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Psychedelic drug therapy a potential ‘breakthrough’ for alcohol dependence
Results from the first randomized, placebo-controlled trial of psilocybin for alcohol dependence showed that during the 8 months after first treatment dose, participants who received psilocybin had less than half as many heavy drinking days as their counterparts who received placebo.
In addition, 7 months after the last dose of medication, twice as many psilocybin-treated patients as placebo-treated patients were abstinent.
The effects observed with psilocybin were “considerably larger” than those of currently approved treatments for AUD, senior investigator Michael Bogenschutz, MD, psychiatrist and director of the NYU Langone Center for Psychedelic Medicine, New York, said during an Aug. 24 press briefing.
If the findings hold up in future trials, psilocybin will be a “real breakthrough” in the treatment of the condition, Dr. Bogenschutz said.
The findings were published online in JAMA Psychiatry.
83% reduction in drinking days
The study included 93 adults (mean age, 46 years) with alcohol dependence who consumed an average of seven drinks on the days they drank and had had at least four heavy drinking days during the month prior to treatment.
Of the participants, 48 were randomly assigned to receive two doses of psilocybin, and 45 were assigned to receive an antihistamine (diphenhydramine) placebo. Study medication was administered during 2 day-long sessions at week 4 and week 8.
The participants also received 12 psychotherapy sessions over a 12-week period. All were assessed at intervals from the beginning of the study until 32 weeks after the first medication session.
The primary outcome was percentage of days in which the patient drank heavily during the 32-week period following first medication dose. Heavy drinking was defined as having five or more drinks in a day for a man and four or more drinks in a day for a woman.
The percentage of heavy drinking days during the 32-week period was 9.7% for the psilocybin group and 23.6% for the placebo group, for a mean difference of 13.9% (P = .01).
“Compared to their baseline before the study, after receiving medication, the psilocybin group decreased their heavy drinking days by 83%, while the placebo group reduced their heavy drinking by 51%,” Dr. Bogenschutz reported.
During the last month of follow-up, which was 7 months after the final dose of study medication, 48% of the psilocybin group were entirely abstinent vs. 24% of the placebo group.
“It is remarkable that the effects of psilocybin treatment persisted for 7 months after people received the last dose of medication. This suggests that psilocybin is treating the underlying disorder of alcohol addiction rather than merely treating symptoms,” Dr. Bogenschutz noted.
Total alcohol consumption and problems related to alcohol use were also significantly less in the psilocybin group.
‘Encouraged and hopeful’
Adverse events related to psilocybin were mostly mild, self-limiting, and consistent with other recent trials that evaluated the drug’s effects in various conditions.
However, the current investigators note that they implemented measures to ensure safety, including careful medical and psychiatric screening, therapy, and monitoring that was provided by well-trained therapists, including a licensed psychiatrist. In addition, medications were available to treat acute psychiatric reactions.
A cited limitation of the study was that blinding was not maintained because the average intensity of experience with psilocybin was high, whereas it was low with diphenhydramine.
This difference undermined the masking of treatment such that more than 90% of participants and therapists correctly guessed the treatment assignment.
Another limitation was that objective measures to validate self-reported drinking outcomes were available for only 54% of study participants.
Despite these limitations, the study builds on earlier work by the NYU team that showed that two doses of psilocybin taken over a period of 8 weeks significantly reduced alcohol use and cravings in patients with AUD.
“We’re very encouraged by these findings and hopeful about where they could lead. Personally, it’s been very meaningful and rewarding for me to do this work and inspiring to witness the remarkable recoveries that some of our participants have experienced,” Dr. Bogenschutz told briefing attendees.
Urgent need
The authors of an accompanying editorial note that novel medications for alcohol dependence are “sorely needed. Recent renewed interest in the potential of hallucinogens for treating psychiatric disorders, including AUD, represents a potential move in that direction.”
Henry Kranzler, MD, and Emily Hartwell, PhD, both with the Center for Studies of Addiction, University of Pennsylvania, Philadelphia, write that the new findings “underscore the potential of developing psilocybin as an addition to the alcohol treatment pharmacopeia.”
They question, however, the feasibility of using hallucinogens in routine clinical practice because intensive psychotherapy, such as that provided in this study, requires a significant investment of time and labor.
“Such concomitant therapy, if necessary to realize the therapeutic benefits of psilocybin for treating AUD, could limit its uptake by clinicians,” Dr. Kranzler and Dr. Hartwell write.
The study was funded by the Heffter Research Institute and by individual donations from Carey and Claudia Turnbull, Dr. Efrem Nulman, Rodrigo Niño, and Cody Swift. Dr. Bogenschutz reports having received research funds from and serving as a consultant to Mind Medicine, the Multidisciplinary Association for Psychedelic Studies, B. More, AJNA Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences. Dr. Kranzler and Dr. Hartwell have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from the first randomized, placebo-controlled trial of psilocybin for alcohol dependence showed that during the 8 months after first treatment dose, participants who received psilocybin had less than half as many heavy drinking days as their counterparts who received placebo.
In addition, 7 months after the last dose of medication, twice as many psilocybin-treated patients as placebo-treated patients were abstinent.
The effects observed with psilocybin were “considerably larger” than those of currently approved treatments for AUD, senior investigator Michael Bogenschutz, MD, psychiatrist and director of the NYU Langone Center for Psychedelic Medicine, New York, said during an Aug. 24 press briefing.
If the findings hold up in future trials, psilocybin will be a “real breakthrough” in the treatment of the condition, Dr. Bogenschutz said.
The findings were published online in JAMA Psychiatry.
83% reduction in drinking days
The study included 93 adults (mean age, 46 years) with alcohol dependence who consumed an average of seven drinks on the days they drank and had had at least four heavy drinking days during the month prior to treatment.
Of the participants, 48 were randomly assigned to receive two doses of psilocybin, and 45 were assigned to receive an antihistamine (diphenhydramine) placebo. Study medication was administered during 2 day-long sessions at week 4 and week 8.
The participants also received 12 psychotherapy sessions over a 12-week period. All were assessed at intervals from the beginning of the study until 32 weeks after the first medication session.
The primary outcome was percentage of days in which the patient drank heavily during the 32-week period following first medication dose. Heavy drinking was defined as having five or more drinks in a day for a man and four or more drinks in a day for a woman.
The percentage of heavy drinking days during the 32-week period was 9.7% for the psilocybin group and 23.6% for the placebo group, for a mean difference of 13.9% (P = .01).
“Compared to their baseline before the study, after receiving medication, the psilocybin group decreased their heavy drinking days by 83%, while the placebo group reduced their heavy drinking by 51%,” Dr. Bogenschutz reported.
During the last month of follow-up, which was 7 months after the final dose of study medication, 48% of the psilocybin group were entirely abstinent vs. 24% of the placebo group.
“It is remarkable that the effects of psilocybin treatment persisted for 7 months after people received the last dose of medication. This suggests that psilocybin is treating the underlying disorder of alcohol addiction rather than merely treating symptoms,” Dr. Bogenschutz noted.
Total alcohol consumption and problems related to alcohol use were also significantly less in the psilocybin group.
‘Encouraged and hopeful’
Adverse events related to psilocybin were mostly mild, self-limiting, and consistent with other recent trials that evaluated the drug’s effects in various conditions.
However, the current investigators note that they implemented measures to ensure safety, including careful medical and psychiatric screening, therapy, and monitoring that was provided by well-trained therapists, including a licensed psychiatrist. In addition, medications were available to treat acute psychiatric reactions.
A cited limitation of the study was that blinding was not maintained because the average intensity of experience with psilocybin was high, whereas it was low with diphenhydramine.
This difference undermined the masking of treatment such that more than 90% of participants and therapists correctly guessed the treatment assignment.
Another limitation was that objective measures to validate self-reported drinking outcomes were available for only 54% of study participants.
Despite these limitations, the study builds on earlier work by the NYU team that showed that two doses of psilocybin taken over a period of 8 weeks significantly reduced alcohol use and cravings in patients with AUD.
“We’re very encouraged by these findings and hopeful about where they could lead. Personally, it’s been very meaningful and rewarding for me to do this work and inspiring to witness the remarkable recoveries that some of our participants have experienced,” Dr. Bogenschutz told briefing attendees.
Urgent need
The authors of an accompanying editorial note that novel medications for alcohol dependence are “sorely needed. Recent renewed interest in the potential of hallucinogens for treating psychiatric disorders, including AUD, represents a potential move in that direction.”
Henry Kranzler, MD, and Emily Hartwell, PhD, both with the Center for Studies of Addiction, University of Pennsylvania, Philadelphia, write that the new findings “underscore the potential of developing psilocybin as an addition to the alcohol treatment pharmacopeia.”
They question, however, the feasibility of using hallucinogens in routine clinical practice because intensive psychotherapy, such as that provided in this study, requires a significant investment of time and labor.
“Such concomitant therapy, if necessary to realize the therapeutic benefits of psilocybin for treating AUD, could limit its uptake by clinicians,” Dr. Kranzler and Dr. Hartwell write.
The study was funded by the Heffter Research Institute and by individual donations from Carey and Claudia Turnbull, Dr. Efrem Nulman, Rodrigo Niño, and Cody Swift. Dr. Bogenschutz reports having received research funds from and serving as a consultant to Mind Medicine, the Multidisciplinary Association for Psychedelic Studies, B. More, AJNA Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences. Dr. Kranzler and Dr. Hartwell have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from the first randomized, placebo-controlled trial of psilocybin for alcohol dependence showed that during the 8 months after first treatment dose, participants who received psilocybin had less than half as many heavy drinking days as their counterparts who received placebo.
In addition, 7 months after the last dose of medication, twice as many psilocybin-treated patients as placebo-treated patients were abstinent.
The effects observed with psilocybin were “considerably larger” than those of currently approved treatments for AUD, senior investigator Michael Bogenschutz, MD, psychiatrist and director of the NYU Langone Center for Psychedelic Medicine, New York, said during an Aug. 24 press briefing.
If the findings hold up in future trials, psilocybin will be a “real breakthrough” in the treatment of the condition, Dr. Bogenschutz said.
The findings were published online in JAMA Psychiatry.
83% reduction in drinking days
The study included 93 adults (mean age, 46 years) with alcohol dependence who consumed an average of seven drinks on the days they drank and had had at least four heavy drinking days during the month prior to treatment.
Of the participants, 48 were randomly assigned to receive two doses of psilocybin, and 45 were assigned to receive an antihistamine (diphenhydramine) placebo. Study medication was administered during 2 day-long sessions at week 4 and week 8.
The participants also received 12 psychotherapy sessions over a 12-week period. All were assessed at intervals from the beginning of the study until 32 weeks after the first medication session.
The primary outcome was percentage of days in which the patient drank heavily during the 32-week period following first medication dose. Heavy drinking was defined as having five or more drinks in a day for a man and four or more drinks in a day for a woman.
The percentage of heavy drinking days during the 32-week period was 9.7% for the psilocybin group and 23.6% for the placebo group, for a mean difference of 13.9% (P = .01).
“Compared to their baseline before the study, after receiving medication, the psilocybin group decreased their heavy drinking days by 83%, while the placebo group reduced their heavy drinking by 51%,” Dr. Bogenschutz reported.
During the last month of follow-up, which was 7 months after the final dose of study medication, 48% of the psilocybin group were entirely abstinent vs. 24% of the placebo group.
“It is remarkable that the effects of psilocybin treatment persisted for 7 months after people received the last dose of medication. This suggests that psilocybin is treating the underlying disorder of alcohol addiction rather than merely treating symptoms,” Dr. Bogenschutz noted.
Total alcohol consumption and problems related to alcohol use were also significantly less in the psilocybin group.
‘Encouraged and hopeful’
Adverse events related to psilocybin were mostly mild, self-limiting, and consistent with other recent trials that evaluated the drug’s effects in various conditions.
However, the current investigators note that they implemented measures to ensure safety, including careful medical and psychiatric screening, therapy, and monitoring that was provided by well-trained therapists, including a licensed psychiatrist. In addition, medications were available to treat acute psychiatric reactions.
A cited limitation of the study was that blinding was not maintained because the average intensity of experience with psilocybin was high, whereas it was low with diphenhydramine.
This difference undermined the masking of treatment such that more than 90% of participants and therapists correctly guessed the treatment assignment.
Another limitation was that objective measures to validate self-reported drinking outcomes were available for only 54% of study participants.
Despite these limitations, the study builds on earlier work by the NYU team that showed that two doses of psilocybin taken over a period of 8 weeks significantly reduced alcohol use and cravings in patients with AUD.
“We’re very encouraged by these findings and hopeful about where they could lead. Personally, it’s been very meaningful and rewarding for me to do this work and inspiring to witness the remarkable recoveries that some of our participants have experienced,” Dr. Bogenschutz told briefing attendees.
Urgent need
The authors of an accompanying editorial note that novel medications for alcohol dependence are “sorely needed. Recent renewed interest in the potential of hallucinogens for treating psychiatric disorders, including AUD, represents a potential move in that direction.”
Henry Kranzler, MD, and Emily Hartwell, PhD, both with the Center for Studies of Addiction, University of Pennsylvania, Philadelphia, write that the new findings “underscore the potential of developing psilocybin as an addition to the alcohol treatment pharmacopeia.”
They question, however, the feasibility of using hallucinogens in routine clinical practice because intensive psychotherapy, such as that provided in this study, requires a significant investment of time and labor.
“Such concomitant therapy, if necessary to realize the therapeutic benefits of psilocybin for treating AUD, could limit its uptake by clinicians,” Dr. Kranzler and Dr. Hartwell write.
The study was funded by the Heffter Research Institute and by individual donations from Carey and Claudia Turnbull, Dr. Efrem Nulman, Rodrigo Niño, and Cody Swift. Dr. Bogenschutz reports having received research funds from and serving as a consultant to Mind Medicine, the Multidisciplinary Association for Psychedelic Studies, B. More, AJNA Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences. Dr. Kranzler and Dr. Hartwell have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA PSYCHIATRY
Metformin fails as early COVID-19 treatment but shows potential
Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.
However, metformin showed some potential in a secondary analysis.
Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.
“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”
In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.
A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.
The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).
The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.
The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.
Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.
The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.
However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.
“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.
The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.
“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”
Ineffective drugs are inefficient use of resources
“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.
At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.
The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.
“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”
The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.
However, metformin showed some potential in a secondary analysis.
Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.
“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”
In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.
A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.
The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).
The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.
The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.
Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.
The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.
However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.
“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.
The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.
“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”
Ineffective drugs are inefficient use of resources
“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.
At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.
The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.
“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”
The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.
However, metformin showed some potential in a secondary analysis.
Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.
“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”
In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.
A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.
The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).
The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.
The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.
Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.
The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.
However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.
“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.
The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.
“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”
Ineffective drugs are inefficient use of resources
“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.
At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.
The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.
“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”
The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Erlotinib promising for cancer prevention in familial adenomatous polyposis
“If existing data are confirmed and extended through future research, this strategy has the potential for substantial impact on clinical practice by decreasing, delaying, or augmenting endoscopic and surgical interventions as the mainstay for duodenal cancer prevention in this high-risk patient population,” the study team says.
FAP is a rare genetic condition that markedly raises the risk for colorectal polyps and cancer.
“The biological pathway that leads to the development of polyps and colon cancer in patients with FAP is the same biological pathway as patients in the general population,” study investigator Niloy Jewel Samadder, MD, with the Mayo Clinic, Rochester, Minn., said in a news release.
“Our trial looked at opportunities to use chemoprevention agents in patients with FAP to inhibit the development of precancerous polyps in the small bowel and colorectum,” Dr. Samadder explains.
In an earlier study, the researchers found that the combination of the COX-2 inhibitor sulindac (150 mg twice daily) and erlotinib (75 mg daily) reduced duodenal polyp burden.
However, the dual-drug strategy was associated with a relatively high adverse event (AE) rate, which may limit use of the combination for chemoprevention, as reported previously.
This phase 2 study tested whether erlotinib’s AE profile would be improved with a once-weekly dosing schedule while still reducing polyp burden.
The study was first published online in the journal Gut.
In the single-arm, multicenter study, 46 adults with FAP (mean age, 44 years; 48% women) self-administered 350 mg of erlotinib by mouth one time per week for 6 months. All but four participants completed the 6-month study.
After 6 months of weekly erlotinib, duodenal polyp burden was significantly reduced, with a mean percent reduction of 29.6% (95% confidence interval: –39.6% to –19.7%; P < .0001).
The benefit was observed in patients with either Spigelman 2 or Spigelman 3 duodenal polyp burden.
“Though only 12% of patients noted a decrease in Spigelman stage from 3 to 2 associated with therapy, the majority of patients (86%) had stable disease while on treatment,” the study team reports.
GI polyp number (a secondary outcome) was also decreased after 6 months of treatment with erlotinib (median decrease of 30.8%; P = .0256).
While once-weekly erlotinib was “generally” well tolerated, grade 2 or 3 AEs were reported in 72% of patients; two suffered grade 3 toxicity. Nonetheless, the AE rate was significantly more than the expected null hypothesis rate of 50%, the study team states.
Four patients withdrew from the study because of drug-induced AEs, which included grade 3 rash acneiform, grade 2 infections (hand, foot, and mouth disease), grade 1 fatigue, and grade 1 rash acneiform. No grade 4 AEs were reported.
The most common AE was an erlotinib-induced acneiform-like rash, which occurred in 56.5% of study patients. The rash was managed with topical cortisone and/or clindamycin. Additional erlotinib-induced AEs included oral mucositis (6.5%), diarrhea (50%), and nausea (26.1%).
Summing up, Dr. Samadder and colleagues note that FAP “portends a heritable, systemic predisposition to cancer, and the ultimate goal of cancer preventive intervention is to interrupt the development of neoplasia, need for surgery, and ultimately death from cancer, with an acceptable AE profile.”
The findings from this phase 2 trial support further study of erlotinib as “an effective, acceptable cancer preventive agent for FAP-associated gastrointestinal polyposis,” they conclude.
The study was sponsored by the National Cancer Institute. Dr. Samadder is a consultant for Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals.
A version of this article first appeared on Medscape.com.
“If existing data are confirmed and extended through future research, this strategy has the potential for substantial impact on clinical practice by decreasing, delaying, or augmenting endoscopic and surgical interventions as the mainstay for duodenal cancer prevention in this high-risk patient population,” the study team says.
FAP is a rare genetic condition that markedly raises the risk for colorectal polyps and cancer.
“The biological pathway that leads to the development of polyps and colon cancer in patients with FAP is the same biological pathway as patients in the general population,” study investigator Niloy Jewel Samadder, MD, with the Mayo Clinic, Rochester, Minn., said in a news release.
“Our trial looked at opportunities to use chemoprevention agents in patients with FAP to inhibit the development of precancerous polyps in the small bowel and colorectum,” Dr. Samadder explains.
In an earlier study, the researchers found that the combination of the COX-2 inhibitor sulindac (150 mg twice daily) and erlotinib (75 mg daily) reduced duodenal polyp burden.
However, the dual-drug strategy was associated with a relatively high adverse event (AE) rate, which may limit use of the combination for chemoprevention, as reported previously.
This phase 2 study tested whether erlotinib’s AE profile would be improved with a once-weekly dosing schedule while still reducing polyp burden.
The study was first published online in the journal Gut.
In the single-arm, multicenter study, 46 adults with FAP (mean age, 44 years; 48% women) self-administered 350 mg of erlotinib by mouth one time per week for 6 months. All but four participants completed the 6-month study.
After 6 months of weekly erlotinib, duodenal polyp burden was significantly reduced, with a mean percent reduction of 29.6% (95% confidence interval: –39.6% to –19.7%; P < .0001).
The benefit was observed in patients with either Spigelman 2 or Spigelman 3 duodenal polyp burden.
“Though only 12% of patients noted a decrease in Spigelman stage from 3 to 2 associated with therapy, the majority of patients (86%) had stable disease while on treatment,” the study team reports.
GI polyp number (a secondary outcome) was also decreased after 6 months of treatment with erlotinib (median decrease of 30.8%; P = .0256).
While once-weekly erlotinib was “generally” well tolerated, grade 2 or 3 AEs were reported in 72% of patients; two suffered grade 3 toxicity. Nonetheless, the AE rate was significantly more than the expected null hypothesis rate of 50%, the study team states.
Four patients withdrew from the study because of drug-induced AEs, which included grade 3 rash acneiform, grade 2 infections (hand, foot, and mouth disease), grade 1 fatigue, and grade 1 rash acneiform. No grade 4 AEs were reported.
The most common AE was an erlotinib-induced acneiform-like rash, which occurred in 56.5% of study patients. The rash was managed with topical cortisone and/or clindamycin. Additional erlotinib-induced AEs included oral mucositis (6.5%), diarrhea (50%), and nausea (26.1%).
Summing up, Dr. Samadder and colleagues note that FAP “portends a heritable, systemic predisposition to cancer, and the ultimate goal of cancer preventive intervention is to interrupt the development of neoplasia, need for surgery, and ultimately death from cancer, with an acceptable AE profile.”
The findings from this phase 2 trial support further study of erlotinib as “an effective, acceptable cancer preventive agent for FAP-associated gastrointestinal polyposis,” they conclude.
The study was sponsored by the National Cancer Institute. Dr. Samadder is a consultant for Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals.
A version of this article first appeared on Medscape.com.
“If existing data are confirmed and extended through future research, this strategy has the potential for substantial impact on clinical practice by decreasing, delaying, or augmenting endoscopic and surgical interventions as the mainstay for duodenal cancer prevention in this high-risk patient population,” the study team says.
FAP is a rare genetic condition that markedly raises the risk for colorectal polyps and cancer.
“The biological pathway that leads to the development of polyps and colon cancer in patients with FAP is the same biological pathway as patients in the general population,” study investigator Niloy Jewel Samadder, MD, with the Mayo Clinic, Rochester, Minn., said in a news release.
“Our trial looked at opportunities to use chemoprevention agents in patients with FAP to inhibit the development of precancerous polyps in the small bowel and colorectum,” Dr. Samadder explains.
In an earlier study, the researchers found that the combination of the COX-2 inhibitor sulindac (150 mg twice daily) and erlotinib (75 mg daily) reduced duodenal polyp burden.
However, the dual-drug strategy was associated with a relatively high adverse event (AE) rate, which may limit use of the combination for chemoprevention, as reported previously.
This phase 2 study tested whether erlotinib’s AE profile would be improved with a once-weekly dosing schedule while still reducing polyp burden.
The study was first published online in the journal Gut.
In the single-arm, multicenter study, 46 adults with FAP (mean age, 44 years; 48% women) self-administered 350 mg of erlotinib by mouth one time per week for 6 months. All but four participants completed the 6-month study.
After 6 months of weekly erlotinib, duodenal polyp burden was significantly reduced, with a mean percent reduction of 29.6% (95% confidence interval: –39.6% to –19.7%; P < .0001).
The benefit was observed in patients with either Spigelman 2 or Spigelman 3 duodenal polyp burden.
“Though only 12% of patients noted a decrease in Spigelman stage from 3 to 2 associated with therapy, the majority of patients (86%) had stable disease while on treatment,” the study team reports.
GI polyp number (a secondary outcome) was also decreased after 6 months of treatment with erlotinib (median decrease of 30.8%; P = .0256).
While once-weekly erlotinib was “generally” well tolerated, grade 2 or 3 AEs were reported in 72% of patients; two suffered grade 3 toxicity. Nonetheless, the AE rate was significantly more than the expected null hypothesis rate of 50%, the study team states.
Four patients withdrew from the study because of drug-induced AEs, which included grade 3 rash acneiform, grade 2 infections (hand, foot, and mouth disease), grade 1 fatigue, and grade 1 rash acneiform. No grade 4 AEs were reported.
The most common AE was an erlotinib-induced acneiform-like rash, which occurred in 56.5% of study patients. The rash was managed with topical cortisone and/or clindamycin. Additional erlotinib-induced AEs included oral mucositis (6.5%), diarrhea (50%), and nausea (26.1%).
Summing up, Dr. Samadder and colleagues note that FAP “portends a heritable, systemic predisposition to cancer, and the ultimate goal of cancer preventive intervention is to interrupt the development of neoplasia, need for surgery, and ultimately death from cancer, with an acceptable AE profile.”
The findings from this phase 2 trial support further study of erlotinib as “an effective, acceptable cancer preventive agent for FAP-associated gastrointestinal polyposis,” they conclude.
The study was sponsored by the National Cancer Institute. Dr. Samadder is a consultant for Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals.
A version of this article first appeared on Medscape.com.
FROM GUT
Why it’s important for dermatologists to learn about JAK inhibitors
PORTLAND, ORE. – according to Andrew Blauvelt, MD, MBA.
“In dermatology, you need to know about JAK inhibitors, and you need to know how to use them,” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the annual meeting of the Pacific Dermatologic Association. “Making the choice, ‘I’m not going to use those drugs because of safety concerns,’ may be okay in 2022, but we are going to be getting a lot more indications for these drugs. So instead of avoiding JAK inhibitors, I would say try to learn [about] them, understand them, and get your messaging out on safety.”
It’s difficult to imagine a clinician-researcher who has more experience with the use of biologics and JAK inhibitors in AD than Dr. Blauvelt, who has been the international investigator on several important trials of treatments that include dupilumab, tralokinumab, abrocitinib, and upadacitinib for AD such as CHRONOS, ECZTEND, JADE REGIMEN, and HEADS UP. At the meeting, he discussed his clinical approach to selecting systemic agents for AD and shared prescribing tips. He began by noting that the approval of dupilumab for moderate to severe AD in 2017 ushered in a new era of treating the disease systemically.
“When it was approved, experts went right to dupilumab if they could, and avoided the use of cyclosporine or methotrexate,” said Dr. Blauvelt, who is also an elected member of the American Society for Clinical Investigation and the International Eczema Council. “I still think that dupilumab is a great agent to start with. We’ve had a bit of difficulty improving upon it.”
Following dupilumab’s approval, three other systemic options became available for patients with moderate to severe AD: the human IgG4 monoclonal antibody tralokinumab that binds to interleukin-13, which is administered subcutaneously; and, more recently, the oral JAK inhibitors abrocitinib and upadacitinib, approved in January for moderate to severe AD.
“I’m a big fan of JAK inhibitors because I think they offer things that biologic and topical therapies can’t offer,” Dr. Blauvelt said. “Patients like the pills versus shots. They also like the speed; JAK inhibitors work faster than dupilumab and tralokinumab. So, if you have a patient with bad AD who wants to get better quickly, that would be a reason to choose a JAK inhibitor over a biologic if you can.”
When Dr. Blauvelt has asked AD clinical trial participants if they’d rather be treated with a biologic agent or with a JAK inhibitor, about half choose one over the other.
“Patients who shy away from the safety issues would choose the biologic trial while the ones who wanted the fast relief would choose the JAK trial,” he said. “But if you present both options and the patients prefer a pill, I think the JAK inhibitors do better with a rapid control of inflammation as well as pruritus – the latter within 2 days of taking the pills.”
When counseling patients initiating a JAK inhibitor, Dr. Blauvelt mentioned three advantages, compared with biologics: the pill formulation, the rapidity of response in pruritus control, and better efficacy. “The downside is the safety,” he said. “Safety is the elephant in the room for the JAK inhibitors.”
The risks listed in the boxed warning in the labeling for JAK inhibitors include: an increased risk of serious bacterial, fungal, and opportunistic infections such as TB; a higher rate of all-cause mortality, including cardiovascular death; a higher rate of MACE (major adverse cardiovascular events, defined as cardiovascular death, MI, and stroke); the potential for malignancy, including lymphoma; and the potential for thrombosis, including an increased incidence of pulmonary embolism (PE).
“Risk of thrombosis seems to be a class effect for all JAK inhibitors,” Dr. Blauvelt said. “As far as I know, it’s idiosyncratic. For nearly all the DVT [deep vein thrombosis] cases that have been reported, patients had baseline risk factors for DVT and PE, which are obesity, smoking, and use of oral contraceptives.”
Dr. Blauvelt pointed out that the boxed warning related to mortality, malignancies, and MACE stemmed from a long-term trial of the JAK inhibitor tofacitinib in RA patients. “Those patients had to be at least 50 years old, 75% of them were on concomitant methotrexate and/or prednisone, and they had to have at least one cardiac risk factor to get into the trial,” he said.
“I’m not saying those things can’t happen in dermatology patients, but if you look at the safety data of JAK inhibitors in the AD studies and in the alopecia areata studies, we are seeing a few cases of these things here and there, but not major signals,” he said. To date, “they look safer in dermatologic diseases compared to tofacitinib in RA data in older populations.”
He emphasized the importance of discussing each of the risks in the boxed warning with patients who are candidates for JAK inhibitor therapy.
Dr. Blauvelt likened the lab monitoring required for JAK inhibitors to that required for methotrexate. This means ordering at baseline, a CBC with differential, a chem-20, a lipid panel, and a QuantiFERON-TB Gold test. The JAK inhibitor labels do not include information on the frequency of monitoring, “but I have a distinct opinion on this because of my blood test monitoring experience in the trials for many years,” he said.
“I think it’s good to do follow-up testing at 1 month, then every 3 months in the first year. In my experience, the people who drop blood cell counts or increase their lipids tend to do it in the first year.”
After 1 year of treatment, he continued, follow-up testing once every 6 months is reasonable. “If CPK [creatine phosphokinase] goes up, I don’t worry about it; it’s not clinically relevant. There is no recommendation for CPK monitoring, so if you’re getting that on your chem-20, I’d say don’t worry about it.”
Dr. Blauvelt reported that he is an investigator and a scientific adviser for several pharmaceutical companies developing treatments for AD, including companies that are evaluating or marketing JAK inhibitors for AD, including AbbVie, Incyte, and Pfizer, as well as dupilumab’s joint developers Sanofi and Regeneron.
PORTLAND, ORE. – according to Andrew Blauvelt, MD, MBA.
“In dermatology, you need to know about JAK inhibitors, and you need to know how to use them,” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the annual meeting of the Pacific Dermatologic Association. “Making the choice, ‘I’m not going to use those drugs because of safety concerns,’ may be okay in 2022, but we are going to be getting a lot more indications for these drugs. So instead of avoiding JAK inhibitors, I would say try to learn [about] them, understand them, and get your messaging out on safety.”
It’s difficult to imagine a clinician-researcher who has more experience with the use of biologics and JAK inhibitors in AD than Dr. Blauvelt, who has been the international investigator on several important trials of treatments that include dupilumab, tralokinumab, abrocitinib, and upadacitinib for AD such as CHRONOS, ECZTEND, JADE REGIMEN, and HEADS UP. At the meeting, he discussed his clinical approach to selecting systemic agents for AD and shared prescribing tips. He began by noting that the approval of dupilumab for moderate to severe AD in 2017 ushered in a new era of treating the disease systemically.
“When it was approved, experts went right to dupilumab if they could, and avoided the use of cyclosporine or methotrexate,” said Dr. Blauvelt, who is also an elected member of the American Society for Clinical Investigation and the International Eczema Council. “I still think that dupilumab is a great agent to start with. We’ve had a bit of difficulty improving upon it.”
Following dupilumab’s approval, three other systemic options became available for patients with moderate to severe AD: the human IgG4 monoclonal antibody tralokinumab that binds to interleukin-13, which is administered subcutaneously; and, more recently, the oral JAK inhibitors abrocitinib and upadacitinib, approved in January for moderate to severe AD.
“I’m a big fan of JAK inhibitors because I think they offer things that biologic and topical therapies can’t offer,” Dr. Blauvelt said. “Patients like the pills versus shots. They also like the speed; JAK inhibitors work faster than dupilumab and tralokinumab. So, if you have a patient with bad AD who wants to get better quickly, that would be a reason to choose a JAK inhibitor over a biologic if you can.”
When Dr. Blauvelt has asked AD clinical trial participants if they’d rather be treated with a biologic agent or with a JAK inhibitor, about half choose one over the other.
“Patients who shy away from the safety issues would choose the biologic trial while the ones who wanted the fast relief would choose the JAK trial,” he said. “But if you present both options and the patients prefer a pill, I think the JAK inhibitors do better with a rapid control of inflammation as well as pruritus – the latter within 2 days of taking the pills.”
When counseling patients initiating a JAK inhibitor, Dr. Blauvelt mentioned three advantages, compared with biologics: the pill formulation, the rapidity of response in pruritus control, and better efficacy. “The downside is the safety,” he said. “Safety is the elephant in the room for the JAK inhibitors.”
The risks listed in the boxed warning in the labeling for JAK inhibitors include: an increased risk of serious bacterial, fungal, and opportunistic infections such as TB; a higher rate of all-cause mortality, including cardiovascular death; a higher rate of MACE (major adverse cardiovascular events, defined as cardiovascular death, MI, and stroke); the potential for malignancy, including lymphoma; and the potential for thrombosis, including an increased incidence of pulmonary embolism (PE).
“Risk of thrombosis seems to be a class effect for all JAK inhibitors,” Dr. Blauvelt said. “As far as I know, it’s idiosyncratic. For nearly all the DVT [deep vein thrombosis] cases that have been reported, patients had baseline risk factors for DVT and PE, which are obesity, smoking, and use of oral contraceptives.”
Dr. Blauvelt pointed out that the boxed warning related to mortality, malignancies, and MACE stemmed from a long-term trial of the JAK inhibitor tofacitinib in RA patients. “Those patients had to be at least 50 years old, 75% of them were on concomitant methotrexate and/or prednisone, and they had to have at least one cardiac risk factor to get into the trial,” he said.
“I’m not saying those things can’t happen in dermatology patients, but if you look at the safety data of JAK inhibitors in the AD studies and in the alopecia areata studies, we are seeing a few cases of these things here and there, but not major signals,” he said. To date, “they look safer in dermatologic diseases compared to tofacitinib in RA data in older populations.”
He emphasized the importance of discussing each of the risks in the boxed warning with patients who are candidates for JAK inhibitor therapy.
Dr. Blauvelt likened the lab monitoring required for JAK inhibitors to that required for methotrexate. This means ordering at baseline, a CBC with differential, a chem-20, a lipid panel, and a QuantiFERON-TB Gold test. The JAK inhibitor labels do not include information on the frequency of monitoring, “but I have a distinct opinion on this because of my blood test monitoring experience in the trials for many years,” he said.
“I think it’s good to do follow-up testing at 1 month, then every 3 months in the first year. In my experience, the people who drop blood cell counts or increase their lipids tend to do it in the first year.”
After 1 year of treatment, he continued, follow-up testing once every 6 months is reasonable. “If CPK [creatine phosphokinase] goes up, I don’t worry about it; it’s not clinically relevant. There is no recommendation for CPK monitoring, so if you’re getting that on your chem-20, I’d say don’t worry about it.”
Dr. Blauvelt reported that he is an investigator and a scientific adviser for several pharmaceutical companies developing treatments for AD, including companies that are evaluating or marketing JAK inhibitors for AD, including AbbVie, Incyte, and Pfizer, as well as dupilumab’s joint developers Sanofi and Regeneron.
PORTLAND, ORE. – according to Andrew Blauvelt, MD, MBA.
“In dermatology, you need to know about JAK inhibitors, and you need to know how to use them,” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the annual meeting of the Pacific Dermatologic Association. “Making the choice, ‘I’m not going to use those drugs because of safety concerns,’ may be okay in 2022, but we are going to be getting a lot more indications for these drugs. So instead of avoiding JAK inhibitors, I would say try to learn [about] them, understand them, and get your messaging out on safety.”
It’s difficult to imagine a clinician-researcher who has more experience with the use of biologics and JAK inhibitors in AD than Dr. Blauvelt, who has been the international investigator on several important trials of treatments that include dupilumab, tralokinumab, abrocitinib, and upadacitinib for AD such as CHRONOS, ECZTEND, JADE REGIMEN, and HEADS UP. At the meeting, he discussed his clinical approach to selecting systemic agents for AD and shared prescribing tips. He began by noting that the approval of dupilumab for moderate to severe AD in 2017 ushered in a new era of treating the disease systemically.
“When it was approved, experts went right to dupilumab if they could, and avoided the use of cyclosporine or methotrexate,” said Dr. Blauvelt, who is also an elected member of the American Society for Clinical Investigation and the International Eczema Council. “I still think that dupilumab is a great agent to start with. We’ve had a bit of difficulty improving upon it.”
Following dupilumab’s approval, three other systemic options became available for patients with moderate to severe AD: the human IgG4 monoclonal antibody tralokinumab that binds to interleukin-13, which is administered subcutaneously; and, more recently, the oral JAK inhibitors abrocitinib and upadacitinib, approved in January for moderate to severe AD.
“I’m a big fan of JAK inhibitors because I think they offer things that biologic and topical therapies can’t offer,” Dr. Blauvelt said. “Patients like the pills versus shots. They also like the speed; JAK inhibitors work faster than dupilumab and tralokinumab. So, if you have a patient with bad AD who wants to get better quickly, that would be a reason to choose a JAK inhibitor over a biologic if you can.”
When Dr. Blauvelt has asked AD clinical trial participants if they’d rather be treated with a biologic agent or with a JAK inhibitor, about half choose one over the other.
“Patients who shy away from the safety issues would choose the biologic trial while the ones who wanted the fast relief would choose the JAK trial,” he said. “But if you present both options and the patients prefer a pill, I think the JAK inhibitors do better with a rapid control of inflammation as well as pruritus – the latter within 2 days of taking the pills.”
When counseling patients initiating a JAK inhibitor, Dr. Blauvelt mentioned three advantages, compared with biologics: the pill formulation, the rapidity of response in pruritus control, and better efficacy. “The downside is the safety,” he said. “Safety is the elephant in the room for the JAK inhibitors.”
The risks listed in the boxed warning in the labeling for JAK inhibitors include: an increased risk of serious bacterial, fungal, and opportunistic infections such as TB; a higher rate of all-cause mortality, including cardiovascular death; a higher rate of MACE (major adverse cardiovascular events, defined as cardiovascular death, MI, and stroke); the potential for malignancy, including lymphoma; and the potential for thrombosis, including an increased incidence of pulmonary embolism (PE).
“Risk of thrombosis seems to be a class effect for all JAK inhibitors,” Dr. Blauvelt said. “As far as I know, it’s idiosyncratic. For nearly all the DVT [deep vein thrombosis] cases that have been reported, patients had baseline risk factors for DVT and PE, which are obesity, smoking, and use of oral contraceptives.”
Dr. Blauvelt pointed out that the boxed warning related to mortality, malignancies, and MACE stemmed from a long-term trial of the JAK inhibitor tofacitinib in RA patients. “Those patients had to be at least 50 years old, 75% of them were on concomitant methotrexate and/or prednisone, and they had to have at least one cardiac risk factor to get into the trial,” he said.
“I’m not saying those things can’t happen in dermatology patients, but if you look at the safety data of JAK inhibitors in the AD studies and in the alopecia areata studies, we are seeing a few cases of these things here and there, but not major signals,” he said. To date, “they look safer in dermatologic diseases compared to tofacitinib in RA data in older populations.”
He emphasized the importance of discussing each of the risks in the boxed warning with patients who are candidates for JAK inhibitor therapy.
Dr. Blauvelt likened the lab monitoring required for JAK inhibitors to that required for methotrexate. This means ordering at baseline, a CBC with differential, a chem-20, a lipid panel, and a QuantiFERON-TB Gold test. The JAK inhibitor labels do not include information on the frequency of monitoring, “but I have a distinct opinion on this because of my blood test monitoring experience in the trials for many years,” he said.
“I think it’s good to do follow-up testing at 1 month, then every 3 months in the first year. In my experience, the people who drop blood cell counts or increase their lipids tend to do it in the first year.”
After 1 year of treatment, he continued, follow-up testing once every 6 months is reasonable. “If CPK [creatine phosphokinase] goes up, I don’t worry about it; it’s not clinically relevant. There is no recommendation for CPK monitoring, so if you’re getting that on your chem-20, I’d say don’t worry about it.”
Dr. Blauvelt reported that he is an investigator and a scientific adviser for several pharmaceutical companies developing treatments for AD, including companies that are evaluating or marketing JAK inhibitors for AD, including AbbVie, Incyte, and Pfizer, as well as dupilumab’s joint developers Sanofi and Regeneron.
AT PDA 2022
FDA approves ‘rapid-acting’ oral drug for major depression
The U.S. Food and Drug Administration has approved the first oral N-methyl D-aspartate (NMDA) receptor antagonist for the treatment of major depressive disorder (MDD) in adults, its manufacturer has announced.
Auvelity (Axsome Therapeutics) is a proprietary extended-release oral tablet containing dextromethorphan (45 mg) and bupropion (105 mg).
,” the company said in a news release.
“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, MD, psychiatrist-in-chief, Massachusetts General Hospital, Boston, added in the release.
‘Milestone’ in depression treatment?
Dr. Fava noted that nearly two-thirds of patients treated with currently available antidepressants fail to respond adequately, and those who do may not achieve clinically meaningful responses for up to 6-8 weeks.
“Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition,” he said.
The company noted the drug was studied in a comprehensive clinical program that included more than 1,100 patients with MDD.
The efficacy of the drug was demonstrated in the GEMINI placebo-controlled study – with confirmatory evidence provided by the ASCEND study, which compared it with bupropion sustained-release tablets.
Axsome said it expects to launch the new oral medication in the fourth quarter of this year. It is not approved for use in children.
The full prescribing information and medication guide are available online.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved the first oral N-methyl D-aspartate (NMDA) receptor antagonist for the treatment of major depressive disorder (MDD) in adults, its manufacturer has announced.
Auvelity (Axsome Therapeutics) is a proprietary extended-release oral tablet containing dextromethorphan (45 mg) and bupropion (105 mg).
,” the company said in a news release.
“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, MD, psychiatrist-in-chief, Massachusetts General Hospital, Boston, added in the release.
‘Milestone’ in depression treatment?
Dr. Fava noted that nearly two-thirds of patients treated with currently available antidepressants fail to respond adequately, and those who do may not achieve clinically meaningful responses for up to 6-8 weeks.
“Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition,” he said.
The company noted the drug was studied in a comprehensive clinical program that included more than 1,100 patients with MDD.
The efficacy of the drug was demonstrated in the GEMINI placebo-controlled study – with confirmatory evidence provided by the ASCEND study, which compared it with bupropion sustained-release tablets.
Axsome said it expects to launch the new oral medication in the fourth quarter of this year. It is not approved for use in children.
The full prescribing information and medication guide are available online.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved the first oral N-methyl D-aspartate (NMDA) receptor antagonist for the treatment of major depressive disorder (MDD) in adults, its manufacturer has announced.
Auvelity (Axsome Therapeutics) is a proprietary extended-release oral tablet containing dextromethorphan (45 mg) and bupropion (105 mg).
,” the company said in a news release.
“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, MD, psychiatrist-in-chief, Massachusetts General Hospital, Boston, added in the release.
‘Milestone’ in depression treatment?
Dr. Fava noted that nearly two-thirds of patients treated with currently available antidepressants fail to respond adequately, and those who do may not achieve clinically meaningful responses for up to 6-8 weeks.
“Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition,” he said.
The company noted the drug was studied in a comprehensive clinical program that included more than 1,100 patients with MDD.
The efficacy of the drug was demonstrated in the GEMINI placebo-controlled study – with confirmatory evidence provided by the ASCEND study, which compared it with bupropion sustained-release tablets.
Axsome said it expects to launch the new oral medication in the fourth quarter of this year. It is not approved for use in children.
The full prescribing information and medication guide are available online.
A version of this article first appeared on Medscape.com.
Antibiotic before oral surgery spares endocarditis; study validates guidelines
The strongest evidence yet to support clinical guidelines that recommend that people at high risk of endocarditis, such as those who’ve had previous episode the disease or who have a prosthetic cardiac valve, should take antibiotics before they have a tooth pulled or other types of oral surgery, comes from a new study that used two methodologies.
But it also pointed out that two-thirds of the time they aren’t getting that type of antibiotic coverage.
The researchers conducted a cohort study of almost 8 million retirees with employer-paid Medicare supplemental prescription benefits and dental benefits, then conducted a case-crossover study of 3,774 people from the cohort who’d been hospitalized with infectious endocarditis (IE) and who had invasive dental procedures. The bottom line is that the study supports the clinical guidelines from the American Heart Association and the European Society of Cardiology that recommend antibiotic prophylaxis (AP) before dental procedures for patients at high-risk of IE.
Likewise, lead author Martin Thornhill, MBBS, BDS, PhD, said in an interview, the findings also suggest that existing guidelines in the United Kingdom, which recommend against AP in these patients, “should be reconsidered.”
Those AHA and ESC guidelines, however, are “based on no good quality evidence,” said Dr. Thornhill, professor of translational research in dentistry at the University of Sheffield (England) School of Clinical Dentistry. “Other studies have looked at this, but we’ve done the largest study that has shown the clear association between invasive dental procedures and subsequent development of infective endocarditis.”
In the entire cohort of 7.95 million patients, 3,774 had cases of IE that required hospitalization. The study defined highest risk of IE as meeting one of these six criteria: a previous case of IE; a prosthetic cardiac valve or a valve repair that used prosthetic material; cyanotic congenital heart disease; palliative shunts or conduits to treat CHD; or a congenital heart defect that had been fully repaired, either by surgery or a transcatheter procedure, with prosthetic material or device – the latter within 6 months of the procedure.
Moderate IE risk included patients who had rheumatic heart disease, nonrheumatic valve disease or congenital valve anomalies—including mitral valve prolapse or aortic stenosis—or hypertrophic cardiomyopathy.
Risk classification and poor compliance
Highest-risk patients had significantly higher rates of IE a month after a dental procedure than lower-risk groups: 467.6 cases per 1 million procedures vs. 24.2 for moderate risk and 3.8 for low or unknown risk. A subanalysis found that the odds of IE were significantly increased for two specific dental procedures: extractions, with an odds ratio of 9.22 (95% confidence interval [CI], 5.54-15.88; P < .0001); and other oral surgical procedures, with an OR of 20.18 (95% CI, 11.22-37.74; P < .0001).
The study also found that 32.6% of the high-risk patients undergoing dental procedures got AP. “Clearly that shows a low level of compliance with the guidelines in the U.S.,” Dr. Thornhill said. “That’s something that needs to be addressed.”
The study was unique in that it used both a population cohort study and the case-crossover study. “It didn’t matter which of the two methods we used; we essentially came to the same result, which I think adds further weight to the findings,” Dr. Thornhill said.
This may be the best evidence to support the guidelines that clinicians may get. While the observational nature of this study has its limitations, conducting a randomized clinical trial to further validate the findings would be “logistically impossible,” he said, in that it would require an “absolutely enormous” cohort and coordination between medical and dental databases covering thousands of lives. An RCT would also require not using AP for some patients. “It’s not ethical to keep somebody off of antibiotic prophylaxis when there’s such a high risk of death and severe outcomes,” Dr. Thornhill said.
Ann Bolger, MD, emeritus professor of medicine at the University of California, San Francisco, and coauthor of an editorial comment on the study, said in an interview that this study is noteworthy not only for its dual methodology, but for the quality of the data that matched patients at high risk for IE with prescription and dental records. “The fact that they were able to have those details in enough granularity that they knew whether a dental procedure was likely to meet the criteria for these more invasive exposures really broke it open from my perspective,” she said.
She called the low compliance rate with AHA guidelines “one of the most sobering points of this,” and said it should put clinicians on notice that they must do more to educate and engage with high-risk patients. “The lines of communication here are somewhat fraught; it’s a little bit of a hot potato,” she said. “It’s a really great communications opportunity to get the provider’s attention back on this. You’re a cardiologist; you have to have this conversation when you see your patient with a prosthetic valve or who’s had endocarditis every time they come in. There’s a whole litany, and it takes 3 minutes, but you have to do it.”
The study received funding from Delta Dental of Michigan Research Committee and Renaissance Health Service Corp., and Dr. Thornhill received support from Delta Dental Research and Data Institute for the study. Dr. Bolger participated in the 2007 and 2021 AHA statements on AP to prevent IE.
The strongest evidence yet to support clinical guidelines that recommend that people at high risk of endocarditis, such as those who’ve had previous episode the disease or who have a prosthetic cardiac valve, should take antibiotics before they have a tooth pulled or other types of oral surgery, comes from a new study that used two methodologies.
But it also pointed out that two-thirds of the time they aren’t getting that type of antibiotic coverage.
The researchers conducted a cohort study of almost 8 million retirees with employer-paid Medicare supplemental prescription benefits and dental benefits, then conducted a case-crossover study of 3,774 people from the cohort who’d been hospitalized with infectious endocarditis (IE) and who had invasive dental procedures. The bottom line is that the study supports the clinical guidelines from the American Heart Association and the European Society of Cardiology that recommend antibiotic prophylaxis (AP) before dental procedures for patients at high-risk of IE.
Likewise, lead author Martin Thornhill, MBBS, BDS, PhD, said in an interview, the findings also suggest that existing guidelines in the United Kingdom, which recommend against AP in these patients, “should be reconsidered.”
Those AHA and ESC guidelines, however, are “based on no good quality evidence,” said Dr. Thornhill, professor of translational research in dentistry at the University of Sheffield (England) School of Clinical Dentistry. “Other studies have looked at this, but we’ve done the largest study that has shown the clear association between invasive dental procedures and subsequent development of infective endocarditis.”
In the entire cohort of 7.95 million patients, 3,774 had cases of IE that required hospitalization. The study defined highest risk of IE as meeting one of these six criteria: a previous case of IE; a prosthetic cardiac valve or a valve repair that used prosthetic material; cyanotic congenital heart disease; palliative shunts or conduits to treat CHD; or a congenital heart defect that had been fully repaired, either by surgery or a transcatheter procedure, with prosthetic material or device – the latter within 6 months of the procedure.
Moderate IE risk included patients who had rheumatic heart disease, nonrheumatic valve disease or congenital valve anomalies—including mitral valve prolapse or aortic stenosis—or hypertrophic cardiomyopathy.
Risk classification and poor compliance
Highest-risk patients had significantly higher rates of IE a month after a dental procedure than lower-risk groups: 467.6 cases per 1 million procedures vs. 24.2 for moderate risk and 3.8 for low or unknown risk. A subanalysis found that the odds of IE were significantly increased for two specific dental procedures: extractions, with an odds ratio of 9.22 (95% confidence interval [CI], 5.54-15.88; P < .0001); and other oral surgical procedures, with an OR of 20.18 (95% CI, 11.22-37.74; P < .0001).
The study also found that 32.6% of the high-risk patients undergoing dental procedures got AP. “Clearly that shows a low level of compliance with the guidelines in the U.S.,” Dr. Thornhill said. “That’s something that needs to be addressed.”
The study was unique in that it used both a population cohort study and the case-crossover study. “It didn’t matter which of the two methods we used; we essentially came to the same result, which I think adds further weight to the findings,” Dr. Thornhill said.
This may be the best evidence to support the guidelines that clinicians may get. While the observational nature of this study has its limitations, conducting a randomized clinical trial to further validate the findings would be “logistically impossible,” he said, in that it would require an “absolutely enormous” cohort and coordination between medical and dental databases covering thousands of lives. An RCT would also require not using AP for some patients. “It’s not ethical to keep somebody off of antibiotic prophylaxis when there’s such a high risk of death and severe outcomes,” Dr. Thornhill said.
Ann Bolger, MD, emeritus professor of medicine at the University of California, San Francisco, and coauthor of an editorial comment on the study, said in an interview that this study is noteworthy not only for its dual methodology, but for the quality of the data that matched patients at high risk for IE with prescription and dental records. “The fact that they were able to have those details in enough granularity that they knew whether a dental procedure was likely to meet the criteria for these more invasive exposures really broke it open from my perspective,” she said.
She called the low compliance rate with AHA guidelines “one of the most sobering points of this,” and said it should put clinicians on notice that they must do more to educate and engage with high-risk patients. “The lines of communication here are somewhat fraught; it’s a little bit of a hot potato,” she said. “It’s a really great communications opportunity to get the provider’s attention back on this. You’re a cardiologist; you have to have this conversation when you see your patient with a prosthetic valve or who’s had endocarditis every time they come in. There’s a whole litany, and it takes 3 minutes, but you have to do it.”
The study received funding from Delta Dental of Michigan Research Committee and Renaissance Health Service Corp., and Dr. Thornhill received support from Delta Dental Research and Data Institute for the study. Dr. Bolger participated in the 2007 and 2021 AHA statements on AP to prevent IE.
The strongest evidence yet to support clinical guidelines that recommend that people at high risk of endocarditis, such as those who’ve had previous episode the disease or who have a prosthetic cardiac valve, should take antibiotics before they have a tooth pulled or other types of oral surgery, comes from a new study that used two methodologies.
But it also pointed out that two-thirds of the time they aren’t getting that type of antibiotic coverage.
The researchers conducted a cohort study of almost 8 million retirees with employer-paid Medicare supplemental prescription benefits and dental benefits, then conducted a case-crossover study of 3,774 people from the cohort who’d been hospitalized with infectious endocarditis (IE) and who had invasive dental procedures. The bottom line is that the study supports the clinical guidelines from the American Heart Association and the European Society of Cardiology that recommend antibiotic prophylaxis (AP) before dental procedures for patients at high-risk of IE.
Likewise, lead author Martin Thornhill, MBBS, BDS, PhD, said in an interview, the findings also suggest that existing guidelines in the United Kingdom, which recommend against AP in these patients, “should be reconsidered.”
Those AHA and ESC guidelines, however, are “based on no good quality evidence,” said Dr. Thornhill, professor of translational research in dentistry at the University of Sheffield (England) School of Clinical Dentistry. “Other studies have looked at this, but we’ve done the largest study that has shown the clear association between invasive dental procedures and subsequent development of infective endocarditis.”
In the entire cohort of 7.95 million patients, 3,774 had cases of IE that required hospitalization. The study defined highest risk of IE as meeting one of these six criteria: a previous case of IE; a prosthetic cardiac valve or a valve repair that used prosthetic material; cyanotic congenital heart disease; palliative shunts or conduits to treat CHD; or a congenital heart defect that had been fully repaired, either by surgery or a transcatheter procedure, with prosthetic material or device – the latter within 6 months of the procedure.
Moderate IE risk included patients who had rheumatic heart disease, nonrheumatic valve disease or congenital valve anomalies—including mitral valve prolapse or aortic stenosis—or hypertrophic cardiomyopathy.
Risk classification and poor compliance
Highest-risk patients had significantly higher rates of IE a month after a dental procedure than lower-risk groups: 467.6 cases per 1 million procedures vs. 24.2 for moderate risk and 3.8 for low or unknown risk. A subanalysis found that the odds of IE were significantly increased for two specific dental procedures: extractions, with an odds ratio of 9.22 (95% confidence interval [CI], 5.54-15.88; P < .0001); and other oral surgical procedures, with an OR of 20.18 (95% CI, 11.22-37.74; P < .0001).
The study also found that 32.6% of the high-risk patients undergoing dental procedures got AP. “Clearly that shows a low level of compliance with the guidelines in the U.S.,” Dr. Thornhill said. “That’s something that needs to be addressed.”
The study was unique in that it used both a population cohort study and the case-crossover study. “It didn’t matter which of the two methods we used; we essentially came to the same result, which I think adds further weight to the findings,” Dr. Thornhill said.
This may be the best evidence to support the guidelines that clinicians may get. While the observational nature of this study has its limitations, conducting a randomized clinical trial to further validate the findings would be “logistically impossible,” he said, in that it would require an “absolutely enormous” cohort and coordination between medical and dental databases covering thousands of lives. An RCT would also require not using AP for some patients. “It’s not ethical to keep somebody off of antibiotic prophylaxis when there’s such a high risk of death and severe outcomes,” Dr. Thornhill said.
Ann Bolger, MD, emeritus professor of medicine at the University of California, San Francisco, and coauthor of an editorial comment on the study, said in an interview that this study is noteworthy not only for its dual methodology, but for the quality of the data that matched patients at high risk for IE with prescription and dental records. “The fact that they were able to have those details in enough granularity that they knew whether a dental procedure was likely to meet the criteria for these more invasive exposures really broke it open from my perspective,” she said.
She called the low compliance rate with AHA guidelines “one of the most sobering points of this,” and said it should put clinicians on notice that they must do more to educate and engage with high-risk patients. “The lines of communication here are somewhat fraught; it’s a little bit of a hot potato,” she said. “It’s a really great communications opportunity to get the provider’s attention back on this. You’re a cardiologist; you have to have this conversation when you see your patient with a prosthetic valve or who’s had endocarditis every time they come in. There’s a whole litany, and it takes 3 minutes, but you have to do it.”
The study received funding from Delta Dental of Michigan Research Committee and Renaissance Health Service Corp., and Dr. Thornhill received support from Delta Dental Research and Data Institute for the study. Dr. Bolger participated in the 2007 and 2021 AHA statements on AP to prevent IE.
FROM JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
What ketamine and psilocybin can and cannot do in depression
Recent studies with hallucinogens have raised hopes for an effective drug-based therapy to treat chronic depression. At the German Congress of Psychosomatic Medicine and Psychotherapy, Torsten Passie, MD, PhD, professor of psychiatry and psychotherapy at the Hannover (Germay) Medical School, gave a presentation on the current state of psilocybin and ketamine/esketamine research.
Dr. Passie, who also is head physician of the specialist unit for addiction and addiction prevention at the Diakonisches Werk in Hannover, has been investigating hallucinogenic substances and their application in psychotherapy for decades.
New therapies sought
In depression, gloom extends beyond the patient’s mood. For some time there has been little cause for joy with regard to chronic depression therapy. Established drug therapies hardly perform any better than placebo in meta-analyses, as a study recently confirmed. The pharmaceutical industry pulled out of psycho-pharmaceutical development more than 10 years ago. What’s more, the number of cases is rising, especially among young people, and there are long waiting times for psychotherapy appointments.
It is no wonder that some are welcoming new drug-based approaches with lysergic acid diethylamide (LSD)–like hallucinogens. In 2016, a study on psilocybin was published in The Lancet Psychiatry, although the study was unblinded and included only 24 patients.
Evoking emotions
A range of substances can be classed as hallucinogens, including psilocybin, mescaline, LSD, 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy), and ketamine.
Taking hallucinogens can cause a release of serotonin and dopamine, an increase in activity levels in the brain, a shift in stimulus filtering, an increase in the production of internal stimuli (inner experiences), and a change in sensory integration (for example, synesthesia).
Besides falling into a dreamlike state, patients can achieve an expansion or narrowing of consciousness if they focus on an inner experience. Internal perception increases. Perceptual routines are broken apart. Thought processes become more image-based and are more associative than normal.
Patients therefore are more capable of making new and unusual connections between different biographical or current situations. Previously unconscious ideas can become conscious. At higher doses, ego loss can occur, which can be associated with a mystical feeling of connectedness.
Hallucinogens mainly evoke and heighten emotions. Those effects may be experienced strongly as internal visions or in physical manifestations (for example, crying or laughing). In contrast, conventional antidepressants work by suppressing emotions (that is, emotional blunting).
These different mechanisms result in two contrasting management strategies. For example, SSRI antidepressants cause a patient to perceive workplace bullying as less severe and to do nothing to change the situation; the patient remains passive.
In contrast, a therapeutically guided, emotionally activating experience on hallucinogens can help the patient to try more actively to change the stressful situation.
Ketamine has a special place among hallucinogens. Unlike other hallucinogens, ketamine causes a strong clouding of consciousness, a reduction in physical sensory perception, and significant disruption in thinking and memory. It is therefore only suitable as a short-term intervention and is therapeutically impractical over the long term.
Ketamine’s effects
Ketamine, a racemic mixture of the enantiomers S-ketamine and R-ketamine, was originally used only as an analgesic and anesthetic. Owing to its rapid antidepressant effect, it has since also been used as an emergency medication for severe depression, sometimes in combination with SSRIs or serotonin noradrenaline reuptake inhibitors.
Approximately 60% of patients respond to the treatment. Whereas with conventional antidepressants, onset of action requires 10-14 days, ketamine is effective within a few hours. However, relapse always occurs, usually very quickly. After 2-3 days, the effect is usually approximately that of a placebo. An administration interval of about 2 days is optimal. However, “resistance” to the effect often develops after some time: the drug’s antidepressant effect diminishes.
Ketamine also has some unpleasant side effects, such as depersonalization, dissociation, impaired thinking, nystagmus, and psychotomimetic effects. Nausea and vomiting also occur. Interestingly, the latter does not bother the patient much, owing to the drug’s psychological effects, and it does not lead to treatment discontinuation, said Dr. Passie, who described his clinical experiences with ketamine.
Since ketamine causes a considerable clouding of consciousness, sensory disorders, and significant memory problems, it is not suitable for psychedelic-assisted psychotherapy, unlike LSD or psilocybin, he emphasized.
Ketamine 2.0?
Esketamine, the pure S-enantiomer of ketamine, has been on the market since 2019 in the form of a nasal spray (Spravato). Esketamine has been approved in combination with oral antidepressant therapy for adults with a moderate to severe episode of major depression for acute treatment of a psychiatric emergency.
A meta-analysis from 2022 concluded that the original racemic ketamine is better than the new esketamine in reducing symptoms of depression.
In his own comprehensive study, Dr. Passie concluded that the mental impairments that occur during therapy did not differ significantly between substances. The patients even felt that the side effects from esketamine therapy were much more mentally unpleasant, said Dr. Passie. He concluded that the R-enantiomer may have a kind of protective effect against some of the psychopathological effects of the S-enantiomer (esketamine).
In addition, preclinical studies have indicated that the antidepressant effects of R-enantiomer, which is not contained in esketamine, are longer lasting and stronger.
Another problem is absorption, which can be inconsistent with a nasal spray. It may differ, for example, depending on the ambient humidity or whether the patient has recently had a cold. In addition, the spray is far more expensive than the ketamine injection, said Dr. Passie. Patients must also use the nasal spray under supervision at a medical practice (as with the intravenous application) and must receive follow-up care there. It therefore offers no advantage over the ketamine injection.
According to the Institute for Quality and Efficiency in Healthcare, no additional benefit has been proven for esketamine over standard therapies for adults who have experienced a moderate to severe depressive episode when used as short-term treatment for the rapid reduction of depressive symptoms in a psychiatric emergency. The German Medical Association agreed with this evaluation in October 2021.
In the United Kingdom, the medication was never approved, owing to the fact that it was too expensive and that no studies comparing it with psychotherapy were available.
Add-on psilocybin?
What was experienced under the influence of psilocybin can also be subsequently processed and used in psychotherapy.
The acute effect of psilocybin begins after approximately 40 minutes and lasts for 4-6 hours. The antidepressant effect, if it occurs at all, is of immediate onset. Unlike ketamine/esketamine, psilocybin hardly has any physical side effects.
The neurologic mechanism of action has been investigated recently using fMRI and PET techniques. According to the investigations, the substance causes individual networks of activity in the patient’s brain to interconnect more strongly, said Dr. Passie. The thalamus, the filter station for sensory information, as well as the limbic and paralimbic structures, which generate emotions, and the cortex are all activated more strongly.
Two therapeutic settings
Psilocybin, at least in the context of studies, is used in two settings: psycholytic therapy and psychedelic therapy. Both settings originated in the 1950s and were also used with LSD as the active substance.
Psycholytic therapy with psilocybin entails multiple administrations at low doses (for example, 10-18 mg), incorporated into a longer, mostly psychodynamic therapy of around 50-100 hours (often on an inpatient basis at the beginning). It results in what is described as an extended encounter with oneself. The focus is on psychodynamic experiences, such as memories and internal conflicts. In addition, novel experiences with oneself and self-recognition are important.
Psychedelic therapy generally entails one or two sessions with a high dose (for example, 25-35 mg psilocybin). The preparation and follow-up are limited to a few sessions. These methods refer to so-called transpersonal psychology, which addresses extraordinary states of consciousness in line with religious experiences. It often leads to an intense self-confrontation as well as to new evaluations of self and world. The central element to this therapy is the experience of a mystical ego loss and the concomitant feeling of connectedness, which should help to expand one’s perspective.
Euphoria and disillusionment
The first promising studies with a few patients suffering from depression were followed by others in which the euphoria was allowed to fade away somewhat. In the first direct comparison in a methodically high-grade double-blind study, psilocybin was inferior to the SSRI antidepressant escitalopram.
“There is a great variation in response from person to person,” said Dr. Passie. “The better the study is methodically controlled, the worse the results,” he hypothesized.
“Since the method is up to 50 times more expensive in practice, compared to SSRI therapy over 6-12 weeks, the question clearly must be asked as to whether it really has any great future.”
Outlook for psilocybin
Nevertheless, Dr. Passie still sees potential in psilocybin. He considers an approach in which psilocybin therapy is more firmly incorporated into psychotherapy, with between four and 10 therapy sessions before and after administration of a lower therapeutic dose of the substance, to be more promising.
“With this kind of intensive preparation and follow-up, as well as the repeated psilocybin sessions, the patient can benefit much more than is possible with one or two high-dose sessions,” said Dr. Passie, who also is chair of the International Society for Substance-Assisted Psychotherapy. “The constant ‘in-depth work on the ego’ required for drastic therapeutic changes can be more effective and lead to permanent improvements. I have no doubt about this.”
In Dr. Passie’s opinion, the best approach would involve a dignified inpatient setting with a longer period of follow-up care and consistent posttreatment care, including group therapy. The shape of future psilocybin therapy depends on whether the rather abrupt change seen with high-dose psychedelic therapy is permanent. The answer to this question will be decisive for the method and manner of its future clinical use.
Because of the somewhat negative study results, however, the initial investors are pulling out. Dr. Passie is therefore skeptical about whether the necessary larger studies will take place and whether psilocybin will make it onto the market.
In Switzerland, which is not subject to EU restrictions, more than 30 physicians have been authorized to use psilocybin, LSD, and MDMA in psychotherapy sessions. Still, in some respects this is a special case that cannot be transferred easily to other countries, said Dr. Passie.
Possible psilocybin improvement?
Various chemical derivatives of psychoactive substances have been researched, including a psilocybin variant with the label CYB003. With CYB003, the length of the acute psychedelic experience is reduced from around 6 hours (such as with psilocybin) to 1 hour. The plasma concentration of the substance is less variable between different patients. It is assumed that its effects will also differ less from person to person.
In July, researchers began a study of the use of CYB003 in the treatment of major depression. In the randomized, double-blind, placebo-controlled study with 40 patients, multiple doses of the substance will be administered.
When asked, Dr. Passie was rather skeptical about the study. He considers the approaches with psilocybin derivatives to be the consequences of a “gold-rush atmosphere” and expects there will be no real additional benefit, especially not a reduction in the period of action.
A version of this article first appeared on Medscape.com.
Recent studies with hallucinogens have raised hopes for an effective drug-based therapy to treat chronic depression. At the German Congress of Psychosomatic Medicine and Psychotherapy, Torsten Passie, MD, PhD, professor of psychiatry and psychotherapy at the Hannover (Germay) Medical School, gave a presentation on the current state of psilocybin and ketamine/esketamine research.
Dr. Passie, who also is head physician of the specialist unit for addiction and addiction prevention at the Diakonisches Werk in Hannover, has been investigating hallucinogenic substances and their application in psychotherapy for decades.
New therapies sought
In depression, gloom extends beyond the patient’s mood. For some time there has been little cause for joy with regard to chronic depression therapy. Established drug therapies hardly perform any better than placebo in meta-analyses, as a study recently confirmed. The pharmaceutical industry pulled out of psycho-pharmaceutical development more than 10 years ago. What’s more, the number of cases is rising, especially among young people, and there are long waiting times for psychotherapy appointments.
It is no wonder that some are welcoming new drug-based approaches with lysergic acid diethylamide (LSD)–like hallucinogens. In 2016, a study on psilocybin was published in The Lancet Psychiatry, although the study was unblinded and included only 24 patients.
Evoking emotions
A range of substances can be classed as hallucinogens, including psilocybin, mescaline, LSD, 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy), and ketamine.
Taking hallucinogens can cause a release of serotonin and dopamine, an increase in activity levels in the brain, a shift in stimulus filtering, an increase in the production of internal stimuli (inner experiences), and a change in sensory integration (for example, synesthesia).
Besides falling into a dreamlike state, patients can achieve an expansion or narrowing of consciousness if they focus on an inner experience. Internal perception increases. Perceptual routines are broken apart. Thought processes become more image-based and are more associative than normal.
Patients therefore are more capable of making new and unusual connections between different biographical or current situations. Previously unconscious ideas can become conscious. At higher doses, ego loss can occur, which can be associated with a mystical feeling of connectedness.
Hallucinogens mainly evoke and heighten emotions. Those effects may be experienced strongly as internal visions or in physical manifestations (for example, crying or laughing). In contrast, conventional antidepressants work by suppressing emotions (that is, emotional blunting).
These different mechanisms result in two contrasting management strategies. For example, SSRI antidepressants cause a patient to perceive workplace bullying as less severe and to do nothing to change the situation; the patient remains passive.
In contrast, a therapeutically guided, emotionally activating experience on hallucinogens can help the patient to try more actively to change the stressful situation.
Ketamine has a special place among hallucinogens. Unlike other hallucinogens, ketamine causes a strong clouding of consciousness, a reduction in physical sensory perception, and significant disruption in thinking and memory. It is therefore only suitable as a short-term intervention and is therapeutically impractical over the long term.
Ketamine’s effects
Ketamine, a racemic mixture of the enantiomers S-ketamine and R-ketamine, was originally used only as an analgesic and anesthetic. Owing to its rapid antidepressant effect, it has since also been used as an emergency medication for severe depression, sometimes in combination with SSRIs or serotonin noradrenaline reuptake inhibitors.
Approximately 60% of patients respond to the treatment. Whereas with conventional antidepressants, onset of action requires 10-14 days, ketamine is effective within a few hours. However, relapse always occurs, usually very quickly. After 2-3 days, the effect is usually approximately that of a placebo. An administration interval of about 2 days is optimal. However, “resistance” to the effect often develops after some time: the drug’s antidepressant effect diminishes.
Ketamine also has some unpleasant side effects, such as depersonalization, dissociation, impaired thinking, nystagmus, and psychotomimetic effects. Nausea and vomiting also occur. Interestingly, the latter does not bother the patient much, owing to the drug’s psychological effects, and it does not lead to treatment discontinuation, said Dr. Passie, who described his clinical experiences with ketamine.
Since ketamine causes a considerable clouding of consciousness, sensory disorders, and significant memory problems, it is not suitable for psychedelic-assisted psychotherapy, unlike LSD or psilocybin, he emphasized.
Ketamine 2.0?
Esketamine, the pure S-enantiomer of ketamine, has been on the market since 2019 in the form of a nasal spray (Spravato). Esketamine has been approved in combination with oral antidepressant therapy for adults with a moderate to severe episode of major depression for acute treatment of a psychiatric emergency.
A meta-analysis from 2022 concluded that the original racemic ketamine is better than the new esketamine in reducing symptoms of depression.
In his own comprehensive study, Dr. Passie concluded that the mental impairments that occur during therapy did not differ significantly between substances. The patients even felt that the side effects from esketamine therapy were much more mentally unpleasant, said Dr. Passie. He concluded that the R-enantiomer may have a kind of protective effect against some of the psychopathological effects of the S-enantiomer (esketamine).
In addition, preclinical studies have indicated that the antidepressant effects of R-enantiomer, which is not contained in esketamine, are longer lasting and stronger.
Another problem is absorption, which can be inconsistent with a nasal spray. It may differ, for example, depending on the ambient humidity or whether the patient has recently had a cold. In addition, the spray is far more expensive than the ketamine injection, said Dr. Passie. Patients must also use the nasal spray under supervision at a medical practice (as with the intravenous application) and must receive follow-up care there. It therefore offers no advantage over the ketamine injection.
According to the Institute for Quality and Efficiency in Healthcare, no additional benefit has been proven for esketamine over standard therapies for adults who have experienced a moderate to severe depressive episode when used as short-term treatment for the rapid reduction of depressive symptoms in a psychiatric emergency. The German Medical Association agreed with this evaluation in October 2021.
In the United Kingdom, the medication was never approved, owing to the fact that it was too expensive and that no studies comparing it with psychotherapy were available.
Add-on psilocybin?
What was experienced under the influence of psilocybin can also be subsequently processed and used in psychotherapy.
The acute effect of psilocybin begins after approximately 40 minutes and lasts for 4-6 hours. The antidepressant effect, if it occurs at all, is of immediate onset. Unlike ketamine/esketamine, psilocybin hardly has any physical side effects.
The neurologic mechanism of action has been investigated recently using fMRI and PET techniques. According to the investigations, the substance causes individual networks of activity in the patient’s brain to interconnect more strongly, said Dr. Passie. The thalamus, the filter station for sensory information, as well as the limbic and paralimbic structures, which generate emotions, and the cortex are all activated more strongly.
Two therapeutic settings
Psilocybin, at least in the context of studies, is used in two settings: psycholytic therapy and psychedelic therapy. Both settings originated in the 1950s and were also used with LSD as the active substance.
Psycholytic therapy with psilocybin entails multiple administrations at low doses (for example, 10-18 mg), incorporated into a longer, mostly psychodynamic therapy of around 50-100 hours (often on an inpatient basis at the beginning). It results in what is described as an extended encounter with oneself. The focus is on psychodynamic experiences, such as memories and internal conflicts. In addition, novel experiences with oneself and self-recognition are important.
Psychedelic therapy generally entails one or two sessions with a high dose (for example, 25-35 mg psilocybin). The preparation and follow-up are limited to a few sessions. These methods refer to so-called transpersonal psychology, which addresses extraordinary states of consciousness in line with religious experiences. It often leads to an intense self-confrontation as well as to new evaluations of self and world. The central element to this therapy is the experience of a mystical ego loss and the concomitant feeling of connectedness, which should help to expand one’s perspective.
Euphoria and disillusionment
The first promising studies with a few patients suffering from depression were followed by others in which the euphoria was allowed to fade away somewhat. In the first direct comparison in a methodically high-grade double-blind study, psilocybin was inferior to the SSRI antidepressant escitalopram.
“There is a great variation in response from person to person,” said Dr. Passie. “The better the study is methodically controlled, the worse the results,” he hypothesized.
“Since the method is up to 50 times more expensive in practice, compared to SSRI therapy over 6-12 weeks, the question clearly must be asked as to whether it really has any great future.”
Outlook for psilocybin
Nevertheless, Dr. Passie still sees potential in psilocybin. He considers an approach in which psilocybin therapy is more firmly incorporated into psychotherapy, with between four and 10 therapy sessions before and after administration of a lower therapeutic dose of the substance, to be more promising.
“With this kind of intensive preparation and follow-up, as well as the repeated psilocybin sessions, the patient can benefit much more than is possible with one or two high-dose sessions,” said Dr. Passie, who also is chair of the International Society for Substance-Assisted Psychotherapy. “The constant ‘in-depth work on the ego’ required for drastic therapeutic changes can be more effective and lead to permanent improvements. I have no doubt about this.”
In Dr. Passie’s opinion, the best approach would involve a dignified inpatient setting with a longer period of follow-up care and consistent posttreatment care, including group therapy. The shape of future psilocybin therapy depends on whether the rather abrupt change seen with high-dose psychedelic therapy is permanent. The answer to this question will be decisive for the method and manner of its future clinical use.
Because of the somewhat negative study results, however, the initial investors are pulling out. Dr. Passie is therefore skeptical about whether the necessary larger studies will take place and whether psilocybin will make it onto the market.
In Switzerland, which is not subject to EU restrictions, more than 30 physicians have been authorized to use psilocybin, LSD, and MDMA in psychotherapy sessions. Still, in some respects this is a special case that cannot be transferred easily to other countries, said Dr. Passie.
Possible psilocybin improvement?
Various chemical derivatives of psychoactive substances have been researched, including a psilocybin variant with the label CYB003. With CYB003, the length of the acute psychedelic experience is reduced from around 6 hours (such as with psilocybin) to 1 hour. The plasma concentration of the substance is less variable between different patients. It is assumed that its effects will also differ less from person to person.
In July, researchers began a study of the use of CYB003 in the treatment of major depression. In the randomized, double-blind, placebo-controlled study with 40 patients, multiple doses of the substance will be administered.
When asked, Dr. Passie was rather skeptical about the study. He considers the approaches with psilocybin derivatives to be the consequences of a “gold-rush atmosphere” and expects there will be no real additional benefit, especially not a reduction in the period of action.
A version of this article first appeared on Medscape.com.
Recent studies with hallucinogens have raised hopes for an effective drug-based therapy to treat chronic depression. At the German Congress of Psychosomatic Medicine and Psychotherapy, Torsten Passie, MD, PhD, professor of psychiatry and psychotherapy at the Hannover (Germay) Medical School, gave a presentation on the current state of psilocybin and ketamine/esketamine research.
Dr. Passie, who also is head physician of the specialist unit for addiction and addiction prevention at the Diakonisches Werk in Hannover, has been investigating hallucinogenic substances and their application in psychotherapy for decades.
New therapies sought
In depression, gloom extends beyond the patient’s mood. For some time there has been little cause for joy with regard to chronic depression therapy. Established drug therapies hardly perform any better than placebo in meta-analyses, as a study recently confirmed. The pharmaceutical industry pulled out of psycho-pharmaceutical development more than 10 years ago. What’s more, the number of cases is rising, especially among young people, and there are long waiting times for psychotherapy appointments.
It is no wonder that some are welcoming new drug-based approaches with lysergic acid diethylamide (LSD)–like hallucinogens. In 2016, a study on psilocybin was published in The Lancet Psychiatry, although the study was unblinded and included only 24 patients.
Evoking emotions
A range of substances can be classed as hallucinogens, including psilocybin, mescaline, LSD, 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy), and ketamine.
Taking hallucinogens can cause a release of serotonin and dopamine, an increase in activity levels in the brain, a shift in stimulus filtering, an increase in the production of internal stimuli (inner experiences), and a change in sensory integration (for example, synesthesia).
Besides falling into a dreamlike state, patients can achieve an expansion or narrowing of consciousness if they focus on an inner experience. Internal perception increases. Perceptual routines are broken apart. Thought processes become more image-based and are more associative than normal.
Patients therefore are more capable of making new and unusual connections between different biographical or current situations. Previously unconscious ideas can become conscious. At higher doses, ego loss can occur, which can be associated with a mystical feeling of connectedness.
Hallucinogens mainly evoke and heighten emotions. Those effects may be experienced strongly as internal visions or in physical manifestations (for example, crying or laughing). In contrast, conventional antidepressants work by suppressing emotions (that is, emotional blunting).
These different mechanisms result in two contrasting management strategies. For example, SSRI antidepressants cause a patient to perceive workplace bullying as less severe and to do nothing to change the situation; the patient remains passive.
In contrast, a therapeutically guided, emotionally activating experience on hallucinogens can help the patient to try more actively to change the stressful situation.
Ketamine has a special place among hallucinogens. Unlike other hallucinogens, ketamine causes a strong clouding of consciousness, a reduction in physical sensory perception, and significant disruption in thinking and memory. It is therefore only suitable as a short-term intervention and is therapeutically impractical over the long term.
Ketamine’s effects
Ketamine, a racemic mixture of the enantiomers S-ketamine and R-ketamine, was originally used only as an analgesic and anesthetic. Owing to its rapid antidepressant effect, it has since also been used as an emergency medication for severe depression, sometimes in combination with SSRIs or serotonin noradrenaline reuptake inhibitors.
Approximately 60% of patients respond to the treatment. Whereas with conventional antidepressants, onset of action requires 10-14 days, ketamine is effective within a few hours. However, relapse always occurs, usually very quickly. After 2-3 days, the effect is usually approximately that of a placebo. An administration interval of about 2 days is optimal. However, “resistance” to the effect often develops after some time: the drug’s antidepressant effect diminishes.
Ketamine also has some unpleasant side effects, such as depersonalization, dissociation, impaired thinking, nystagmus, and psychotomimetic effects. Nausea and vomiting also occur. Interestingly, the latter does not bother the patient much, owing to the drug’s psychological effects, and it does not lead to treatment discontinuation, said Dr. Passie, who described his clinical experiences with ketamine.
Since ketamine causes a considerable clouding of consciousness, sensory disorders, and significant memory problems, it is not suitable for psychedelic-assisted psychotherapy, unlike LSD or psilocybin, he emphasized.
Ketamine 2.0?
Esketamine, the pure S-enantiomer of ketamine, has been on the market since 2019 in the form of a nasal spray (Spravato). Esketamine has been approved in combination with oral antidepressant therapy for adults with a moderate to severe episode of major depression for acute treatment of a psychiatric emergency.
A meta-analysis from 2022 concluded that the original racemic ketamine is better than the new esketamine in reducing symptoms of depression.
In his own comprehensive study, Dr. Passie concluded that the mental impairments that occur during therapy did not differ significantly between substances. The patients even felt that the side effects from esketamine therapy were much more mentally unpleasant, said Dr. Passie. He concluded that the R-enantiomer may have a kind of protective effect against some of the psychopathological effects of the S-enantiomer (esketamine).
In addition, preclinical studies have indicated that the antidepressant effects of R-enantiomer, which is not contained in esketamine, are longer lasting and stronger.
Another problem is absorption, which can be inconsistent with a nasal spray. It may differ, for example, depending on the ambient humidity or whether the patient has recently had a cold. In addition, the spray is far more expensive than the ketamine injection, said Dr. Passie. Patients must also use the nasal spray under supervision at a medical practice (as with the intravenous application) and must receive follow-up care there. It therefore offers no advantage over the ketamine injection.
According to the Institute for Quality and Efficiency in Healthcare, no additional benefit has been proven for esketamine over standard therapies for adults who have experienced a moderate to severe depressive episode when used as short-term treatment for the rapid reduction of depressive symptoms in a psychiatric emergency. The German Medical Association agreed with this evaluation in October 2021.
In the United Kingdom, the medication was never approved, owing to the fact that it was too expensive and that no studies comparing it with psychotherapy were available.
Add-on psilocybin?
What was experienced under the influence of psilocybin can also be subsequently processed and used in psychotherapy.
The acute effect of psilocybin begins after approximately 40 minutes and lasts for 4-6 hours. The antidepressant effect, if it occurs at all, is of immediate onset. Unlike ketamine/esketamine, psilocybin hardly has any physical side effects.
The neurologic mechanism of action has been investigated recently using fMRI and PET techniques. According to the investigations, the substance causes individual networks of activity in the patient’s brain to interconnect more strongly, said Dr. Passie. The thalamus, the filter station for sensory information, as well as the limbic and paralimbic structures, which generate emotions, and the cortex are all activated more strongly.
Two therapeutic settings
Psilocybin, at least in the context of studies, is used in two settings: psycholytic therapy and psychedelic therapy. Both settings originated in the 1950s and were also used with LSD as the active substance.
Psycholytic therapy with psilocybin entails multiple administrations at low doses (for example, 10-18 mg), incorporated into a longer, mostly psychodynamic therapy of around 50-100 hours (often on an inpatient basis at the beginning). It results in what is described as an extended encounter with oneself. The focus is on psychodynamic experiences, such as memories and internal conflicts. In addition, novel experiences with oneself and self-recognition are important.
Psychedelic therapy generally entails one or two sessions with a high dose (for example, 25-35 mg psilocybin). The preparation and follow-up are limited to a few sessions. These methods refer to so-called transpersonal psychology, which addresses extraordinary states of consciousness in line with religious experiences. It often leads to an intense self-confrontation as well as to new evaluations of self and world. The central element to this therapy is the experience of a mystical ego loss and the concomitant feeling of connectedness, which should help to expand one’s perspective.
Euphoria and disillusionment
The first promising studies with a few patients suffering from depression were followed by others in which the euphoria was allowed to fade away somewhat. In the first direct comparison in a methodically high-grade double-blind study, psilocybin was inferior to the SSRI antidepressant escitalopram.
“There is a great variation in response from person to person,” said Dr. Passie. “The better the study is methodically controlled, the worse the results,” he hypothesized.
“Since the method is up to 50 times more expensive in practice, compared to SSRI therapy over 6-12 weeks, the question clearly must be asked as to whether it really has any great future.”
Outlook for psilocybin
Nevertheless, Dr. Passie still sees potential in psilocybin. He considers an approach in which psilocybin therapy is more firmly incorporated into psychotherapy, with between four and 10 therapy sessions before and after administration of a lower therapeutic dose of the substance, to be more promising.
“With this kind of intensive preparation and follow-up, as well as the repeated psilocybin sessions, the patient can benefit much more than is possible with one or two high-dose sessions,” said Dr. Passie, who also is chair of the International Society for Substance-Assisted Psychotherapy. “The constant ‘in-depth work on the ego’ required for drastic therapeutic changes can be more effective and lead to permanent improvements. I have no doubt about this.”
In Dr. Passie’s opinion, the best approach would involve a dignified inpatient setting with a longer period of follow-up care and consistent posttreatment care, including group therapy. The shape of future psilocybin therapy depends on whether the rather abrupt change seen with high-dose psychedelic therapy is permanent. The answer to this question will be decisive for the method and manner of its future clinical use.
Because of the somewhat negative study results, however, the initial investors are pulling out. Dr. Passie is therefore skeptical about whether the necessary larger studies will take place and whether psilocybin will make it onto the market.
In Switzerland, which is not subject to EU restrictions, more than 30 physicians have been authorized to use psilocybin, LSD, and MDMA in psychotherapy sessions. Still, in some respects this is a special case that cannot be transferred easily to other countries, said Dr. Passie.
Possible psilocybin improvement?
Various chemical derivatives of psychoactive substances have been researched, including a psilocybin variant with the label CYB003. With CYB003, the length of the acute psychedelic experience is reduced from around 6 hours (such as with psilocybin) to 1 hour. The plasma concentration of the substance is less variable between different patients. It is assumed that its effects will also differ less from person to person.
In July, researchers began a study of the use of CYB003 in the treatment of major depression. In the randomized, double-blind, placebo-controlled study with 40 patients, multiple doses of the substance will be administered.
When asked, Dr. Passie was rather skeptical about the study. He considers the approaches with psilocybin derivatives to be the consequences of a “gold-rush atmosphere” and expects there will be no real additional benefit, especially not a reduction in the period of action.
A version of this article first appeared on Medscape.com.
Estrogen replacement therapy in endometrial cancer survivors
In the United States, uterine cancer is the fourth most common cancer among women, behind breast, lung/bronchus, and colorectal cancer. There are expected to be almost 66,000 new cases of uterine cancer in 2022.1 The majority of uterine cancers are endometrioid in histology and tend to be low grade, diagnosed at an early stage, and have a good prognosis. While our molecular understanding of endometrial cancers (EC) has changed significantly in recent years, low-grade endometrioid adenocarcinomas have historically been described as type 1 ECs. Type 1 ECs are typically caused by excess estrogen exposure (often unopposed or lacking progesterone protection) and are preceded by endometrial hyperplasia. Excess estrogen can come from exogenous sources (such as unopposed estrogen replacement therapy or tamoxifen, a commonly used treatment in estrogen receptor–positive breast cancer that acts as an estrogen agonist in the endometrium in postmenopausal patients) or endogenous ones (such as obesity).
Peripheral adipose tissue converts androgens into estrogens; paired with the decreased levels of sex hormone–binding globulin seen in obesity, there is more unbound or free serum estrogen (specifically estradiol) in obese women. Estrogen acts on the endometrium to cause proliferation and, if unopposed or imbalanced in relation to progesterone exposure, can ultimately lead to hyperplasia and malignancy.
If excess and unopposed estrogen exposure are major risk factors for the development of EC, is it safe to consider estrogen replacement therapy (ERT) in patients after EC treatment?
The short answer is the data are limited, but in a patient with a history of low-risk early-stage EC who undergoes appropriate counseling, it is likely safe to consider ERT.
Among EC survivors, there has been only one prospective randomized controlled trial that assessed the effect of recurrence rate and survival in women on ERT after EC treatment.2 Patients with stage I or occult stage II endometrial adenocarcinoma treated with at least a total hysterectomy and bilateral salpingo-oophorectomy were randomized to ERT versus placebo for 3 years of treatment, with therapy starting once recovered and within 20 weeks after surgery. Trial participation required an indication for ERT, such as vasomotor symptoms, vaginal atrophy, or increased risk of cardiovascular disease or osteoporosis.
The trial accrued 1,236 patients, falling short of its goal of 2,108 patients after enrollment decreased following the publication of the Women’s Health Initiative results in 2002. This publication prompted a review of the ERT study protocol that found that between decreased accrual and lower than expected recurrence rate, goal accrual would be impossible. Of those enrolled, participants were overwhelmingly white (84%-85%), 41-70 years old (80%-82%), and had stage IA or IB disease (88%). Median follow-up was almost 3 years.
Twenty-six (2.1%) patients experienced cancer recurrence, with similar rates in both groups. Three-year progression-free and overall survival were high overall among all study participants (94.8% and 96.5%). Unfortunately, because the study was closed early, definitive conclusions about the noninferiority of ERT versus placebo regarding oncologic outcomes in early-stage endometrial adenocarcinoma could not be made.
A subsequent meta-analysis looked at the effect of hormone therapy (HT) on recurrence rate in EC survivors.3 Five observational studies were included along with the previously discussed randomized controlled trial. Among 1,975 participants across six studies, there were cancer recurrences in 19 of 896 (2.1%) HT users and 64 of 1,079 (5.9%) controls. HT did not negatively affect cancer recurrence or overall survival. There was significant heterogeneity between studies as to dosing, duration, and type of HT given (some used estrogen-only replacement, others used estrogen and progesterone replacement, and some used both estrogen only and the combination of estrogen and progesterone replacement). Among the five nonrandomized studies included, a protective effect of combined HT on EC recurrence was noted. One study included patients with stage III disease, but only four patients received HT in this cohort.
Given the data we have, ERT does not appear to significantly affect oncologic outcomes in low-risk, early-stage EC survivors. We do not have data to support this same assertion in more advanced, high-risk disease. Before initiation of any ERT in an EC survivor, there should be a detailed discussion to weigh the risks and benefits of starting therapy. The goal of treatment should be to use the lowest dose of ERT possible to treat symptoms, with planned surveillance visits for symptom check-in and assessment of readiness to start tapering treatment.
Footnote: vaginal estrogen therapy
There are no randomized trials assessing the safety of vaginal estrogen preparations or their effect on oncologic outcomes in EC survivors. Observational data from the Women’s Health Initiative showed no increased risk of endometrial cancer in patients who used vaginal estrogen with an intact uterus.4 A recently published retrospective study among 244 gynecologic cancer survivors found low rates of disease recurrence and adverse outcomes among women who used vaginal estrogen for genitourinary symptoms.5 Among EC survivors, the incidence of recurrence was 2.4% for patients with stage I/II disease and 4.3% for stage III/IV disease, with a median follow-up of 80.2 months. While there appears to be some systemic absorption with vaginal estrogen use, this can be quite challenging to measure because of the current sensitivity of serum estradiol and estrone assays. Given the significantly lower serum levels with vaginal estrogen preparations compared with ERT, vaginal estrogen use appears to be safe in EC survivors.
Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Cancer Stat Facts: Uterine Cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed 12 Aug. 2022. https://seer.cancer.gov/statfacts/html/corp.html.
2. Barakat RR et al. J Clin Oncol. 2006;24(4):587-92.
3. Shim SH et al. Eur J Cancer. 2014;50(9):1628-37.
4. Crandall CJ et al. Menopause. 2018 Jan;25(1):11-20.
5. Chambers LM et al. Int J Gynecol Cancer. 2020 Apr;30(4):515-24.
In the United States, uterine cancer is the fourth most common cancer among women, behind breast, lung/bronchus, and colorectal cancer. There are expected to be almost 66,000 new cases of uterine cancer in 2022.1 The majority of uterine cancers are endometrioid in histology and tend to be low grade, diagnosed at an early stage, and have a good prognosis. While our molecular understanding of endometrial cancers (EC) has changed significantly in recent years, low-grade endometrioid adenocarcinomas have historically been described as type 1 ECs. Type 1 ECs are typically caused by excess estrogen exposure (often unopposed or lacking progesterone protection) and are preceded by endometrial hyperplasia. Excess estrogen can come from exogenous sources (such as unopposed estrogen replacement therapy or tamoxifen, a commonly used treatment in estrogen receptor–positive breast cancer that acts as an estrogen agonist in the endometrium in postmenopausal patients) or endogenous ones (such as obesity).
Peripheral adipose tissue converts androgens into estrogens; paired with the decreased levels of sex hormone–binding globulin seen in obesity, there is more unbound or free serum estrogen (specifically estradiol) in obese women. Estrogen acts on the endometrium to cause proliferation and, if unopposed or imbalanced in relation to progesterone exposure, can ultimately lead to hyperplasia and malignancy.
If excess and unopposed estrogen exposure are major risk factors for the development of EC, is it safe to consider estrogen replacement therapy (ERT) in patients after EC treatment?
The short answer is the data are limited, but in a patient with a history of low-risk early-stage EC who undergoes appropriate counseling, it is likely safe to consider ERT.
Among EC survivors, there has been only one prospective randomized controlled trial that assessed the effect of recurrence rate and survival in women on ERT after EC treatment.2 Patients with stage I or occult stage II endometrial adenocarcinoma treated with at least a total hysterectomy and bilateral salpingo-oophorectomy were randomized to ERT versus placebo for 3 years of treatment, with therapy starting once recovered and within 20 weeks after surgery. Trial participation required an indication for ERT, such as vasomotor symptoms, vaginal atrophy, or increased risk of cardiovascular disease or osteoporosis.
The trial accrued 1,236 patients, falling short of its goal of 2,108 patients after enrollment decreased following the publication of the Women’s Health Initiative results in 2002. This publication prompted a review of the ERT study protocol that found that between decreased accrual and lower than expected recurrence rate, goal accrual would be impossible. Of those enrolled, participants were overwhelmingly white (84%-85%), 41-70 years old (80%-82%), and had stage IA or IB disease (88%). Median follow-up was almost 3 years.
Twenty-six (2.1%) patients experienced cancer recurrence, with similar rates in both groups. Three-year progression-free and overall survival were high overall among all study participants (94.8% and 96.5%). Unfortunately, because the study was closed early, definitive conclusions about the noninferiority of ERT versus placebo regarding oncologic outcomes in early-stage endometrial adenocarcinoma could not be made.
A subsequent meta-analysis looked at the effect of hormone therapy (HT) on recurrence rate in EC survivors.3 Five observational studies were included along with the previously discussed randomized controlled trial. Among 1,975 participants across six studies, there were cancer recurrences in 19 of 896 (2.1%) HT users and 64 of 1,079 (5.9%) controls. HT did not negatively affect cancer recurrence or overall survival. There was significant heterogeneity between studies as to dosing, duration, and type of HT given (some used estrogen-only replacement, others used estrogen and progesterone replacement, and some used both estrogen only and the combination of estrogen and progesterone replacement). Among the five nonrandomized studies included, a protective effect of combined HT on EC recurrence was noted. One study included patients with stage III disease, but only four patients received HT in this cohort.
Given the data we have, ERT does not appear to significantly affect oncologic outcomes in low-risk, early-stage EC survivors. We do not have data to support this same assertion in more advanced, high-risk disease. Before initiation of any ERT in an EC survivor, there should be a detailed discussion to weigh the risks and benefits of starting therapy. The goal of treatment should be to use the lowest dose of ERT possible to treat symptoms, with planned surveillance visits for symptom check-in and assessment of readiness to start tapering treatment.
Footnote: vaginal estrogen therapy
There are no randomized trials assessing the safety of vaginal estrogen preparations or their effect on oncologic outcomes in EC survivors. Observational data from the Women’s Health Initiative showed no increased risk of endometrial cancer in patients who used vaginal estrogen with an intact uterus.4 A recently published retrospective study among 244 gynecologic cancer survivors found low rates of disease recurrence and adverse outcomes among women who used vaginal estrogen for genitourinary symptoms.5 Among EC survivors, the incidence of recurrence was 2.4% for patients with stage I/II disease and 4.3% for stage III/IV disease, with a median follow-up of 80.2 months. While there appears to be some systemic absorption with vaginal estrogen use, this can be quite challenging to measure because of the current sensitivity of serum estradiol and estrone assays. Given the significantly lower serum levels with vaginal estrogen preparations compared with ERT, vaginal estrogen use appears to be safe in EC survivors.
Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Cancer Stat Facts: Uterine Cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed 12 Aug. 2022. https://seer.cancer.gov/statfacts/html/corp.html.
2. Barakat RR et al. J Clin Oncol. 2006;24(4):587-92.
3. Shim SH et al. Eur J Cancer. 2014;50(9):1628-37.
4. Crandall CJ et al. Menopause. 2018 Jan;25(1):11-20.
5. Chambers LM et al. Int J Gynecol Cancer. 2020 Apr;30(4):515-24.
In the United States, uterine cancer is the fourth most common cancer among women, behind breast, lung/bronchus, and colorectal cancer. There are expected to be almost 66,000 new cases of uterine cancer in 2022.1 The majority of uterine cancers are endometrioid in histology and tend to be low grade, diagnosed at an early stage, and have a good prognosis. While our molecular understanding of endometrial cancers (EC) has changed significantly in recent years, low-grade endometrioid adenocarcinomas have historically been described as type 1 ECs. Type 1 ECs are typically caused by excess estrogen exposure (often unopposed or lacking progesterone protection) and are preceded by endometrial hyperplasia. Excess estrogen can come from exogenous sources (such as unopposed estrogen replacement therapy or tamoxifen, a commonly used treatment in estrogen receptor–positive breast cancer that acts as an estrogen agonist in the endometrium in postmenopausal patients) or endogenous ones (such as obesity).
Peripheral adipose tissue converts androgens into estrogens; paired with the decreased levels of sex hormone–binding globulin seen in obesity, there is more unbound or free serum estrogen (specifically estradiol) in obese women. Estrogen acts on the endometrium to cause proliferation and, if unopposed or imbalanced in relation to progesterone exposure, can ultimately lead to hyperplasia and malignancy.
If excess and unopposed estrogen exposure are major risk factors for the development of EC, is it safe to consider estrogen replacement therapy (ERT) in patients after EC treatment?
The short answer is the data are limited, but in a patient with a history of low-risk early-stage EC who undergoes appropriate counseling, it is likely safe to consider ERT.
Among EC survivors, there has been only one prospective randomized controlled trial that assessed the effect of recurrence rate and survival in women on ERT after EC treatment.2 Patients with stage I or occult stage II endometrial adenocarcinoma treated with at least a total hysterectomy and bilateral salpingo-oophorectomy were randomized to ERT versus placebo for 3 years of treatment, with therapy starting once recovered and within 20 weeks after surgery. Trial participation required an indication for ERT, such as vasomotor symptoms, vaginal atrophy, or increased risk of cardiovascular disease or osteoporosis.
The trial accrued 1,236 patients, falling short of its goal of 2,108 patients after enrollment decreased following the publication of the Women’s Health Initiative results in 2002. This publication prompted a review of the ERT study protocol that found that between decreased accrual and lower than expected recurrence rate, goal accrual would be impossible. Of those enrolled, participants were overwhelmingly white (84%-85%), 41-70 years old (80%-82%), and had stage IA or IB disease (88%). Median follow-up was almost 3 years.
Twenty-six (2.1%) patients experienced cancer recurrence, with similar rates in both groups. Three-year progression-free and overall survival were high overall among all study participants (94.8% and 96.5%). Unfortunately, because the study was closed early, definitive conclusions about the noninferiority of ERT versus placebo regarding oncologic outcomes in early-stage endometrial adenocarcinoma could not be made.
A subsequent meta-analysis looked at the effect of hormone therapy (HT) on recurrence rate in EC survivors.3 Five observational studies were included along with the previously discussed randomized controlled trial. Among 1,975 participants across six studies, there were cancer recurrences in 19 of 896 (2.1%) HT users and 64 of 1,079 (5.9%) controls. HT did not negatively affect cancer recurrence or overall survival. There was significant heterogeneity between studies as to dosing, duration, and type of HT given (some used estrogen-only replacement, others used estrogen and progesterone replacement, and some used both estrogen only and the combination of estrogen and progesterone replacement). Among the five nonrandomized studies included, a protective effect of combined HT on EC recurrence was noted. One study included patients with stage III disease, but only four patients received HT in this cohort.
Given the data we have, ERT does not appear to significantly affect oncologic outcomes in low-risk, early-stage EC survivors. We do not have data to support this same assertion in more advanced, high-risk disease. Before initiation of any ERT in an EC survivor, there should be a detailed discussion to weigh the risks and benefits of starting therapy. The goal of treatment should be to use the lowest dose of ERT possible to treat symptoms, with planned surveillance visits for symptom check-in and assessment of readiness to start tapering treatment.
Footnote: vaginal estrogen therapy
There are no randomized trials assessing the safety of vaginal estrogen preparations or their effect on oncologic outcomes in EC survivors. Observational data from the Women’s Health Initiative showed no increased risk of endometrial cancer in patients who used vaginal estrogen with an intact uterus.4 A recently published retrospective study among 244 gynecologic cancer survivors found low rates of disease recurrence and adverse outcomes among women who used vaginal estrogen for genitourinary symptoms.5 Among EC survivors, the incidence of recurrence was 2.4% for patients with stage I/II disease and 4.3% for stage III/IV disease, with a median follow-up of 80.2 months. While there appears to be some systemic absorption with vaginal estrogen use, this can be quite challenging to measure because of the current sensitivity of serum estradiol and estrone assays. Given the significantly lower serum levels with vaginal estrogen preparations compared with ERT, vaginal estrogen use appears to be safe in EC survivors.
Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Cancer Stat Facts: Uterine Cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Accessed 12 Aug. 2022. https://seer.cancer.gov/statfacts/html/corp.html.
2. Barakat RR et al. J Clin Oncol. 2006;24(4):587-92.
3. Shim SH et al. Eur J Cancer. 2014;50(9):1628-37.
4. Crandall CJ et al. Menopause. 2018 Jan;25(1):11-20.
5. Chambers LM et al. Int J Gynecol Cancer. 2020 Apr;30(4):515-24.
Obesity drug shortage triggers frustrations, workarounds
The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.
But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
‘Unprecedented demand’ for Wegovy derailed when plant went offline
The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”
A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.
“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.
“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.
“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The liraglutide/Saxenda workaround
The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A ‘reasonable’ evidence base, but more work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.
Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.
Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.
“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”
The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
The tirzepatide coupon program works ‘off label’ for obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.
Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.
“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.
But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.
“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.
Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even more workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.
“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.
Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.
A version of this article first appeared on Medscape.com.
The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.
But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
‘Unprecedented demand’ for Wegovy derailed when plant went offline
The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”
A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.
“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.
“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.
“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The liraglutide/Saxenda workaround
The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A ‘reasonable’ evidence base, but more work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.
Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.
Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.
“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”
The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
The tirzepatide coupon program works ‘off label’ for obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.
Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.
“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.
But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.
“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.
Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even more workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.
“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.
Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.
A version of this article first appeared on Medscape.com.
The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.
But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
‘Unprecedented demand’ for Wegovy derailed when plant went offline
The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”
A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.
“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.
“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.
“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The liraglutide/Saxenda workaround
The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A ‘reasonable’ evidence base, but more work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.
Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.
Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.
“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”
The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
The tirzepatide coupon program works ‘off label’ for obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.
Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.
“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.
But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.
“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.
Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even more workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.
“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.
Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.
A version of this article first appeared on Medscape.com.
FDA approves Enhertu (trastuzumab deruxtecan) for HER2 lung cancer
Patients with lung cancer now have another treatment option: If their tumors are found to carry HER2 mutations, they can now be treated with trastuzumab deruxtecan (Enhertu), a drug that specifically targets that defect.
This product is already approved for used in HER2-positive breast cancer and gastric cancer. 
The FDA also approved companion diagnostic tests to detect HER2 mutations: Life Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that if no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Specifically, the new indication is used in patients with unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have already received a prior systemic therapy.
About 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis.
“HER2 mutant non–small cell lung cancer is an aggressive form of disease, which commonly affects young patients who have faced limited treatment options and a poor prognosis to date,” said Dave Fredrickson, executive vice-president of the oncology business unit at AstraZeneca.
The new approval “provides these patients with the opportunity to benefit from a targeted therapy and highlights the importance of testing for predictive markers, including HER2 in lung cancer, at the time of diagnosis to ensure patients receive the most appropriate treatment for their specific disease,” he commented in a company press release.
This is an accelerated approval, based on overall response rate data from the DESTINY-Lung02 phase 2 trial, the company noted. An interim efficacy analysis in a prespecified patient cohort showed that trastuzumab deruxtecan (at 5.4 mg/kg) demonstrated a confirmed overall response rate of 57.7% (n = 52; 95% confidence interval, 43.2%-71.3%) in patients with HER2-mutant unresectable or metastatic nonsquamous NSCLC who had received one prior systemic therapy as assessed by blinded independent central review. Complete responses were seen in 1.9% of patients (n = 1) and partial responses in 55.8% of patients (n = 29), with a median duration of response of 8.7 months (95% CI, 7.1-NE).
The FDA noted that for the 52 patients in the primary efficacy population of the DESTINY-Lung02 trial, the median age was 58 years (range, 30-78 years); 69% were female; and 79% were Asian, 12% were White, and 10% were of other races.
Clinical data welcomed by experts
Clinical data are already available from the DESTINY-Lung 01 trial, and the results were welcomed enthusiastically by experts when they were published in the New England Journal of Medicine earlier this year.
“These results establish the new standard of care for patients with NSCLC harboring HER2 mutations,” Antonio Passaro, MD, PhD, from the European Institute of Oncology IRCCS, Milan, and Solange Peters, MD, PhD, from Lausanne (Switzerland) University Hospital, wrote in an accompanying editorial.
This trial involved 91 patients, all treated with trastuzumab deruxtecan (at 6.4 mg/kg of body weight every 3 weeks). The median duration of treatment was 6.9 months, and the median follow-up was 13.1 months.
The results showed a 55% centrally confirmed objective response, and median duration of response was 9.3 months.
In addition, the investigators reported a median progression-free survival of 8.2 months and a median overall survival of almost 18 months, both of which they described as “encouraging” in this patient population.
However, the results also highlighted a problem with the drug in this patient population. Notably, 26% of patients experienced interstitial lung disease, which resulted in death in two patients. The drug was also withdrawn in 16 patients and interrupted in 8 patients because of this adverse event.
Editorialists Dr. Passaro and Dr. Peters described this finding as “a concern” and note that “the incidence of interstitial lung disease is significantly higher among patients with lung cancer than among those with breast or gastric cancers, which may indicate a role of smoking-related damage.”
They also highlighted the need for an “investigation of the clinical efficacy of a reduced dose of trastuzumab deruxtecan,” and so the dose was reduced for the DESTINY-Lung02 trial.
A version of this article first appeared on Medscape.com.
Patients with lung cancer now have another treatment option: If their tumors are found to carry HER2 mutations, they can now be treated with trastuzumab deruxtecan (Enhertu), a drug that specifically targets that defect.
This product is already approved for used in HER2-positive breast cancer and gastric cancer.
The FDA also approved companion diagnostic tests to detect HER2 mutations: Life Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that if no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Specifically, the new indication is used in patients with unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have already received a prior systemic therapy.
About 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis.
“HER2 mutant non–small cell lung cancer is an aggressive form of disease, which commonly affects young patients who have faced limited treatment options and a poor prognosis to date,” said Dave Fredrickson, executive vice-president of the oncology business unit at AstraZeneca.
The new approval “provides these patients with the opportunity to benefit from a targeted therapy and highlights the importance of testing for predictive markers, including HER2 in lung cancer, at the time of diagnosis to ensure patients receive the most appropriate treatment for their specific disease,” he commented in a company press release.
This is an accelerated approval, based on overall response rate data from the DESTINY-Lung02 phase 2 trial, the company noted. An interim efficacy analysis in a prespecified patient cohort showed that trastuzumab deruxtecan (at 5.4 mg/kg) demonstrated a confirmed overall response rate of 57.7% (n = 52; 95% confidence interval, 43.2%-71.3%) in patients with HER2-mutant unresectable or metastatic nonsquamous NSCLC who had received one prior systemic therapy as assessed by blinded independent central review. Complete responses were seen in 1.9% of patients (n = 1) and partial responses in 55.8% of patients (n = 29), with a median duration of response of 8.7 months (95% CI, 7.1-NE).
The FDA noted that for the 52 patients in the primary efficacy population of the DESTINY-Lung02 trial, the median age was 58 years (range, 30-78 years); 69% were female; and 79% were Asian, 12% were White, and 10% were of other races.
Clinical data welcomed by experts
Clinical data are already available from the DESTINY-Lung 01 trial, and the results were welcomed enthusiastically by experts when they were published in the New England Journal of Medicine earlier this year.
“These results establish the new standard of care for patients with NSCLC harboring HER2 mutations,” Antonio Passaro, MD, PhD, from the European Institute of Oncology IRCCS, Milan, and Solange Peters, MD, PhD, from Lausanne (Switzerland) University Hospital, wrote in an accompanying editorial.
This trial involved 91 patients, all treated with trastuzumab deruxtecan (at 6.4 mg/kg of body weight every 3 weeks). The median duration of treatment was 6.9 months, and the median follow-up was 13.1 months.
The results showed a 55% centrally confirmed objective response, and median duration of response was 9.3 months.
In addition, the investigators reported a median progression-free survival of 8.2 months and a median overall survival of almost 18 months, both of which they described as “encouraging” in this patient population.
However, the results also highlighted a problem with the drug in this patient population. Notably, 26% of patients experienced interstitial lung disease, which resulted in death in two patients. The drug was also withdrawn in 16 patients and interrupted in 8 patients because of this adverse event.
Editorialists Dr. Passaro and Dr. Peters described this finding as “a concern” and note that “the incidence of interstitial lung disease is significantly higher among patients with lung cancer than among those with breast or gastric cancers, which may indicate a role of smoking-related damage.”
They also highlighted the need for an “investigation of the clinical efficacy of a reduced dose of trastuzumab deruxtecan,” and so the dose was reduced for the DESTINY-Lung02 trial.
A version of this article first appeared on Medscape.com.
Patients with lung cancer now have another treatment option: If their tumors are found to carry HER2 mutations, they can now be treated with trastuzumab deruxtecan (Enhertu), a drug that specifically targets that defect.
This product is already approved for used in HER2-positive breast cancer and gastric cancer.
The FDA also approved companion diagnostic tests to detect HER2 mutations: Life Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that if no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Specifically, the new indication is used in patients with unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have already received a prior systemic therapy.
About 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis.
“HER2 mutant non–small cell lung cancer is an aggressive form of disease, which commonly affects young patients who have faced limited treatment options and a poor prognosis to date,” said Dave Fredrickson, executive vice-president of the oncology business unit at AstraZeneca.
The new approval “provides these patients with the opportunity to benefit from a targeted therapy and highlights the importance of testing for predictive markers, including HER2 in lung cancer, at the time of diagnosis to ensure patients receive the most appropriate treatment for their specific disease,” he commented in a company press release.
This is an accelerated approval, based on overall response rate data from the DESTINY-Lung02 phase 2 trial, the company noted. An interim efficacy analysis in a prespecified patient cohort showed that trastuzumab deruxtecan (at 5.4 mg/kg) demonstrated a confirmed overall response rate of 57.7% (n = 52; 95% confidence interval, 43.2%-71.3%) in patients with HER2-mutant unresectable or metastatic nonsquamous NSCLC who had received one prior systemic therapy as assessed by blinded independent central review. Complete responses were seen in 1.9% of patients (n = 1) and partial responses in 55.8% of patients (n = 29), with a median duration of response of 8.7 months (95% CI, 7.1-NE).
The FDA noted that for the 52 patients in the primary efficacy population of the DESTINY-Lung02 trial, the median age was 58 years (range, 30-78 years); 69% were female; and 79% were Asian, 12% were White, and 10% were of other races.
Clinical data welcomed by experts
Clinical data are already available from the DESTINY-Lung 01 trial, and the results were welcomed enthusiastically by experts when they were published in the New England Journal of Medicine earlier this year.
“These results establish the new standard of care for patients with NSCLC harboring HER2 mutations,” Antonio Passaro, MD, PhD, from the European Institute of Oncology IRCCS, Milan, and Solange Peters, MD, PhD, from Lausanne (Switzerland) University Hospital, wrote in an accompanying editorial.
This trial involved 91 patients, all treated with trastuzumab deruxtecan (at 6.4 mg/kg of body weight every 3 weeks). The median duration of treatment was 6.9 months, and the median follow-up was 13.1 months.
The results showed a 55% centrally confirmed objective response, and median duration of response was 9.3 months.
In addition, the investigators reported a median progression-free survival of 8.2 months and a median overall survival of almost 18 months, both of which they described as “encouraging” in this patient population.
However, the results also highlighted a problem with the drug in this patient population. Notably, 26% of patients experienced interstitial lung disease, which resulted in death in two patients. The drug was also withdrawn in 16 patients and interrupted in 8 patients because of this adverse event.
Editorialists Dr. Passaro and Dr. Peters described this finding as “a concern” and note that “the incidence of interstitial lung disease is significantly higher among patients with lung cancer than among those with breast or gastric cancers, which may indicate a role of smoking-related damage.”
They also highlighted the need for an “investigation of the clinical efficacy of a reduced dose of trastuzumab deruxtecan,” and so the dose was reduced for the DESTINY-Lung02 trial.
A version of this article first appeared on Medscape.com.