluids. If there is an effect here (and that’s a big if), it might be not about the tea they drink, but about what they don’t drink. One can’t tell at the moment. It seems unlikely that a large randomized controlled trial could be done to disambiguate” added Dr. Sydes
“Being only a conference abstract, it is difficult to assess the quality of this research,” Baptiste Leurent, PhD, a medical statistician also working at University College London, said. Not only was the cohort study observational, so were all the other studies included in the meta-analysis, he pointed out.
“Therefore, no cause-effect conclusions can be drawn. The association could simply be due to other factors, such as those drinking more tea having a healthier lifestyle. It does not seem that the authors tried to control for confounders, which is usually difficult in meta-analysis,” Dr. Leurent said.
“There is reason to be a bit skeptical at this point; we really need to have the full details to assess it properly,” said Jonathan Cook of the Centre for Statistics in Medicine at the University of Oxford (England). “It’s a fair attempt to look at this, but not cutting edge, [using] fairly standard approaches.”
Similar studies have shown a reduced risk associated with coffee drinking, noted Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University in Birmingham.
“The important take-home message is that lifestyle is important in managing risk of developing type 2 diabetes,” Dr. Mellor said.
“That includes choosing low-calorie drinks including mainly water as well as unsweetened tea and coffee as your drinks of choice as part of a healthy lifestyle.”
The study was funded by the Young Talents Project of Hubei Provincial Health Commission, the Science and Technology Research Key Project of Education Department of Hubei Province, the Sanuo Diabetes Charity Foundation, and the Xiangyang Science and Technology Plan Project, all based in China. Dr. Li had no conflicts of interest to disclose. Dr. McConway is a Trustee and on the advisory committee of The Science Media Centre. Dr. Sattar has consulted for many companies that make diabetes and cardiovascular drugs and has been involved in multiple trials of lifestyle approaches for the prevention and remission of diabetes. Dr. Sydes, Dr. Leurent, Dr. Cook, and Dr. Mellor had no conflicts of interest to report.
type 2 diabetes/tea-drinking claim
type 2 diabetes/tea-drinking claim
FROM EASD 2022
Roflumilast foam effectively eases seborrheic dermatitis
.
More than half experienced clearance of their symptoms, and three out of five achieved a significant improvement in pruritus, it was revealed during a late-breaking session at the annual congress of the European Academy of Dermatology and Venereology.
Common condition led to rapid recruitment
“Seborrheic dermatitis is a disease that’s very common, yet in my opinion, undertreated in dermatology,” said Andrew Blauvelt, MD, MBA, who presented the findings.
“It’s so common that when we did this trial, I was very surprised to see how easy it was to recruit,” said Dr. Blauvelt, a dermatologist who is president of the Oregon Medical Research Center, Portland. “Patients came in rapidly, out of the woodwork – they were desperate.”
While there are several tried and tested treatments for the condition, such as topical steroids and antifungal agents, he noted that they have their limitations: “Sometimes efficacy, sometimes the ability to be used on hair-bearing areas.”
Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor that is available for topical use in a 0.3% cream formulation (Zoryve). This formulation gained FDA approval for plaque psoriasis for patients ages 12 and older this summer and is also under investigation as a treatment for atopic dermatitis.
It’s the same product in both preparations, Dr. Blauvelt said during the discussion period. “The only major difference between the cream and the foam is the propellant used to make it into a foam. Otherwise, they have the exact same list of ingredients.”
Dr. Blauvelt reported that just over 450 patients had been recruited at 53 U.S. centers into the 8-week, double-blind, placebo-controlled trial.
For inclusion, patients had to have moderate seborrheic dermatitis, defined as an Investigator’s Global Assessment (IGA) score of three or more. Dr. Blauvelt noted that patients as young as 9 years old could be recruited, and there was no upper age limit. The average age of participating patients, however, was around 42 years.
Multiple improvements seen in ‘happy trial’
The primary endpoint was an IGA score of 0 or 1 with at least a 2-grade improvement (IGA success) after 8 weeks of treatment. This was achieved by 80% of patients who were treated with roflumilast 0.3% foam, compared with 60% of those who were treated with the vehicle (P less than .0001).
Dr. Blauvelt pointed out that significant improvements had also been seen after 2 weeks (about 42% vs. about 26%; P = .0003) and 4 weeks (about 72% vs. about 49%; P less than .0001) of treatment.
“Now if we raise the bar a little higher” and ask how many patients were completely clear of their seborrheic dermatitis, Dr. Blauvelt said, it was 50% at 8 weeks, more than a third at 4 weeks, over 15% at 2 weeks with the foam, and significantly lower at just under 30%, 15%, and 7% in the vehicle group.
A 4-point or more improvement in the Worst Itch Numeric Rating Scale (WI-NRS) – accepted as the minimally clinically important difference – was achieved by more than 60% of patients treated with the foam at week 8, just under 50% at week 4, and just over 30% at week 2. Corresponding rates in the vehicle group were around 40%, 30%, and 15%.
“Many patients responded in this trial. So much so that when I was doing it, I called it the ‘happy trial.’ Every time I saw patients in this trial, they seemed to be happy,” Dr. Blauvelt said anecdotally.
“In terms of adverse events, the drug turned out to be very safe, and there didn’t seem to be any issues with any things that we see with, for example, oral phosphodiesterase inhibitors,” he added.
The tolerability findings suggest that the foam vehicle “was an excellent vehicle to be used for this particular drug,” with no signs of skin irritation, as rated by patients or investigators.
Lesson for practice: Advise patients to moisturize?
“It seems like the vehicle would be a good skincare product for patients,” observed the session’s cochair, Jo Lambert, MD, PhD, professor and academic head of the department of dermatology at Ghent University Hospital, Belgium.
It was “a pretty dramatic vehicle response, right?” Dr. Blauvelt responded. “We normally don’t think of telling seborrheic dermatitis patients to moisturize,” he added.
“I think one of the interesting findings is perhaps we should be telling them to moisturize their scalp or moisturize their face, or it could be something unique to this particular foam.”
The study was funded by Arcutis Biotherapeutics. Dr. Blauvelt disclosed that he was an investigator for the trial and acted as consultant to the company, receiving grants/research funding and/or honoraria. Several of the study’s co-investigators are employees of Arcutis. Dr. Lambert was not involved in the study and cochaired the late-breaking session during which the STRATUM trial findings were reported.
A version of this article first appeared on Medscape.com.
.
More than half experienced clearance of their symptoms, and three out of five achieved a significant improvement in pruritus, it was revealed during a late-breaking session at the annual congress of the European Academy of Dermatology and Venereology.
Common condition led to rapid recruitment
“Seborrheic dermatitis is a disease that’s very common, yet in my opinion, undertreated in dermatology,” said Andrew Blauvelt, MD, MBA, who presented the findings.
“It’s so common that when we did this trial, I was very surprised to see how easy it was to recruit,” said Dr. Blauvelt, a dermatologist who is president of the Oregon Medical Research Center, Portland. “Patients came in rapidly, out of the woodwork – they were desperate.”
While there are several tried and tested treatments for the condition, such as topical steroids and antifungal agents, he noted that they have their limitations: “Sometimes efficacy, sometimes the ability to be used on hair-bearing areas.”
Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor that is available for topical use in a 0.3% cream formulation (Zoryve). This formulation gained FDA approval for plaque psoriasis for patients ages 12 and older this summer and is also under investigation as a treatment for atopic dermatitis.
It’s the same product in both preparations, Dr. Blauvelt said during the discussion period. “The only major difference between the cream and the foam is the propellant used to make it into a foam. Otherwise, they have the exact same list of ingredients.”
Dr. Blauvelt reported that just over 450 patients had been recruited at 53 U.S. centers into the 8-week, double-blind, placebo-controlled trial.
For inclusion, patients had to have moderate seborrheic dermatitis, defined as an Investigator’s Global Assessment (IGA) score of three or more. Dr. Blauvelt noted that patients as young as 9 years old could be recruited, and there was no upper age limit. The average age of participating patients, however, was around 42 years.
Multiple improvements seen in ‘happy trial’
The primary endpoint was an IGA score of 0 or 1 with at least a 2-grade improvement (IGA success) after 8 weeks of treatment. This was achieved by 80% of patients who were treated with roflumilast 0.3% foam, compared with 60% of those who were treated with the vehicle (P less than .0001).
Dr. Blauvelt pointed out that significant improvements had also been seen after 2 weeks (about 42% vs. about 26%; P = .0003) and 4 weeks (about 72% vs. about 49%; P less than .0001) of treatment.
“Now if we raise the bar a little higher” and ask how many patients were completely clear of their seborrheic dermatitis, Dr. Blauvelt said, it was 50% at 8 weeks, more than a third at 4 weeks, over 15% at 2 weeks with the foam, and significantly lower at just under 30%, 15%, and 7% in the vehicle group.
A 4-point or more improvement in the Worst Itch Numeric Rating Scale (WI-NRS) – accepted as the minimally clinically important difference – was achieved by more than 60% of patients treated with the foam at week 8, just under 50% at week 4, and just over 30% at week 2. Corresponding rates in the vehicle group were around 40%, 30%, and 15%.
“Many patients responded in this trial. So much so that when I was doing it, I called it the ‘happy trial.’ Every time I saw patients in this trial, they seemed to be happy,” Dr. Blauvelt said anecdotally.
“In terms of adverse events, the drug turned out to be very safe, and there didn’t seem to be any issues with any things that we see with, for example, oral phosphodiesterase inhibitors,” he added.
The tolerability findings suggest that the foam vehicle “was an excellent vehicle to be used for this particular drug,” with no signs of skin irritation, as rated by patients or investigators.
Lesson for practice: Advise patients to moisturize?
“It seems like the vehicle would be a good skincare product for patients,” observed the session’s cochair, Jo Lambert, MD, PhD, professor and academic head of the department of dermatology at Ghent University Hospital, Belgium.
It was “a pretty dramatic vehicle response, right?” Dr. Blauvelt responded. “We normally don’t think of telling seborrheic dermatitis patients to moisturize,” he added.
“I think one of the interesting findings is perhaps we should be telling them to moisturize their scalp or moisturize their face, or it could be something unique to this particular foam.”
The study was funded by Arcutis Biotherapeutics. Dr. Blauvelt disclosed that he was an investigator for the trial and acted as consultant to the company, receiving grants/research funding and/or honoraria. Several of the study’s co-investigators are employees of Arcutis. Dr. Lambert was not involved in the study and cochaired the late-breaking session during which the STRATUM trial findings were reported.
A version of this article first appeared on Medscape.com.
.
More than half experienced clearance of their symptoms, and three out of five achieved a significant improvement in pruritus, it was revealed during a late-breaking session at the annual congress of the European Academy of Dermatology and Venereology.
Common condition led to rapid recruitment
“Seborrheic dermatitis is a disease that’s very common, yet in my opinion, undertreated in dermatology,” said Andrew Blauvelt, MD, MBA, who presented the findings.
“It’s so common that when we did this trial, I was very surprised to see how easy it was to recruit,” said Dr. Blauvelt, a dermatologist who is president of the Oregon Medical Research Center, Portland. “Patients came in rapidly, out of the woodwork – they were desperate.”
While there are several tried and tested treatments for the condition, such as topical steroids and antifungal agents, he noted that they have their limitations: “Sometimes efficacy, sometimes the ability to be used on hair-bearing areas.”
Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor that is available for topical use in a 0.3% cream formulation (Zoryve). This formulation gained FDA approval for plaque psoriasis for patients ages 12 and older this summer and is also under investigation as a treatment for atopic dermatitis.
It’s the same product in both preparations, Dr. Blauvelt said during the discussion period. “The only major difference between the cream and the foam is the propellant used to make it into a foam. Otherwise, they have the exact same list of ingredients.”
Dr. Blauvelt reported that just over 450 patients had been recruited at 53 U.S. centers into the 8-week, double-blind, placebo-controlled trial.
For inclusion, patients had to have moderate seborrheic dermatitis, defined as an Investigator’s Global Assessment (IGA) score of three or more. Dr. Blauvelt noted that patients as young as 9 years old could be recruited, and there was no upper age limit. The average age of participating patients, however, was around 42 years.
Multiple improvements seen in ‘happy trial’
The primary endpoint was an IGA score of 0 or 1 with at least a 2-grade improvement (IGA success) after 8 weeks of treatment. This was achieved by 80% of patients who were treated with roflumilast 0.3% foam, compared with 60% of those who were treated with the vehicle (P less than .0001).
Dr. Blauvelt pointed out that significant improvements had also been seen after 2 weeks (about 42% vs. about 26%; P = .0003) and 4 weeks (about 72% vs. about 49%; P less than .0001) of treatment.
“Now if we raise the bar a little higher” and ask how many patients were completely clear of their seborrheic dermatitis, Dr. Blauvelt said, it was 50% at 8 weeks, more than a third at 4 weeks, over 15% at 2 weeks with the foam, and significantly lower at just under 30%, 15%, and 7% in the vehicle group.
A 4-point or more improvement in the Worst Itch Numeric Rating Scale (WI-NRS) – accepted as the minimally clinically important difference – was achieved by more than 60% of patients treated with the foam at week 8, just under 50% at week 4, and just over 30% at week 2. Corresponding rates in the vehicle group were around 40%, 30%, and 15%.
“Many patients responded in this trial. So much so that when I was doing it, I called it the ‘happy trial.’ Every time I saw patients in this trial, they seemed to be happy,” Dr. Blauvelt said anecdotally.
“In terms of adverse events, the drug turned out to be very safe, and there didn’t seem to be any issues with any things that we see with, for example, oral phosphodiesterase inhibitors,” he added.
The tolerability findings suggest that the foam vehicle “was an excellent vehicle to be used for this particular drug,” with no signs of skin irritation, as rated by patients or investigators.
Lesson for practice: Advise patients to moisturize?
“It seems like the vehicle would be a good skincare product for patients,” observed the session’s cochair, Jo Lambert, MD, PhD, professor and academic head of the department of dermatology at Ghent University Hospital, Belgium.
It was “a pretty dramatic vehicle response, right?” Dr. Blauvelt responded. “We normally don’t think of telling seborrheic dermatitis patients to moisturize,” he added.
“I think one of the interesting findings is perhaps we should be telling them to moisturize their scalp or moisturize their face, or it could be something unique to this particular foam.”
The study was funded by Arcutis Biotherapeutics. Dr. Blauvelt disclosed that he was an investigator for the trial and acted as consultant to the company, receiving grants/research funding and/or honoraria. Several of the study’s co-investigators are employees of Arcutis. Dr. Lambert was not involved in the study and cochaired the late-breaking session during which the STRATUM trial findings were reported.
A version of this article first appeared on Medscape.com.
FROM THE EADV CONGRESS
Overall survival dips with vitamin D deficiency in melanoma
, according to research presented at the annual congress of the European Academy of Dermatology and Venereology.
Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.
The research adds to existing evidence that “vitamin D levels can play an important and independent role in patients’ survival outcomes,” study investigator Inés Gracia-Darder, MD, told this news organization. “The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients,” said Dr. Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.
Known association, but not much data
“It is not a new finding,” but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.
“Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor,” Dr. De Smedt said in an interview, indicating that it’s not just overall survival that might be affected.
“So we assume that also has an effect on melanoma-specific survival,” she added.
That assumption, however, is not supported by the data Dr. Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.
Retrospective cohort analysis
Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.
For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.
A measurement less than 10 ng/mL is considered vitamin D deficiency, Dr. De Smedt said. “But there is a difference between countries, and there’s also a difference between societies,” noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.
Independent association with overall survival
Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Dr. Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.
Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.
Other predictive factors were having a higher Breslow index, as well as older age and gender.
Time to recommend vitamin D supplementation?
So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?
“In our practice, we analyze the vitamin D levels of our patients,” Dr. Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so they are very likely to become vitamin D deficient.
While dietary changes or supplements might be suggested, there’s no real evidence to support upping vitamin D levels to date, so “future prospective studies are needed,” Dr. Gracia-Darder added.
Such studies have already started, including one in Italy, one in Australia, and another study that Dr. De Smedt has been involved with for the past few years.
Called the ViDMe study, it’s a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.
It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.
“The study is still blinded,” Dr. De Smedt said. “We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results.”
The study reported by Dr. Gracia-Darder did not receive any specific funding. Dr. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. Dr. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.
A version of this article first appeared on Medscape.com.
, according to research presented at the annual congress of the European Academy of Dermatology and Venereology.
Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.
The research adds to existing evidence that “vitamin D levels can play an important and independent role in patients’ survival outcomes,” study investigator Inés Gracia-Darder, MD, told this news organization. “The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients,” said Dr. Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.
Known association, but not much data
“It is not a new finding,” but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.
“Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor,” Dr. De Smedt said in an interview, indicating that it’s not just overall survival that might be affected.
“So we assume that also has an effect on melanoma-specific survival,” she added.
That assumption, however, is not supported by the data Dr. Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.
Retrospective cohort analysis
Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.
For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.
A measurement less than 10 ng/mL is considered vitamin D deficiency, Dr. De Smedt said. “But there is a difference between countries, and there’s also a difference between societies,” noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.
Independent association with overall survival
Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Dr. Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.
Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.
Other predictive factors were having a higher Breslow index, as well as older age and gender.
Time to recommend vitamin D supplementation?
So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?
“In our practice, we analyze the vitamin D levels of our patients,” Dr. Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so they are very likely to become vitamin D deficient.
While dietary changes or supplements might be suggested, there’s no real evidence to support upping vitamin D levels to date, so “future prospective studies are needed,” Dr. Gracia-Darder added.
Such studies have already started, including one in Italy, one in Australia, and another study that Dr. De Smedt has been involved with for the past few years.
Called the ViDMe study, it’s a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.
It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.
“The study is still blinded,” Dr. De Smedt said. “We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results.”
The study reported by Dr. Gracia-Darder did not receive any specific funding. Dr. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. Dr. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.
A version of this article first appeared on Medscape.com.
, according to research presented at the annual congress of the European Academy of Dermatology and Venereology.
Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.
The research adds to existing evidence that “vitamin D levels can play an important and independent role in patients’ survival outcomes,” study investigator Inés Gracia-Darder, MD, told this news organization. “The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients,” said Dr. Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.
Known association, but not much data
“It is not a new finding,” but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.
“Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor,” Dr. De Smedt said in an interview, indicating that it’s not just overall survival that might be affected.
“So we assume that also has an effect on melanoma-specific survival,” she added.
That assumption, however, is not supported by the data Dr. Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.
Retrospective cohort analysis
Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.
For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.
A measurement less than 10 ng/mL is considered vitamin D deficiency, Dr. De Smedt said. “But there is a difference between countries, and there’s also a difference between societies,” noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.
Independent association with overall survival
Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Dr. Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.
Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.
Other predictive factors were having a higher Breslow index, as well as older age and gender.
Time to recommend vitamin D supplementation?
So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?
“In our practice, we analyze the vitamin D levels of our patients,” Dr. Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so they are very likely to become vitamin D deficient.
While dietary changes or supplements might be suggested, there’s no real evidence to support upping vitamin D levels to date, so “future prospective studies are needed,” Dr. Gracia-Darder added.
Such studies have already started, including one in Italy, one in Australia, and another study that Dr. De Smedt has been involved with for the past few years.
Called the ViDMe study, it’s a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.
It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.
“The study is still blinded,” Dr. De Smedt said. “We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results.”
The study reported by Dr. Gracia-Darder did not receive any specific funding. Dr. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. Dr. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.
A version of this article first appeared on Medscape.com.
FROM THE EADV CONGRESS
Finding HBV ‘cure’ may mean going ‘back to the drawing board’
LONDON – Achieving a functional cure for hepatitis B virus (HBV) is not going to be easily achieved with the drugs that are currently in development, according to a presentation at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.
“Intriguing results have been presented at ILC 2022 that must be carefully interpreted,” said Jean-Michel Pawlotsky, MD, PhD, of Henri Mondor Hospital in Créteil, France, during the viral hepatitis highlights session on the closing day of the meeting.
“New HBV drug development looks more complicated than initially expected and its goals and strategies need to be redefined and refocused,” he added
“This is really something that came from the discussions we had during the sessions but also in the corridors,” Dr. Pawlotsky added. “We know it’s going to be difficult; we have to reset, restart – not from zero, but from not much – and revise our strategy,” he suggested.
There are many new drugs under investigation for HBV, Dr. Pawlotsky said, noting that the number of studies being presented at the meeting was reminiscent of the flurry of activity before a functional cure for hepatitis C had been found. “It’s good to see that this is happening again for HBV,” he said.
Indeed, there are many new direct-acting antiviral agents, immunomodulatory, or other approaches being tested, and some of the more advanced studies are “teaching us a few things and probably raising more questions than getting answers,” Dr. Pawlotsky said.
The B-CLEAR study
One these studies is the phase 2b B-CLEAR study presented during the late-breaker session. This study involved bepirovirsen, an antisense oligonucleotide, and tested its efficacy and safety in patients with chronic hepatitis B virus infection who were either on or off stable nucleos(t)ide analogue (NA/NUC) therapy.
A similar proportion (28% and 29%, respectively) of patients achieved an hepatitis B surface antigen (HBsAg) level below the lower limit of quantification at the end of 24 weeks treatment. However, the effect on HBsAg varied according to the treatment arm, with changes to the dosing or switching to placebo indicating that the effect might wane when the treatment is stopped or if the dose is reduced.
“Interestingly, ALT elevations were observed in association with most HBsAg declines,” Dr. Pawlotsky pointed out. “I think we still have to determine whether this is good flare/bad flare, good sign/bad sign, of what is going to happen afterward.”
The REEF studies
Another approach highlighted was the combination of the silencing or small interfering RNA (siRNA) JNJ-3989 with the capsid assembly modulator (CAM) JNJ-6379 in the phase 2 REEF-1 and REEF-2 studies.
REEF-1, conducted in patients who were either hepatitis B e antigen (HBeAg) positive or negative who were not treated with NA/NUC or were NA/NUC suppressed, showed a dose-dependent, but variable effect among individual patients as might be expected at the end of 48 weeks’ treatment. This was sustained at week 72, which was 24 weeks’ follow-up after stopping treatment.
However, pointed out Dr. Pawlotsky “I think the most important part of this is that if you add a CAM on top of the siRNA, you do not improve the effect on HBsAg levels.”
Then there is the REEF-2 study, testing the same combination but in only patients who were NA suppressed or HBeAg negative alongside standard NA/NUC therapy. As well as being the first novel combination treatment trial to report, this was essentially a stopping trial, Kosh Agarwal, BMedSci (Hons), MBBS, MD, one of the study’s investigators explained separately at a media briefing.
Patients (n = 130) were treated for 48 weeks, then all treatment – including NA/NUC – was discontinued, with 48 weeks of follow-up after discontinuation, said Dr. Agarwal, who is a consultant hepatologist based at the Institute of Liver Studies at King’s College Hospital, London. He presented data from the first 24 week period after treatment had ended.
At the end of treatment, the combination had resulted in a mean reduction in HBsAg of 1.89 log10 IU/mL versus a reduction of 0.06 for the NA/NUC-only group, which acted as the control group in this trial. But “no patient in this study lost their surface antigen, i.e., were cured of their hepatitis B in the active arm or in the control arm,” Dr. Agarwal said.
“We didn’t achieve a cure, but a significant proportion were in a ‘controlled’ viral stage,” said Dr. Agarwal. Indeed, during his presentation of the findings, he showed that HBsAg inhibition was maintained in the majority (72%) of patients after stopping the combination.
While the trial’s primary endpoint wasn’t met, “it’s a really important study,” said Dr. Agarwal. “This [study] was fulfilled and delivered in the COVID era, so a lot of patients were looked after very carefully by sites in Europe,” he observed.
Further follow-up from the trial is expected, and Dr. Agarwal said that the subsequent discussion will “take us back to the drawing board to think about whether we need better antiviral treatments or whether we need to think about different combinations, and whether actually stopping treatment with every treatment is the right strategy to take.”
Both Dr. Agarwal and Dr. Pawlotsky flagged up the case of one patient in the trial who had been in the control arm and had experienced severe HBV reactivation that required a liver transplant.
“This patient is a warning signal,” Dr. Pawlotsky suggested in his talk. “When we think about NUC stopping, we have to think about the potential benefit in terms of HbsAg loss but also the potential risks.”
While Dr. Agarwal had noted that it highlights that “careful design of retreatment criteria is important in studies assessing the NA/NUC-stopping concept”.
Monoclonal antibody shows promise
Other combinations could involve an siRNA and an immunomodulatory agent and, during the poster sessions at the meeting, Dr. Agarwal also presented data from an ongoing phase 1 study with a novel, neutralizing monoclonal antibody called VIR-3434.
This monoclonal antibody is novel because it is thought to have several modes of action, first by binding to HBV and affecting its entry into liver cells, then by presenting the virus to T cells and stimulating a ‘vaccinal’ or immune effect, and then by helping the with the clearance of HBsAg and delivery of the virus to dendritic cells.
In the study, single doses of VIR-3434 were found to be well tolerated and to produce rapid reductions in HBsAg, with the highest dose used (300 mg) producing the greatest and most durable effect up to week 8.
VIR-3434 is also being tested in combination with other drugs in the phase 2 MARCH trial. One of these combinations is VIR-3434 together with an investigational siRNA dubbed VIR-2218. Preclinical work presented at ILC 2022 suggests that this combination appears to be capable of reducing HBsAg to a greater extent than using either agent alone.
Rethinking the strategy to get to a cure
Of course, VIR-3434 is one of several immunomodulatory compounds in development. There are therapeutic vaccines, drugs targeting the innate immune response, other monoclonal antibodies, T-cell receptors, checkpoint inhibitors and PD-L1 inhibitors. Then there are other compounds such as entry inhibitors, apoptosis inducers, and farnesoid X receptor agonists.
“I finish this meeting with more questions than answers,” Dr. Pawlotsky said. “What is the right target to enhance specific anti-HBV immunity? Does in vivo induction of immune responses translate into any beneficial effect on HBV infection? Will therapeutic vaccines every work in a viral infection?”
Moreover, he asked, “how can we avoid the side effect of enhancing multiple and complex nonspecific immune responses? Are treatment-induced flares good flares or bad flares? All of these are questions that are really unanswered and that we’ll have to get answers to in the near future.”
The B-CLEAR study was sponsored by GlaxoSmithKline. The REEF-2 study was sponsored by Janssen Research & Development. The VIR-3434 studies were funded by Vir Biotechnology. Dr. Pawlotsky has received grant and research support, acted as a consultant, adviser, or speaker, and participated in advisory boards for multiple pharmaceutical and biotechnology companies. This news organization was unable to verify Dr. Agarwal’s ties to Vir Biotechnology, but he presented one of the posters on VIR-3434 at the meeting and has been involved in the phase 1 study that was reported.
LONDON – Achieving a functional cure for hepatitis B virus (HBV) is not going to be easily achieved with the drugs that are currently in development, according to a presentation at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.
“Intriguing results have been presented at ILC 2022 that must be carefully interpreted,” said Jean-Michel Pawlotsky, MD, PhD, of Henri Mondor Hospital in Créteil, France, during the viral hepatitis highlights session on the closing day of the meeting.
“New HBV drug development looks more complicated than initially expected and its goals and strategies need to be redefined and refocused,” he added
“This is really something that came from the discussions we had during the sessions but also in the corridors,” Dr. Pawlotsky added. “We know it’s going to be difficult; we have to reset, restart – not from zero, but from not much – and revise our strategy,” he suggested.
There are many new drugs under investigation for HBV, Dr. Pawlotsky said, noting that the number of studies being presented at the meeting was reminiscent of the flurry of activity before a functional cure for hepatitis C had been found. “It’s good to see that this is happening again for HBV,” he said.
Indeed, there are many new direct-acting antiviral agents, immunomodulatory, or other approaches being tested, and some of the more advanced studies are “teaching us a few things and probably raising more questions than getting answers,” Dr. Pawlotsky said.
The B-CLEAR study
One these studies is the phase 2b B-CLEAR study presented during the late-breaker session. This study involved bepirovirsen, an antisense oligonucleotide, and tested its efficacy and safety in patients with chronic hepatitis B virus infection who were either on or off stable nucleos(t)ide analogue (NA/NUC) therapy.
A similar proportion (28% and 29%, respectively) of patients achieved an hepatitis B surface antigen (HBsAg) level below the lower limit of quantification at the end of 24 weeks treatment. However, the effect on HBsAg varied according to the treatment arm, with changes to the dosing or switching to placebo indicating that the effect might wane when the treatment is stopped or if the dose is reduced.
“Interestingly, ALT elevations were observed in association with most HBsAg declines,” Dr. Pawlotsky pointed out. “I think we still have to determine whether this is good flare/bad flare, good sign/bad sign, of what is going to happen afterward.”
The REEF studies
Another approach highlighted was the combination of the silencing or small interfering RNA (siRNA) JNJ-3989 with the capsid assembly modulator (CAM) JNJ-6379 in the phase 2 REEF-1 and REEF-2 studies.
REEF-1, conducted in patients who were either hepatitis B e antigen (HBeAg) positive or negative who were not treated with NA/NUC or were NA/NUC suppressed, showed a dose-dependent, but variable effect among individual patients as might be expected at the end of 48 weeks’ treatment. This was sustained at week 72, which was 24 weeks’ follow-up after stopping treatment.
However, pointed out Dr. Pawlotsky “I think the most important part of this is that if you add a CAM on top of the siRNA, you do not improve the effect on HBsAg levels.”
Then there is the REEF-2 study, testing the same combination but in only patients who were NA suppressed or HBeAg negative alongside standard NA/NUC therapy. As well as being the first novel combination treatment trial to report, this was essentially a stopping trial, Kosh Agarwal, BMedSci (Hons), MBBS, MD, one of the study’s investigators explained separately at a media briefing.
Patients (n = 130) were treated for 48 weeks, then all treatment – including NA/NUC – was discontinued, with 48 weeks of follow-up after discontinuation, said Dr. Agarwal, who is a consultant hepatologist based at the Institute of Liver Studies at King’s College Hospital, London. He presented data from the first 24 week period after treatment had ended.
At the end of treatment, the combination had resulted in a mean reduction in HBsAg of 1.89 log10 IU/mL versus a reduction of 0.06 for the NA/NUC-only group, which acted as the control group in this trial. But “no patient in this study lost their surface antigen, i.e., were cured of their hepatitis B in the active arm or in the control arm,” Dr. Agarwal said.
“We didn’t achieve a cure, but a significant proportion were in a ‘controlled’ viral stage,” said Dr. Agarwal. Indeed, during his presentation of the findings, he showed that HBsAg inhibition was maintained in the majority (72%) of patients after stopping the combination.
While the trial’s primary endpoint wasn’t met, “it’s a really important study,” said Dr. Agarwal. “This [study] was fulfilled and delivered in the COVID era, so a lot of patients were looked after very carefully by sites in Europe,” he observed.
Further follow-up from the trial is expected, and Dr. Agarwal said that the subsequent discussion will “take us back to the drawing board to think about whether we need better antiviral treatments or whether we need to think about different combinations, and whether actually stopping treatment with every treatment is the right strategy to take.”
Both Dr. Agarwal and Dr. Pawlotsky flagged up the case of one patient in the trial who had been in the control arm and had experienced severe HBV reactivation that required a liver transplant.
“This patient is a warning signal,” Dr. Pawlotsky suggested in his talk. “When we think about NUC stopping, we have to think about the potential benefit in terms of HbsAg loss but also the potential risks.”
While Dr. Agarwal had noted that it highlights that “careful design of retreatment criteria is important in studies assessing the NA/NUC-stopping concept”.
Monoclonal antibody shows promise
Other combinations could involve an siRNA and an immunomodulatory agent and, during the poster sessions at the meeting, Dr. Agarwal also presented data from an ongoing phase 1 study with a novel, neutralizing monoclonal antibody called VIR-3434.
This monoclonal antibody is novel because it is thought to have several modes of action, first by binding to HBV and affecting its entry into liver cells, then by presenting the virus to T cells and stimulating a ‘vaccinal’ or immune effect, and then by helping the with the clearance of HBsAg and delivery of the virus to dendritic cells.
In the study, single doses of VIR-3434 were found to be well tolerated and to produce rapid reductions in HBsAg, with the highest dose used (300 mg) producing the greatest and most durable effect up to week 8.
VIR-3434 is also being tested in combination with other drugs in the phase 2 MARCH trial. One of these combinations is VIR-3434 together with an investigational siRNA dubbed VIR-2218. Preclinical work presented at ILC 2022 suggests that this combination appears to be capable of reducing HBsAg to a greater extent than using either agent alone.
Rethinking the strategy to get to a cure
Of course, VIR-3434 is one of several immunomodulatory compounds in development. There are therapeutic vaccines, drugs targeting the innate immune response, other monoclonal antibodies, T-cell receptors, checkpoint inhibitors and PD-L1 inhibitors. Then there are other compounds such as entry inhibitors, apoptosis inducers, and farnesoid X receptor agonists.
“I finish this meeting with more questions than answers,” Dr. Pawlotsky said. “What is the right target to enhance specific anti-HBV immunity? Does in vivo induction of immune responses translate into any beneficial effect on HBV infection? Will therapeutic vaccines every work in a viral infection?”
Moreover, he asked, “how can we avoid the side effect of enhancing multiple and complex nonspecific immune responses? Are treatment-induced flares good flares or bad flares? All of these are questions that are really unanswered and that we’ll have to get answers to in the near future.”
The B-CLEAR study was sponsored by GlaxoSmithKline. The REEF-2 study was sponsored by Janssen Research & Development. The VIR-3434 studies were funded by Vir Biotechnology. Dr. Pawlotsky has received grant and research support, acted as a consultant, adviser, or speaker, and participated in advisory boards for multiple pharmaceutical and biotechnology companies. This news organization was unable to verify Dr. Agarwal’s ties to Vir Biotechnology, but he presented one of the posters on VIR-3434 at the meeting and has been involved in the phase 1 study that was reported.
LONDON – Achieving a functional cure for hepatitis B virus (HBV) is not going to be easily achieved with the drugs that are currently in development, according to a presentation at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.
“Intriguing results have been presented at ILC 2022 that must be carefully interpreted,” said Jean-Michel Pawlotsky, MD, PhD, of Henri Mondor Hospital in Créteil, France, during the viral hepatitis highlights session on the closing day of the meeting.
“New HBV drug development looks more complicated than initially expected and its goals and strategies need to be redefined and refocused,” he added
“This is really something that came from the discussions we had during the sessions but also in the corridors,” Dr. Pawlotsky added. “We know it’s going to be difficult; we have to reset, restart – not from zero, but from not much – and revise our strategy,” he suggested.
There are many new drugs under investigation for HBV, Dr. Pawlotsky said, noting that the number of studies being presented at the meeting was reminiscent of the flurry of activity before a functional cure for hepatitis C had been found. “It’s good to see that this is happening again for HBV,” he said.
Indeed, there are many new direct-acting antiviral agents, immunomodulatory, or other approaches being tested, and some of the more advanced studies are “teaching us a few things and probably raising more questions than getting answers,” Dr. Pawlotsky said.
The B-CLEAR study
One these studies is the phase 2b B-CLEAR study presented during the late-breaker session. This study involved bepirovirsen, an antisense oligonucleotide, and tested its efficacy and safety in patients with chronic hepatitis B virus infection who were either on or off stable nucleos(t)ide analogue (NA/NUC) therapy.
A similar proportion (28% and 29%, respectively) of patients achieved an hepatitis B surface antigen (HBsAg) level below the lower limit of quantification at the end of 24 weeks treatment. However, the effect on HBsAg varied according to the treatment arm, with changes to the dosing or switching to placebo indicating that the effect might wane when the treatment is stopped or if the dose is reduced.
“Interestingly, ALT elevations were observed in association with most HBsAg declines,” Dr. Pawlotsky pointed out. “I think we still have to determine whether this is good flare/bad flare, good sign/bad sign, of what is going to happen afterward.”
The REEF studies
Another approach highlighted was the combination of the silencing or small interfering RNA (siRNA) JNJ-3989 with the capsid assembly modulator (CAM) JNJ-6379 in the phase 2 REEF-1 and REEF-2 studies.
REEF-1, conducted in patients who were either hepatitis B e antigen (HBeAg) positive or negative who were not treated with NA/NUC or were NA/NUC suppressed, showed a dose-dependent, but variable effect among individual patients as might be expected at the end of 48 weeks’ treatment. This was sustained at week 72, which was 24 weeks’ follow-up after stopping treatment.
However, pointed out Dr. Pawlotsky “I think the most important part of this is that if you add a CAM on top of the siRNA, you do not improve the effect on HBsAg levels.”
Then there is the REEF-2 study, testing the same combination but in only patients who were NA suppressed or HBeAg negative alongside standard NA/NUC therapy. As well as being the first novel combination treatment trial to report, this was essentially a stopping trial, Kosh Agarwal, BMedSci (Hons), MBBS, MD, one of the study’s investigators explained separately at a media briefing.
Patients (n = 130) were treated for 48 weeks, then all treatment – including NA/NUC – was discontinued, with 48 weeks of follow-up after discontinuation, said Dr. Agarwal, who is a consultant hepatologist based at the Institute of Liver Studies at King’s College Hospital, London. He presented data from the first 24 week period after treatment had ended.
At the end of treatment, the combination had resulted in a mean reduction in HBsAg of 1.89 log10 IU/mL versus a reduction of 0.06 for the NA/NUC-only group, which acted as the control group in this trial. But “no patient in this study lost their surface antigen, i.e., were cured of their hepatitis B in the active arm or in the control arm,” Dr. Agarwal said.
“We didn’t achieve a cure, but a significant proportion were in a ‘controlled’ viral stage,” said Dr. Agarwal. Indeed, during his presentation of the findings, he showed that HBsAg inhibition was maintained in the majority (72%) of patients after stopping the combination.
While the trial’s primary endpoint wasn’t met, “it’s a really important study,” said Dr. Agarwal. “This [study] was fulfilled and delivered in the COVID era, so a lot of patients were looked after very carefully by sites in Europe,” he observed.
Further follow-up from the trial is expected, and Dr. Agarwal said that the subsequent discussion will “take us back to the drawing board to think about whether we need better antiviral treatments or whether we need to think about different combinations, and whether actually stopping treatment with every treatment is the right strategy to take.”
Both Dr. Agarwal and Dr. Pawlotsky flagged up the case of one patient in the trial who had been in the control arm and had experienced severe HBV reactivation that required a liver transplant.
“This patient is a warning signal,” Dr. Pawlotsky suggested in his talk. “When we think about NUC stopping, we have to think about the potential benefit in terms of HbsAg loss but also the potential risks.”
While Dr. Agarwal had noted that it highlights that “careful design of retreatment criteria is important in studies assessing the NA/NUC-stopping concept”.
Monoclonal antibody shows promise
Other combinations could involve an siRNA and an immunomodulatory agent and, during the poster sessions at the meeting, Dr. Agarwal also presented data from an ongoing phase 1 study with a novel, neutralizing monoclonal antibody called VIR-3434.
This monoclonal antibody is novel because it is thought to have several modes of action, first by binding to HBV and affecting its entry into liver cells, then by presenting the virus to T cells and stimulating a ‘vaccinal’ or immune effect, and then by helping the with the clearance of HBsAg and delivery of the virus to dendritic cells.
In the study, single doses of VIR-3434 were found to be well tolerated and to produce rapid reductions in HBsAg, with the highest dose used (300 mg) producing the greatest and most durable effect up to week 8.
VIR-3434 is also being tested in combination with other drugs in the phase 2 MARCH trial. One of these combinations is VIR-3434 together with an investigational siRNA dubbed VIR-2218. Preclinical work presented at ILC 2022 suggests that this combination appears to be capable of reducing HBsAg to a greater extent than using either agent alone.
Rethinking the strategy to get to a cure
Of course, VIR-3434 is one of several immunomodulatory compounds in development. There are therapeutic vaccines, drugs targeting the innate immune response, other monoclonal antibodies, T-cell receptors, checkpoint inhibitors and PD-L1 inhibitors. Then there are other compounds such as entry inhibitors, apoptosis inducers, and farnesoid X receptor agonists.
“I finish this meeting with more questions than answers,” Dr. Pawlotsky said. “What is the right target to enhance specific anti-HBV immunity? Does in vivo induction of immune responses translate into any beneficial effect on HBV infection? Will therapeutic vaccines every work in a viral infection?”
Moreover, he asked, “how can we avoid the side effect of enhancing multiple and complex nonspecific immune responses? Are treatment-induced flares good flares or bad flares? All of these are questions that are really unanswered and that we’ll have to get answers to in the near future.”
The B-CLEAR study was sponsored by GlaxoSmithKline. The REEF-2 study was sponsored by Janssen Research & Development. The VIR-3434 studies were funded by Vir Biotechnology. Dr. Pawlotsky has received grant and research support, acted as a consultant, adviser, or speaker, and participated in advisory boards for multiple pharmaceutical and biotechnology companies. This news organization was unable to verify Dr. Agarwal’s ties to Vir Biotechnology, but he presented one of the posters on VIR-3434 at the meeting and has been involved in the phase 1 study that was reported.
AT ILC 2022
Statins in NAFLD: Taking a closer look at benefits
LONDON – Substantial reductions in liver fat and fibrosis can be achieved with statin therapy, according to research presented at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.
Statins are thought to have multiple beneficial actions in people with fatty liver disease, but there has been little insight into how they may be exerting such effects.
Now, data from the Rotterdam Study and others suggest that statins may be reducing the formation of lipid droplets as well as influencing the expression of important inflammatory genes.
The results “require further confirmation,” the team behind the work said, which was done at Erasmus Medical Center in Rotterdam, the Netherlands, in collaboration with researchers at The First Affiliated Hospital of Wenzhou (China) Medical University.
“Statins are inversely associated with multiple components of the NAFLD [nonalcoholic fatty liver disease] spectrum,” said Ibrahim Ayada, a PhD student in the department of gastroenterology and hepatology at Erasmus MC.
“Statins can inhibit lipid synthesis in organoids and statins also exhibit healthy inflammatory effects, which might contribute to the hepatoprotective effects that we observe in our population studies,” Mr. Ayada said.
A rising problem that needs addressing
Together NAFLD and NASH constitute a significant and increasing health burden, Mr. Ayada observed, noting that there were an estimated 64 million people in the United States and 52 million people in Europe, at least, with the rise mirroring the obesity pandemic.
“The number of patients visiting outpatient clinics has nearly doubled within a study period of 5 years,” he said.
“There is no pharmacologic therapy,” he reminded his audience, observing that fatty liver disease was a major indication for liver transplantation.
Statins are a long-standing staple of cardiovascular disease management and are known to have pleiotropic effects, Mr. Ayada explained. Their use in NAFLD and non-alcoholic steatohepatitis (NASH) has been purported but is supported by inconclusive evidence.
Indeed, a prior Cochrane review performed in 2013 found only two studies that were eligible for analysis and had “high risk of bias and a small numbers of participants,” according to the review’s authors.
Examining the connection
To look at the possible benefits of statins in people with NASH and examine how these effects might be occurring, Mr. Ayada and collaborators first took data from the Rotterdam Study, a large population-based prospective cohort that has been collecting data on its participants since the early 90s.
Data on over 4,500 participants were examined and of these, just over 1,000 had NAFLD. Statin versus no statin use was found to be associated with around a 30% reduction in fatty liver disease, with an odds ratio or 0.72 for NAFLD.
Then, looking only at a subset of patients with biopsy-proven NAFLD, statin use was associated with a 45% reduction in NASH (OR, 0.55) and a 24% reduction in fibrosis, although only the NASH reduction was significant (P = .031). The purpose of this cohort is to look at potential biomarkers and all participants had donated blood, urine, and stool samples; all were of Chinese descent, Mr. Ayada said.
“We then pooled our results with existing evidence in a meta-analysis,” said Mr. Ayada, including 16 studies. While results showed an overall inverse association, only the findings for a reduction in NAFLD and fibrosis were significant; the relationship between statins and NASH was not significant.
Investigating mechanistic effects
Then, for the second part of their work, Mr. Ayada and associates looked at potential mechanistic effects of statins.
“We did part two because we knew part one was going to be cross-sectional and we could only show the association and not causality, so we tried to shed some light on possible pathways,” he said.
To do this they used a novel model of liver organoids developed to study fatty liver disease and test potential therapeutics. In this model human liver organoids are exposed to sodium lactate, sodium pyruvate, and octanoic acid, which induce the formation of lipid droplets. Exposing the organoids to statins – simvastatin and lovastatin were used in the experiments – resulted in a reduced number of the induced lipid droplets.
“Although all concentrations of statins significantly inhibited the lipid size versus the control, the major effect was quite modest,” observed Mr. Ayada. The effect was most noticeable at the highest dose used (10 micromolar), and what they think might be happening is that the statins are clearing the smaller droplets first, leaving the larger ones behind.
Next, they looked at the effect of statin treatment on inflammatory gene expression in liver-derived monocytes. These will turn into macrophages and play a key role in chronic inflammation, Mr. Ayada explained. Initial results suggest that several proinflammatory cytokines such as interleukin-1 beta, IL-6, and IL-8 may be downplayed by statin therapy.
An anti-inflammatory effect of statins was also reported in unrelated poster presentations at the congress. While researchers Seul Ki Han and associated from South Korea showed an anti-inflammatory effect of a combination of simvastatin and ezetimibe (SAT083), a Dutch team found that atorvastatin reduced the infiltration of hepatic macrophages, neutrophils, and monocytes, as well as lowering levels of proinflammatory cytokines (SAT033).
Statins for NASH – a missed opportunity?
“As far as I am aware there is no robust evidence from large, randomized trials to suggest statins lessen chances of NAFLD, or improve its surrogate markers such as ALT or GGT [gamma-glutamyltransferase] levels,” Naveed Sattar, PhD, FRCP, FRCPath, FRSE, FMedSci, commented in an interview.
“The Rotterdam study is merely cross-sectional and cannot answer the question of causality,” added Dr. Sattar, who is professor of metabolic medicine and Honorary Consultant in Cardiovascular & Medical Science at the University of Glasgow. “It may be people who have less NAFLD are more likely to be prescribed statins, perhaps because doctors are wary of prescribing statins to those with slightly deranged liver tests,” he qualified.
Moreover, said Dr. Sattar, “prior evidence shows statins are underused in people with heart disease but who have NAFLD, which represents a missed opportunity to prevent heart disease.
“If statins had positive effects for preventing conversion of NAFLD to NASH or lessening fibrosis, I believe we would have known that by now.”
As for use of statins in future treatments of fatty liver disease, Dr. Sattar said: “I would not pin my hopes on statins to improve liver health, but doctors need to remember statins are safe in people with NAFLD or NASH and they should not be withheld in those who have existing cardiovascular disease or at elevated risk.”
The study received no commercial funding. Mr. Ayada and Dr. Sattar had no relevant conflicts of interest.
LONDON – Substantial reductions in liver fat and fibrosis can be achieved with statin therapy, according to research presented at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.
Statins are thought to have multiple beneficial actions in people with fatty liver disease, but there has been little insight into how they may be exerting such effects.
Now, data from the Rotterdam Study and others suggest that statins may be reducing the formation of lipid droplets as well as influencing the expression of important inflammatory genes.
The results “require further confirmation,” the team behind the work said, which was done at Erasmus Medical Center in Rotterdam, the Netherlands, in collaboration with researchers at The First Affiliated Hospital of Wenzhou (China) Medical University.
“Statins are inversely associated with multiple components of the NAFLD [nonalcoholic fatty liver disease] spectrum,” said Ibrahim Ayada, a PhD student in the department of gastroenterology and hepatology at Erasmus MC.
“Statins can inhibit lipid synthesis in organoids and statins also exhibit healthy inflammatory effects, which might contribute to the hepatoprotective effects that we observe in our population studies,” Mr. Ayada said.
A rising problem that needs addressing
Together NAFLD and NASH constitute a significant and increasing health burden, Mr. Ayada observed, noting that there were an estimated 64 million people in the United States and 52 million people in Europe, at least, with the rise mirroring the obesity pandemic.
“The number of patients visiting outpatient clinics has nearly doubled within a study period of 5 years,” he said.
“There is no pharmacologic therapy,” he reminded his audience, observing that fatty liver disease was a major indication for liver transplantation.
Statins are a long-standing staple of cardiovascular disease management and are known to have pleiotropic effects, Mr. Ayada explained. Their use in NAFLD and non-alcoholic steatohepatitis (NASH) has been purported but is supported by inconclusive evidence.
Indeed, a prior Cochrane review performed in 2013 found only two studies that were eligible for analysis and had “high risk of bias and a small numbers of participants,” according to the review’s authors.
Examining the connection
To look at the possible benefits of statins in people with NASH and examine how these effects might be occurring, Mr. Ayada and collaborators first took data from the Rotterdam Study, a large population-based prospective cohort that has been collecting data on its participants since the early 90s.
Data on over 4,500 participants were examined and of these, just over 1,000 had NAFLD. Statin versus no statin use was found to be associated with around a 30% reduction in fatty liver disease, with an odds ratio or 0.72 for NAFLD.
Then, looking only at a subset of patients with biopsy-proven NAFLD, statin use was associated with a 45% reduction in NASH (OR, 0.55) and a 24% reduction in fibrosis, although only the NASH reduction was significant (P = .031). The purpose of this cohort is to look at potential biomarkers and all participants had donated blood, urine, and stool samples; all were of Chinese descent, Mr. Ayada said.
“We then pooled our results with existing evidence in a meta-analysis,” said Mr. Ayada, including 16 studies. While results showed an overall inverse association, only the findings for a reduction in NAFLD and fibrosis were significant; the relationship between statins and NASH was not significant.
Investigating mechanistic effects
Then, for the second part of their work, Mr. Ayada and associates looked at potential mechanistic effects of statins.
“We did part two because we knew part one was going to be cross-sectional and we could only show the association and not causality, so we tried to shed some light on possible pathways,” he said.
To do this they used a novel model of liver organoids developed to study fatty liver disease and test potential therapeutics. In this model human liver organoids are exposed to sodium lactate, sodium pyruvate, and octanoic acid, which induce the formation of lipid droplets. Exposing the organoids to statins – simvastatin and lovastatin were used in the experiments – resulted in a reduced number of the induced lipid droplets.
“Although all concentrations of statins significantly inhibited the lipid size versus the control, the major effect was quite modest,” observed Mr. Ayada. The effect was most noticeable at the highest dose used (10 micromolar), and what they think might be happening is that the statins are clearing the smaller droplets first, leaving the larger ones behind.
Next, they looked at the effect of statin treatment on inflammatory gene expression in liver-derived monocytes. These will turn into macrophages and play a key role in chronic inflammation, Mr. Ayada explained. Initial results suggest that several proinflammatory cytokines such as interleukin-1 beta, IL-6, and IL-8 may be downplayed by statin therapy.
An anti-inflammatory effect of statins was also reported in unrelated poster presentations at the congress. While researchers Seul Ki Han and associated from South Korea showed an anti-inflammatory effect of a combination of simvastatin and ezetimibe (SAT083), a Dutch team found that atorvastatin reduced the infiltration of hepatic macrophages, neutrophils, and monocytes, as well as lowering levels of proinflammatory cytokines (SAT033).
Statins for NASH – a missed opportunity?
“As far as I am aware there is no robust evidence from large, randomized trials to suggest statins lessen chances of NAFLD, or improve its surrogate markers such as ALT or GGT [gamma-glutamyltransferase] levels,” Naveed Sattar, PhD, FRCP, FRCPath, FRSE, FMedSci, commented in an interview.
“The Rotterdam study is merely cross-sectional and cannot answer the question of causality,” added Dr. Sattar, who is professor of metabolic medicine and Honorary Consultant in Cardiovascular & Medical Science at the University of Glasgow. “It may be people who have less NAFLD are more likely to be prescribed statins, perhaps because doctors are wary of prescribing statins to those with slightly deranged liver tests,” he qualified.
Moreover, said Dr. Sattar, “prior evidence shows statins are underused in people with heart disease but who have NAFLD, which represents a missed opportunity to prevent heart disease.
“If statins had positive effects for preventing conversion of NAFLD to NASH or lessening fibrosis, I believe we would have known that by now.”
As for use of statins in future treatments of fatty liver disease, Dr. Sattar said: “I would not pin my hopes on statins to improve liver health, but doctors need to remember statins are safe in people with NAFLD or NASH and they should not be withheld in those who have existing cardiovascular disease or at elevated risk.”
The study received no commercial funding. Mr. Ayada and Dr. Sattar had no relevant conflicts of interest.
LONDON – Substantial reductions in liver fat and fibrosis can be achieved with statin therapy, according to research presented at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.
Statins are thought to have multiple beneficial actions in people with fatty liver disease, but there has been little insight into how they may be exerting such effects.
Now, data from the Rotterdam Study and others suggest that statins may be reducing the formation of lipid droplets as well as influencing the expression of important inflammatory genes.
The results “require further confirmation,” the team behind the work said, which was done at Erasmus Medical Center in Rotterdam, the Netherlands, in collaboration with researchers at The First Affiliated Hospital of Wenzhou (China) Medical University.
“Statins are inversely associated with multiple components of the NAFLD [nonalcoholic fatty liver disease] spectrum,” said Ibrahim Ayada, a PhD student in the department of gastroenterology and hepatology at Erasmus MC.
“Statins can inhibit lipid synthesis in organoids and statins also exhibit healthy inflammatory effects, which might contribute to the hepatoprotective effects that we observe in our population studies,” Mr. Ayada said.
A rising problem that needs addressing
Together NAFLD and NASH constitute a significant and increasing health burden, Mr. Ayada observed, noting that there were an estimated 64 million people in the United States and 52 million people in Europe, at least, with the rise mirroring the obesity pandemic.
“The number of patients visiting outpatient clinics has nearly doubled within a study period of 5 years,” he said.
“There is no pharmacologic therapy,” he reminded his audience, observing that fatty liver disease was a major indication for liver transplantation.
Statins are a long-standing staple of cardiovascular disease management and are known to have pleiotropic effects, Mr. Ayada explained. Their use in NAFLD and non-alcoholic steatohepatitis (NASH) has been purported but is supported by inconclusive evidence.
Indeed, a prior Cochrane review performed in 2013 found only two studies that were eligible for analysis and had “high risk of bias and a small numbers of participants,” according to the review’s authors.
Examining the connection
To look at the possible benefits of statins in people with NASH and examine how these effects might be occurring, Mr. Ayada and collaborators first took data from the Rotterdam Study, a large population-based prospective cohort that has been collecting data on its participants since the early 90s.
Data on over 4,500 participants were examined and of these, just over 1,000 had NAFLD. Statin versus no statin use was found to be associated with around a 30% reduction in fatty liver disease, with an odds ratio or 0.72 for NAFLD.
Then, looking only at a subset of patients with biopsy-proven NAFLD, statin use was associated with a 45% reduction in NASH (OR, 0.55) and a 24% reduction in fibrosis, although only the NASH reduction was significant (P = .031). The purpose of this cohort is to look at potential biomarkers and all participants had donated blood, urine, and stool samples; all were of Chinese descent, Mr. Ayada said.
“We then pooled our results with existing evidence in a meta-analysis,” said Mr. Ayada, including 16 studies. While results showed an overall inverse association, only the findings for a reduction in NAFLD and fibrosis were significant; the relationship between statins and NASH was not significant.
Investigating mechanistic effects
Then, for the second part of their work, Mr. Ayada and associates looked at potential mechanistic effects of statins.
“We did part two because we knew part one was going to be cross-sectional and we could only show the association and not causality, so we tried to shed some light on possible pathways,” he said.
To do this they used a novel model of liver organoids developed to study fatty liver disease and test potential therapeutics. In this model human liver organoids are exposed to sodium lactate, sodium pyruvate, and octanoic acid, which induce the formation of lipid droplets. Exposing the organoids to statins – simvastatin and lovastatin were used in the experiments – resulted in a reduced number of the induced lipid droplets.
“Although all concentrations of statins significantly inhibited the lipid size versus the control, the major effect was quite modest,” observed Mr. Ayada. The effect was most noticeable at the highest dose used (10 micromolar), and what they think might be happening is that the statins are clearing the smaller droplets first, leaving the larger ones behind.
Next, they looked at the effect of statin treatment on inflammatory gene expression in liver-derived monocytes. These will turn into macrophages and play a key role in chronic inflammation, Mr. Ayada explained. Initial results suggest that several proinflammatory cytokines such as interleukin-1 beta, IL-6, and IL-8 may be downplayed by statin therapy.
An anti-inflammatory effect of statins was also reported in unrelated poster presentations at the congress. While researchers Seul Ki Han and associated from South Korea showed an anti-inflammatory effect of a combination of simvastatin and ezetimibe (SAT083), a Dutch team found that atorvastatin reduced the infiltration of hepatic macrophages, neutrophils, and monocytes, as well as lowering levels of proinflammatory cytokines (SAT033).
Statins for NASH – a missed opportunity?
“As far as I am aware there is no robust evidence from large, randomized trials to suggest statins lessen chances of NAFLD, or improve its surrogate markers such as ALT or GGT [gamma-glutamyltransferase] levels,” Naveed Sattar, PhD, FRCP, FRCPath, FRSE, FMedSci, commented in an interview.
“The Rotterdam study is merely cross-sectional and cannot answer the question of causality,” added Dr. Sattar, who is professor of metabolic medicine and Honorary Consultant in Cardiovascular & Medical Science at the University of Glasgow. “It may be people who have less NAFLD are more likely to be prescribed statins, perhaps because doctors are wary of prescribing statins to those with slightly deranged liver tests,” he qualified.
Moreover, said Dr. Sattar, “prior evidence shows statins are underused in people with heart disease but who have NAFLD, which represents a missed opportunity to prevent heart disease.
“If statins had positive effects for preventing conversion of NAFLD to NASH or lessening fibrosis, I believe we would have known that by now.”
As for use of statins in future treatments of fatty liver disease, Dr. Sattar said: “I would not pin my hopes on statins to improve liver health, but doctors need to remember statins are safe in people with NAFLD or NASH and they should not be withheld in those who have existing cardiovascular disease or at elevated risk.”
The study received no commercial funding. Mr. Ayada and Dr. Sattar had no relevant conflicts of interest.
AT ILC 2022
Phase 3 data shows bulevirtide benefit in hepatitis D
LONDON – Bulevirtide may not just treat but perhaps be a potential cure for hepatitis D in some patients, as was suggested at the annual International Liver Congress.
Data from an ongoing phase 3 trial showed that, after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable hepatitis delta virus (HDV) RNA levels and normalized ALT levels.
“The good message for our patients is that the initial data of the smaller phase 2 trials will really be confirmed, so the drug works,” Heiner Wedemeyer, MD, said at a media briefing ahead of his presentation at the meeting sponsored by the European Association for the Study of the Liver .
“It induces a decline in viral load and, very importantly for us as hepatologists, liver enzymes normalize, this is really good news” added Dr. Wedemeyer, who is the clinic director of the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.
“This is really an almost historic moment for hepatology,” he said. “It’s the first time that these patients have an antiviral treatment; they are afraid of dying and now they have a hope.”
Giving his thoughts, Thomas Berg, MD, Secretary General of EASL, said: “We are entering into a golden age of hepatology science when it comes to viral hepatitis.
Dr. Berg, also of University Clinic Leipzig (Germany), added: “We have several million people worldwide living with viral hepatitis; we have a cure for hepatitis C but there’s no cure for hepatitis B or hepatitis D, so these data give me great hope that we have scientific momentum with us.”
Pivotal phase 3 study
The MYR301 trial is an important and pivotal study for bulevirtide, which is a first-in-class HDV entry inhibitor. While it was approved for use Europe in 2020 under the brand name Hepcludex, the drug remains investigational in the United States.
“We were really surprised that EMA [European Medicines Agency] went forward, granting approval because there was no alternative available at that time,” Dr. Wedemeyer said. That approval is conditional, however, and was based on the results of phase 2 studies with the proviso that further data needed would need to be provided. Hopefully, the phase 3 findings will mean that the drug will receive full official approval, he said.
Overall, 150 patients with chronic hepatitis D were recruited into the phase 3 study and randomized to receive one of two doses of bulevirtide (2 mg or 10 mg) for 144 weeks or delayed treatment for 48 weeks followed by the higher dose of the drug until the remainder of the treatment period. Bulevirtide was given as once-daily subcutaneous injection.
The mean age of participants was 41 years, the majority (82.7%) were White, and just under half already had liver cirrhosis. For inclusion, Dr. Wedemeyer said that they had to have compensated cirrhosis.
Just over half had received prior interferon therapy and almost two-thirds were receiving concomitant nucleos(t)ide (NUC) treatment.
Key results
The primary endpoint was defined as a combination of decreased HDV RNA (defined as undetectable or a 2 log or greater decrease) and normalized ALT (defined as 3.1 U/L or less in women and 4.1 U/L or less in men). This was assessed after 48 weeks’ treatment and was achieved by 45% of participants given the 2-mg dose of bulevirtide, 48% of those given the 10-mg dose, and by 2% of those who had delayed treatment (P < .0001 for both doses, compared with delayed treatment).
The treatment benefit was consistent across all subgroups of patients, including those with cirrhosis, Dr. Wedemeyer reported.
Looking at some of the secondary endpoints, he reported that, when considering only decreased HDV RNA, the rate of response was over 70% with both dose of bulevirtide at week 48, compared with just 4% for delayed treatment (P < .0001), although there was no significant difference in rates of undetectable HDV RNA between the two doses. ALT normalization rates were 51%-56% versus 12% for delayed treatment (P < .0001).
A further benefit was seen in liver stiffness, with values reduced by at least three points at week 48 with either dose of bulevirtide, compared with an increase of almost 1 point for delayed treatment.
As for side effects, one of the concerns for bulevirtide is an increase in serum bile acids, but when this occurred, it occurred early and remained steady over the course of treatment, with a less pronounced effect in the 2 mg–dosed group than the 10 mg–dosed group. There were no serious adverse reactions related to bulevirtide or any adverse event that led to stopping the drug.
“There are always questions that need to be answered,” Dr. Wedemeyer acknowledged. Indeed, it’s unclear for how long patients need to be treated and if treatment with interferon is needed. In the phase 2 studies (MYR202 and MYR203), bulevirtide was given at the same time as pegylated interferon alpha (peg-IFNa) or tenofovir, whereas in the phase 3 MYR301 trial, it was given as monotherapy.
Real-world experience
“We have already some real-world data in parallel to this phase 3 trial,” Dr. Wedemeyer said. “So, for us in the hepatitis D field, it is a really exciting time; [it’s] completely novel data and game-changing for patients.”
“The results are similar to our real life study, but in our real-life study, we have some patients treated with interferon and some not treated with interferon,” Hélène Fontaine, MD, of Hôpital Cochin in Paris, observed in an interview.
She reported preliminary results from the prospective BuleDelta cohort, which showed a virologic response rate of 58% and ALT normalization in 46% of patients.
“Virologic response was achieved in more patients receiving bulevirtide in combination with interferon,” she said. Indeed, 84% of patient who received peg-IFNa versus 39% of those who did not achieved a virologic response. However, rates of ALT normalization were more frequent in those received bulevirtide monotherapy than in combination with peg-IFN1 (54% vs. 35%).
A greater benefit of combining bulevirtide with interferon therapy was also seen in another real-world study presented by Victor de Lédinghen, MD, PhD, of Bordeaux (France) University Hospital. After 18 months of treatment, bulevirtide plus peg-IFNa was associated with undetectable HDV RNA in 57% of patients versus 33% of those given the drug as monotherapy.
“Of course, if you add interferon, it’s better than without but you cannot use interferon in all patients,” he observed in an interview.
Results are good but could be better, he suggested, noting that the results are dependent on patients injecting themselves correctly on a daily basis.
At the media briefing Dr. Wedemeyer also commented on how bulevirtide must be delivered.
“The only, let’s say, disadvantage is that it has to be injected because it’s a peptide, which requires daily injections, but patients managed very well,” Dr. Wedemeyer said.
“There is some evidence from single cases that we may stop treatment and that the virus does not come back,” he said, but stressed that patients should not stop treatment on their own as the risk is not known.
“For patients with advanced disease I consider this as a maintenance treatment,” Dr. Wedemeyer said, at least for the time being.
The MYR3201 study was funded by Gilead Sciences. The BuleDelta cohort is sponsored by the ANRS Maladies Infectieuses Emergencies. Dr. Wedemeyer acknowledged research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences and MYR as well as having ties to multiple pharmaceutical and biotechnology companies. Dr. Berg, Dr. Fontaine, and Dr. de Lédinghen had no conflicts of interest to report.
LONDON – Bulevirtide may not just treat but perhaps be a potential cure for hepatitis D in some patients, as was suggested at the annual International Liver Congress.
Data from an ongoing phase 3 trial showed that, after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable hepatitis delta virus (HDV) RNA levels and normalized ALT levels.
“The good message for our patients is that the initial data of the smaller phase 2 trials will really be confirmed, so the drug works,” Heiner Wedemeyer, MD, said at a media briefing ahead of his presentation at the meeting sponsored by the European Association for the Study of the Liver .
“It induces a decline in viral load and, very importantly for us as hepatologists, liver enzymes normalize, this is really good news” added Dr. Wedemeyer, who is the clinic director of the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.
“This is really an almost historic moment for hepatology,” he said. “It’s the first time that these patients have an antiviral treatment; they are afraid of dying and now they have a hope.”
Giving his thoughts, Thomas Berg, MD, Secretary General of EASL, said: “We are entering into a golden age of hepatology science when it comes to viral hepatitis.
Dr. Berg, also of University Clinic Leipzig (Germany), added: “We have several million people worldwide living with viral hepatitis; we have a cure for hepatitis C but there’s no cure for hepatitis B or hepatitis D, so these data give me great hope that we have scientific momentum with us.”
Pivotal phase 3 study
The MYR301 trial is an important and pivotal study for bulevirtide, which is a first-in-class HDV entry inhibitor. While it was approved for use Europe in 2020 under the brand name Hepcludex, the drug remains investigational in the United States.
“We were really surprised that EMA [European Medicines Agency] went forward, granting approval because there was no alternative available at that time,” Dr. Wedemeyer said. That approval is conditional, however, and was based on the results of phase 2 studies with the proviso that further data needed would need to be provided. Hopefully, the phase 3 findings will mean that the drug will receive full official approval, he said.
Overall, 150 patients with chronic hepatitis D were recruited into the phase 3 study and randomized to receive one of two doses of bulevirtide (2 mg or 10 mg) for 144 weeks or delayed treatment for 48 weeks followed by the higher dose of the drug until the remainder of the treatment period. Bulevirtide was given as once-daily subcutaneous injection.
The mean age of participants was 41 years, the majority (82.7%) were White, and just under half already had liver cirrhosis. For inclusion, Dr. Wedemeyer said that they had to have compensated cirrhosis.
Just over half had received prior interferon therapy and almost two-thirds were receiving concomitant nucleos(t)ide (NUC) treatment.
Key results
The primary endpoint was defined as a combination of decreased HDV RNA (defined as undetectable or a 2 log or greater decrease) and normalized ALT (defined as 3.1 U/L or less in women and 4.1 U/L or less in men). This was assessed after 48 weeks’ treatment and was achieved by 45% of participants given the 2-mg dose of bulevirtide, 48% of those given the 10-mg dose, and by 2% of those who had delayed treatment (P < .0001 for both doses, compared with delayed treatment).
The treatment benefit was consistent across all subgroups of patients, including those with cirrhosis, Dr. Wedemeyer reported.
Looking at some of the secondary endpoints, he reported that, when considering only decreased HDV RNA, the rate of response was over 70% with both dose of bulevirtide at week 48, compared with just 4% for delayed treatment (P < .0001), although there was no significant difference in rates of undetectable HDV RNA between the two doses. ALT normalization rates were 51%-56% versus 12% for delayed treatment (P < .0001).
A further benefit was seen in liver stiffness, with values reduced by at least three points at week 48 with either dose of bulevirtide, compared with an increase of almost 1 point for delayed treatment.
As for side effects, one of the concerns for bulevirtide is an increase in serum bile acids, but when this occurred, it occurred early and remained steady over the course of treatment, with a less pronounced effect in the 2 mg–dosed group than the 10 mg–dosed group. There were no serious adverse reactions related to bulevirtide or any adverse event that led to stopping the drug.
“There are always questions that need to be answered,” Dr. Wedemeyer acknowledged. Indeed, it’s unclear for how long patients need to be treated and if treatment with interferon is needed. In the phase 2 studies (MYR202 and MYR203), bulevirtide was given at the same time as pegylated interferon alpha (peg-IFNa) or tenofovir, whereas in the phase 3 MYR301 trial, it was given as monotherapy.
Real-world experience
“We have already some real-world data in parallel to this phase 3 trial,” Dr. Wedemeyer said. “So, for us in the hepatitis D field, it is a really exciting time; [it’s] completely novel data and game-changing for patients.”
“The results are similar to our real life study, but in our real-life study, we have some patients treated with interferon and some not treated with interferon,” Hélène Fontaine, MD, of Hôpital Cochin in Paris, observed in an interview.
She reported preliminary results from the prospective BuleDelta cohort, which showed a virologic response rate of 58% and ALT normalization in 46% of patients.
“Virologic response was achieved in more patients receiving bulevirtide in combination with interferon,” she said. Indeed, 84% of patient who received peg-IFNa versus 39% of those who did not achieved a virologic response. However, rates of ALT normalization were more frequent in those received bulevirtide monotherapy than in combination with peg-IFN1 (54% vs. 35%).
A greater benefit of combining bulevirtide with interferon therapy was also seen in another real-world study presented by Victor de Lédinghen, MD, PhD, of Bordeaux (France) University Hospital. After 18 months of treatment, bulevirtide plus peg-IFNa was associated with undetectable HDV RNA in 57% of patients versus 33% of those given the drug as monotherapy.
“Of course, if you add interferon, it’s better than without but you cannot use interferon in all patients,” he observed in an interview.
Results are good but could be better, he suggested, noting that the results are dependent on patients injecting themselves correctly on a daily basis.
At the media briefing Dr. Wedemeyer also commented on how bulevirtide must be delivered.
“The only, let’s say, disadvantage is that it has to be injected because it’s a peptide, which requires daily injections, but patients managed very well,” Dr. Wedemeyer said.
“There is some evidence from single cases that we may stop treatment and that the virus does not come back,” he said, but stressed that patients should not stop treatment on their own as the risk is not known.
“For patients with advanced disease I consider this as a maintenance treatment,” Dr. Wedemeyer said, at least for the time being.
The MYR3201 study was funded by Gilead Sciences. The BuleDelta cohort is sponsored by the ANRS Maladies Infectieuses Emergencies. Dr. Wedemeyer acknowledged research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences and MYR as well as having ties to multiple pharmaceutical and biotechnology companies. Dr. Berg, Dr. Fontaine, and Dr. de Lédinghen had no conflicts of interest to report.
LONDON – Bulevirtide may not just treat but perhaps be a potential cure for hepatitis D in some patients, as was suggested at the annual International Liver Congress.
Data from an ongoing phase 3 trial showed that, after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable hepatitis delta virus (HDV) RNA levels and normalized ALT levels.
“The good message for our patients is that the initial data of the smaller phase 2 trials will really be confirmed, so the drug works,” Heiner Wedemeyer, MD, said at a media briefing ahead of his presentation at the meeting sponsored by the European Association for the Study of the Liver .
“It induces a decline in viral load and, very importantly for us as hepatologists, liver enzymes normalize, this is really good news” added Dr. Wedemeyer, who is the clinic director of the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.
“This is really an almost historic moment for hepatology,” he said. “It’s the first time that these patients have an antiviral treatment; they are afraid of dying and now they have a hope.”
Giving his thoughts, Thomas Berg, MD, Secretary General of EASL, said: “We are entering into a golden age of hepatology science when it comes to viral hepatitis.
Dr. Berg, also of University Clinic Leipzig (Germany), added: “We have several million people worldwide living with viral hepatitis; we have a cure for hepatitis C but there’s no cure for hepatitis B or hepatitis D, so these data give me great hope that we have scientific momentum with us.”
Pivotal phase 3 study
The MYR301 trial is an important and pivotal study for bulevirtide, which is a first-in-class HDV entry inhibitor. While it was approved for use Europe in 2020 under the brand name Hepcludex, the drug remains investigational in the United States.
“We were really surprised that EMA [European Medicines Agency] went forward, granting approval because there was no alternative available at that time,” Dr. Wedemeyer said. That approval is conditional, however, and was based on the results of phase 2 studies with the proviso that further data needed would need to be provided. Hopefully, the phase 3 findings will mean that the drug will receive full official approval, he said.
Overall, 150 patients with chronic hepatitis D were recruited into the phase 3 study and randomized to receive one of two doses of bulevirtide (2 mg or 10 mg) for 144 weeks or delayed treatment for 48 weeks followed by the higher dose of the drug until the remainder of the treatment period. Bulevirtide was given as once-daily subcutaneous injection.
The mean age of participants was 41 years, the majority (82.7%) were White, and just under half already had liver cirrhosis. For inclusion, Dr. Wedemeyer said that they had to have compensated cirrhosis.
Just over half had received prior interferon therapy and almost two-thirds were receiving concomitant nucleos(t)ide (NUC) treatment.
Key results
The primary endpoint was defined as a combination of decreased HDV RNA (defined as undetectable or a 2 log or greater decrease) and normalized ALT (defined as 3.1 U/L or less in women and 4.1 U/L or less in men). This was assessed after 48 weeks’ treatment and was achieved by 45% of participants given the 2-mg dose of bulevirtide, 48% of those given the 10-mg dose, and by 2% of those who had delayed treatment (P < .0001 for both doses, compared with delayed treatment).
The treatment benefit was consistent across all subgroups of patients, including those with cirrhosis, Dr. Wedemeyer reported.
Looking at some of the secondary endpoints, he reported that, when considering only decreased HDV RNA, the rate of response was over 70% with both dose of bulevirtide at week 48, compared with just 4% for delayed treatment (P < .0001), although there was no significant difference in rates of undetectable HDV RNA between the two doses. ALT normalization rates were 51%-56% versus 12% for delayed treatment (P < .0001).
A further benefit was seen in liver stiffness, with values reduced by at least three points at week 48 with either dose of bulevirtide, compared with an increase of almost 1 point for delayed treatment.
As for side effects, one of the concerns for bulevirtide is an increase in serum bile acids, but when this occurred, it occurred early and remained steady over the course of treatment, with a less pronounced effect in the 2 mg–dosed group than the 10 mg–dosed group. There were no serious adverse reactions related to bulevirtide or any adverse event that led to stopping the drug.
“There are always questions that need to be answered,” Dr. Wedemeyer acknowledged. Indeed, it’s unclear for how long patients need to be treated and if treatment with interferon is needed. In the phase 2 studies (MYR202 and MYR203), bulevirtide was given at the same time as pegylated interferon alpha (peg-IFNa) or tenofovir, whereas in the phase 3 MYR301 trial, it was given as monotherapy.
Real-world experience
“We have already some real-world data in parallel to this phase 3 trial,” Dr. Wedemeyer said. “So, for us in the hepatitis D field, it is a really exciting time; [it’s] completely novel data and game-changing for patients.”
“The results are similar to our real life study, but in our real-life study, we have some patients treated with interferon and some not treated with interferon,” Hélène Fontaine, MD, of Hôpital Cochin in Paris, observed in an interview.
She reported preliminary results from the prospective BuleDelta cohort, which showed a virologic response rate of 58% and ALT normalization in 46% of patients.
“Virologic response was achieved in more patients receiving bulevirtide in combination with interferon,” she said. Indeed, 84% of patient who received peg-IFNa versus 39% of those who did not achieved a virologic response. However, rates of ALT normalization were more frequent in those received bulevirtide monotherapy than in combination with peg-IFN1 (54% vs. 35%).
A greater benefit of combining bulevirtide with interferon therapy was also seen in another real-world study presented by Victor de Lédinghen, MD, PhD, of Bordeaux (France) University Hospital. After 18 months of treatment, bulevirtide plus peg-IFNa was associated with undetectable HDV RNA in 57% of patients versus 33% of those given the drug as monotherapy.
“Of course, if you add interferon, it’s better than without but you cannot use interferon in all patients,” he observed in an interview.
Results are good but could be better, he suggested, noting that the results are dependent on patients injecting themselves correctly on a daily basis.
At the media briefing Dr. Wedemeyer also commented on how bulevirtide must be delivered.
“The only, let’s say, disadvantage is that it has to be injected because it’s a peptide, which requires daily injections, but patients managed very well,” Dr. Wedemeyer said.
“There is some evidence from single cases that we may stop treatment and that the virus does not come back,” he said, but stressed that patients should not stop treatment on their own as the risk is not known.
“For patients with advanced disease I consider this as a maintenance treatment,” Dr. Wedemeyer said, at least for the time being.
The MYR3201 study was funded by Gilead Sciences. The BuleDelta cohort is sponsored by the ANRS Maladies Infectieuses Emergencies. Dr. Wedemeyer acknowledged research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences and MYR as well as having ties to multiple pharmaceutical and biotechnology companies. Dr. Berg, Dr. Fontaine, and Dr. de Lédinghen had no conflicts of interest to report.
AT ILC 2022
Pemvidutide promising for fatty liver disease
LONDON – Weight loss, lipid reductions, and “robust improvements” in lipid species associated with nonalcoholic fatty liver disease were achieved in patients who were treated with pemvidutide in a first-in-human, phase 1 clinical trial reported at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver.
The presenting study investigator, Stephen A. Harrison, MD, said that pemvidutide, which is also being developed for the treatment of obesity, appeared to be well tolerated. There were no serious or severe adverse events, and no patient had to discontinue treatment because of side effects.
Overall, “pemvidutide represents a promising new agent,” said Dr. Harrison, medical director of Pinnacle Research in San Antonio, Texas.
Dual incretin effect
Pemvidutide is a “balanced” dual agonist of glucagon-like peptide 1 (GLP-1) and glucagon, Dr. Harrison explained in his oral abstract.
“With glucagon, we are working to drive energy expenditure up, and with GLP-1, we’re decreasing food intake,” Dr. Harrison said.
What might set pemvidutide apart from other incretins lies within its structure, Dr. Harrison suggested. The structure has two main regions – one with greater GLP-1 specificity and the other with greater glucagon specificity, and these two areas are linked by a propriety technology called a EuPort™ domain. This is an area which allows the drug to bind to albumin, which increases its serum half-life and enables weekly dosing while slowing its entry into the bloodstream.
“Ultimately, we think that this has impacts, hypothetically, on tolerability and potentially mitigating the need for dose escalation,” said Dr. Harrison.
Weight loss results
The phase 1 study Dr. Harrison presented had a randomized, double-blind, placebo-controlled design with single and multiple ascending doses (SAD/MAD) of pemvidutide being tested. He presented data on the MAD phase only, noting that the SAD phase had been used to determine what doses to use in the latter.
Seventy individuals with a body mass index of between 25 and 40 kg/m2 were recruited and 34 of these were enrolled in the MAD phase of the study. Three doses of pemvidutide were used, given subcutaneously once a week for 12 weeks: Seven participants received 1.2 mg, 9 were given 1.8 mg, 11 had 2.4 mg, and 7 subjects were treated with placebo. Dr. Harrison noted that there were no caloric restrictions in the trial and no lifestyle modifications or interventions.
The average age of study participants ranged from 27 to 35 years and the mean BMI was 30-31 kg/m2 across each group, with their lipid parameters in the upper range of normal.
Clear weight loss reductions were seen across all the pemvidutide groups versus placebo, with the greatest percentage changes in weight loss seen with the two higher doses used. At week 12, there was a 4.9%, 10.3% and 9.0% weight loss in the 1.2-mg, 1.8-mg and 2.4-mg pemvidutide groups compared to 1.6% in placebo-treated individuals.
All patients in the 1.8-mg group achieved a 5% or greater weight loss, Dr. Harrison observed, but there “was a plateauing” effect with the 2.4-mg dose with 89% of patients achieving this target. In comparison, a third of patients on the lowest dose and 20% of those on placebo achieved this target.
The trajectory of weight loss seen in the trial suggests that “the rate of weight loss would continue beyond 12 weeks if we were to continue the therapy” Dr. Harrison said.
Lipid changes and liver fat reductions
Levels of serum lipids from baseline to week 12 fell to a greater extent with pemvidutide treatment than with placebo, in the range of –27% for total cholesterol in the two highest dose groups, –25% for LDL-cholesterol for those groups, –37% for triglycerides for the 1.2- and 1.8-mg groups, and reductions in apolipoprotein B were seen.
“We saw an initial decline in HDL [high-density lipoprotein],” Dr. Harrison said, noting that “this is consistent with prior studies looking at rapid weight loss, and over time, this mitigates as you continue to treat at least based on other mechanisms of action or other drugs with similar mechanisms.”
Pemvidutide treatment was also associated with increased lipid oxidation and decreased lipid synthesis, and “there was a robust decrease in lipids implicated in NASH inflammation,” Dr. Harrison pointed out.
Importantly, in five of eight participants who had high levels of liver fat at baseline – defined as a 5% or greater magnetic resonance imaging–derived proton-density-fat-fraction (MRI-PDFF) – showed a decrease to undetectable limits (1.5% or less). This was a greater than 90% reduction in liver fat, Dr. Harrison said. All five patients were in the 1.8-mg and 2.4-mg groups.
As for side effects, these were “predominantly upper GI, with nausea and vomiting.” These were mild in most cases, but he pointed out that five patients treated with the 1.8-mg dose experienced moderate nausea and three experienced moderate vomiting. Mild diarrhea and constipation were also seen in two of patients given this dose but was not reported in any of the other groups.
During the discussion following the presentation, it was pointed out that there was no clear dose-dependent effect considering the 1.8-mg dose seemed to have a stronger effect in some areas than the 2.4-mg dose. That’s a fair point, Dr. Harrison responded, reiterating it was a small study with a short treatment duration, but that there did look like a plateauing effect, “at least in patients with a mean BMI of between 30 and 31.”
Dr. Harrison was asked about potential effects on insulin levels and if that was a worry because, if glucagon is stimulated, it could increase insulin. That in turn might encourage insulin resistance and promote worse outcomes.
“If you look outside of just this program, glucagon agonism has been dosed in a lot of patients over time, and we haven’t seen that,” Dr. Harrison replied. Pemvidutide is an agonist rather than antagonist, so perhaps the [nonalcoholic steatohepatitis]–inducing effects seen before with glucagon antagonism won’t occur, he suggested.
Dr. Harrison disclosed ties to Altimmune (the study sponsor), Akero, Axcella, Bristol Myers Squibb, Cirius, CiVi Biopharma, Conatus, Corcept, CymaBay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, HistoIndex, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, NorthSea, Pfizer, Sagimet, Viking, and 89Bio.
LONDON – Weight loss, lipid reductions, and “robust improvements” in lipid species associated with nonalcoholic fatty liver disease were achieved in patients who were treated with pemvidutide in a first-in-human, phase 1 clinical trial reported at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver.
The presenting study investigator, Stephen A. Harrison, MD, said that pemvidutide, which is also being developed for the treatment of obesity, appeared to be well tolerated. There were no serious or severe adverse events, and no patient had to discontinue treatment because of side effects.
Overall, “pemvidutide represents a promising new agent,” said Dr. Harrison, medical director of Pinnacle Research in San Antonio, Texas.
Dual incretin effect
Pemvidutide is a “balanced” dual agonist of glucagon-like peptide 1 (GLP-1) and glucagon, Dr. Harrison explained in his oral abstract.
“With glucagon, we are working to drive energy expenditure up, and with GLP-1, we’re decreasing food intake,” Dr. Harrison said.
What might set pemvidutide apart from other incretins lies within its structure, Dr. Harrison suggested. The structure has two main regions – one with greater GLP-1 specificity and the other with greater glucagon specificity, and these two areas are linked by a propriety technology called a EuPort™ domain. This is an area which allows the drug to bind to albumin, which increases its serum half-life and enables weekly dosing while slowing its entry into the bloodstream.
“Ultimately, we think that this has impacts, hypothetically, on tolerability and potentially mitigating the need for dose escalation,” said Dr. Harrison.
Weight loss results
The phase 1 study Dr. Harrison presented had a randomized, double-blind, placebo-controlled design with single and multiple ascending doses (SAD/MAD) of pemvidutide being tested. He presented data on the MAD phase only, noting that the SAD phase had been used to determine what doses to use in the latter.
Seventy individuals with a body mass index of between 25 and 40 kg/m2 were recruited and 34 of these were enrolled in the MAD phase of the study. Three doses of pemvidutide were used, given subcutaneously once a week for 12 weeks: Seven participants received 1.2 mg, 9 were given 1.8 mg, 11 had 2.4 mg, and 7 subjects were treated with placebo. Dr. Harrison noted that there were no caloric restrictions in the trial and no lifestyle modifications or interventions.
The average age of study participants ranged from 27 to 35 years and the mean BMI was 30-31 kg/m2 across each group, with their lipid parameters in the upper range of normal.
Clear weight loss reductions were seen across all the pemvidutide groups versus placebo, with the greatest percentage changes in weight loss seen with the two higher doses used. At week 12, there was a 4.9%, 10.3% and 9.0% weight loss in the 1.2-mg, 1.8-mg and 2.4-mg pemvidutide groups compared to 1.6% in placebo-treated individuals.
All patients in the 1.8-mg group achieved a 5% or greater weight loss, Dr. Harrison observed, but there “was a plateauing” effect with the 2.4-mg dose with 89% of patients achieving this target. In comparison, a third of patients on the lowest dose and 20% of those on placebo achieved this target.
The trajectory of weight loss seen in the trial suggests that “the rate of weight loss would continue beyond 12 weeks if we were to continue the therapy” Dr. Harrison said.
Lipid changes and liver fat reductions
Levels of serum lipids from baseline to week 12 fell to a greater extent with pemvidutide treatment than with placebo, in the range of –27% for total cholesterol in the two highest dose groups, –25% for LDL-cholesterol for those groups, –37% for triglycerides for the 1.2- and 1.8-mg groups, and reductions in apolipoprotein B were seen.
“We saw an initial decline in HDL [high-density lipoprotein],” Dr. Harrison said, noting that “this is consistent with prior studies looking at rapid weight loss, and over time, this mitigates as you continue to treat at least based on other mechanisms of action or other drugs with similar mechanisms.”
Pemvidutide treatment was also associated with increased lipid oxidation and decreased lipid synthesis, and “there was a robust decrease in lipids implicated in NASH inflammation,” Dr. Harrison pointed out.
Importantly, in five of eight participants who had high levels of liver fat at baseline – defined as a 5% or greater magnetic resonance imaging–derived proton-density-fat-fraction (MRI-PDFF) – showed a decrease to undetectable limits (1.5% or less). This was a greater than 90% reduction in liver fat, Dr. Harrison said. All five patients were in the 1.8-mg and 2.4-mg groups.
As for side effects, these were “predominantly upper GI, with nausea and vomiting.” These were mild in most cases, but he pointed out that five patients treated with the 1.8-mg dose experienced moderate nausea and three experienced moderate vomiting. Mild diarrhea and constipation were also seen in two of patients given this dose but was not reported in any of the other groups.
During the discussion following the presentation, it was pointed out that there was no clear dose-dependent effect considering the 1.8-mg dose seemed to have a stronger effect in some areas than the 2.4-mg dose. That’s a fair point, Dr. Harrison responded, reiterating it was a small study with a short treatment duration, but that there did look like a plateauing effect, “at least in patients with a mean BMI of between 30 and 31.”
Dr. Harrison was asked about potential effects on insulin levels and if that was a worry because, if glucagon is stimulated, it could increase insulin. That in turn might encourage insulin resistance and promote worse outcomes.
“If you look outside of just this program, glucagon agonism has been dosed in a lot of patients over time, and we haven’t seen that,” Dr. Harrison replied. Pemvidutide is an agonist rather than antagonist, so perhaps the [nonalcoholic steatohepatitis]–inducing effects seen before with glucagon antagonism won’t occur, he suggested.
Dr. Harrison disclosed ties to Altimmune (the study sponsor), Akero, Axcella, Bristol Myers Squibb, Cirius, CiVi Biopharma, Conatus, Corcept, CymaBay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, HistoIndex, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, NorthSea, Pfizer, Sagimet, Viking, and 89Bio.
LONDON – Weight loss, lipid reductions, and “robust improvements” in lipid species associated with nonalcoholic fatty liver disease were achieved in patients who were treated with pemvidutide in a first-in-human, phase 1 clinical trial reported at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver.
The presenting study investigator, Stephen A. Harrison, MD, said that pemvidutide, which is also being developed for the treatment of obesity, appeared to be well tolerated. There were no serious or severe adverse events, and no patient had to discontinue treatment because of side effects.
Overall, “pemvidutide represents a promising new agent,” said Dr. Harrison, medical director of Pinnacle Research in San Antonio, Texas.
Dual incretin effect
Pemvidutide is a “balanced” dual agonist of glucagon-like peptide 1 (GLP-1) and glucagon, Dr. Harrison explained in his oral abstract.
“With glucagon, we are working to drive energy expenditure up, and with GLP-1, we’re decreasing food intake,” Dr. Harrison said.
What might set pemvidutide apart from other incretins lies within its structure, Dr. Harrison suggested. The structure has two main regions – one with greater GLP-1 specificity and the other with greater glucagon specificity, and these two areas are linked by a propriety technology called a EuPort™ domain. This is an area which allows the drug to bind to albumin, which increases its serum half-life and enables weekly dosing while slowing its entry into the bloodstream.
“Ultimately, we think that this has impacts, hypothetically, on tolerability and potentially mitigating the need for dose escalation,” said Dr. Harrison.
Weight loss results
The phase 1 study Dr. Harrison presented had a randomized, double-blind, placebo-controlled design with single and multiple ascending doses (SAD/MAD) of pemvidutide being tested. He presented data on the MAD phase only, noting that the SAD phase had been used to determine what doses to use in the latter.
Seventy individuals with a body mass index of between 25 and 40 kg/m2 were recruited and 34 of these were enrolled in the MAD phase of the study. Three doses of pemvidutide were used, given subcutaneously once a week for 12 weeks: Seven participants received 1.2 mg, 9 were given 1.8 mg, 11 had 2.4 mg, and 7 subjects were treated with placebo. Dr. Harrison noted that there were no caloric restrictions in the trial and no lifestyle modifications or interventions.
The average age of study participants ranged from 27 to 35 years and the mean BMI was 30-31 kg/m2 across each group, with their lipid parameters in the upper range of normal.
Clear weight loss reductions were seen across all the pemvidutide groups versus placebo, with the greatest percentage changes in weight loss seen with the two higher doses used. At week 12, there was a 4.9%, 10.3% and 9.0% weight loss in the 1.2-mg, 1.8-mg and 2.4-mg pemvidutide groups compared to 1.6% in placebo-treated individuals.
All patients in the 1.8-mg group achieved a 5% or greater weight loss, Dr. Harrison observed, but there “was a plateauing” effect with the 2.4-mg dose with 89% of patients achieving this target. In comparison, a third of patients on the lowest dose and 20% of those on placebo achieved this target.
The trajectory of weight loss seen in the trial suggests that “the rate of weight loss would continue beyond 12 weeks if we were to continue the therapy” Dr. Harrison said.
Lipid changes and liver fat reductions
Levels of serum lipids from baseline to week 12 fell to a greater extent with pemvidutide treatment than with placebo, in the range of –27% for total cholesterol in the two highest dose groups, –25% for LDL-cholesterol for those groups, –37% for triglycerides for the 1.2- and 1.8-mg groups, and reductions in apolipoprotein B were seen.
“We saw an initial decline in HDL [high-density lipoprotein],” Dr. Harrison said, noting that “this is consistent with prior studies looking at rapid weight loss, and over time, this mitigates as you continue to treat at least based on other mechanisms of action or other drugs with similar mechanisms.”
Pemvidutide treatment was also associated with increased lipid oxidation and decreased lipid synthesis, and “there was a robust decrease in lipids implicated in NASH inflammation,” Dr. Harrison pointed out.
Importantly, in five of eight participants who had high levels of liver fat at baseline – defined as a 5% or greater magnetic resonance imaging–derived proton-density-fat-fraction (MRI-PDFF) – showed a decrease to undetectable limits (1.5% or less). This was a greater than 90% reduction in liver fat, Dr. Harrison said. All five patients were in the 1.8-mg and 2.4-mg groups.
As for side effects, these were “predominantly upper GI, with nausea and vomiting.” These were mild in most cases, but he pointed out that five patients treated with the 1.8-mg dose experienced moderate nausea and three experienced moderate vomiting. Mild diarrhea and constipation were also seen in two of patients given this dose but was not reported in any of the other groups.
During the discussion following the presentation, it was pointed out that there was no clear dose-dependent effect considering the 1.8-mg dose seemed to have a stronger effect in some areas than the 2.4-mg dose. That’s a fair point, Dr. Harrison responded, reiterating it was a small study with a short treatment duration, but that there did look like a plateauing effect, “at least in patients with a mean BMI of between 30 and 31.”
Dr. Harrison was asked about potential effects on insulin levels and if that was a worry because, if glucagon is stimulated, it could increase insulin. That in turn might encourage insulin resistance and promote worse outcomes.
“If you look outside of just this program, glucagon agonism has been dosed in a lot of patients over time, and we haven’t seen that,” Dr. Harrison replied. Pemvidutide is an agonist rather than antagonist, so perhaps the [nonalcoholic steatohepatitis]–inducing effects seen before with glucagon antagonism won’t occur, he suggested.
Dr. Harrison disclosed ties to Altimmune (the study sponsor), Akero, Axcella, Bristol Myers Squibb, Cirius, CiVi Biopharma, Conatus, Corcept, CymaBay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, HistoIndex, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, NorthSea, Pfizer, Sagimet, Viking, and 89Bio.
AT ILC 2022