Approximately 68 million cases of sexually transmitted infections are reported in the United States each year, yet antiquated approaches to STI prevention, in addition to health care inequities and lack of funding, have substantially prevented providers and officials from curbing the spread. In response to rising case numbers, the National Academies of Sciences, Engineering, and Medicine released a report this week with recommendations to modernize the nation’s STI surveillance and monitoring systems, increase the capabilities of the STI workforce, and address structural barriers to STI prevention and access to care.

Given the rising rates of STIs and the urgent, unmet need for prevention and treatment, the Centers for Disease Control and Prevention’s National Association of County and City Health Officials commissioned the National Academies to develop actionable recommendations to control STIs. The new report marks a long road toward the public’s willingness to discuss STDs, or what a 1997 Institute of Medicine report described as a “hidden epidemic” that had been largely neglected in public discourse.

Jeffrey Crowley, MPH, committee member and an author of the new National Academies report, said in an interview that, despite the increased openness to discuss STIs in today’s society, STD rates since the late 1990s have gotten much worse. Lack of appropriate governmental funding for research and drug development, structural inequities, and persisting stigmatization are key drivers for rising rates, explained Mr. Crowley.
 

Addressing structural barriers to STI prevention

Playing a prominent role in the National Academies report are issues of structural and institutional barriers to STI prevention and care. In the report, the authors argued that a policy-based approach should seek to promote sexual health and eliminate structural racism and inequities to drive improvements in STI management.

“We think it’s these structural factors that are central to all the inequities that play out,” said Mr. Crowley, “and they either don’t get any attention or, if they do get attention, people don’t really speak concretely enough about how we address them.”

The concrete steps, as outlined in the report, begin with addressing factors that involve the health care industry at large. Automatic STI screening as part of routine visits, alerts in electronic health records that remind clinicians to screen patients, and reminders to test patients can be initial low-cost actions health care systems can take to improve STI testing, particularly in marginalized communities. Mr. Crowley noted that greater evidence is needed to support further steps to address structural factors that contribute to barriers in STI screening and treatment access.

Given the complexities inherent in structural barriers to STI care, the report calls on a whole-government response, in partnership with affected communities, to normalize discussions involving sexual well-being. “We have to ask ourselves how we can build healthier communities and how can we integrate sexual health into that dialogue in a way that improves our response to STI prevention and control,” Mr. Crowley explained.
 

Harnessing AI and dating apps

The report also addresses the power of artificial intelligence to predict STI rates and to discover trends in risk factors, both of which may improve STI surveillance and assist in the development of tailored interventions. The report calls for policy that will enable companies and the government to capitalize on AI to evaluate large collections of data in EHRs, insurance claims databases, social media, search engines, and even dating apps.

In particular, dating apps could be an avenue through which the public and private sectors could improve STI prevention, diagnosis, and treatment. “People want to focus on this idea of whether these apps increase transmission risk,” said Mr. Crowley. “But we would say that this is asking the wrong question, because these technologies are not going away.” He noted that private and public enterprises could work together to leverage these technologies to increase awareness of prevention and testing.
 

Unifying the STI/HIV and COVID-19 workforce

The report also recommends that the nation unify the STI/HIV workforce with the COVID-19 workforce. Given the high levels of expertise in these professional working groups, the report suggests unification could potentially address both the current crisis and possible future disease outbreaks. Combining COVID-19 response teams with underresourced STI/HIV programs may also improve the delivery of STI testing, considering that STI testing programs have had to compete for resources during the pandemic.

Addressing stigma

The National Academies report also addresses the ongoing issue of stigma, which results from “blaming” individuals and the choices they make so as to create shame, embarrassment, and discrimination. Because of stigma, sexually active people may be unwilling to seek recommended screening, which can lead to delays in diagnosis and treatment and can increase the risk for negative health outcomes.

“As a nation, we’ve almost focused too intently on individual-level factors in a way that’s driven stigma and really hasn’t been helpful for combating the problem,” said Mr. Crowley. He added that, instead of focusing solely on individual-level choices, the nation should instead work to reframe sexual health as a key aspect of overall physical, mental, and emotional well-being. Doing so could create more opportunities to address structural barriers to STI prevention and ensure that more prevention and screening services are available in stigma-free environments.

“I know what we’re recommending is ambitious, but it’s not too big to be achieved, and we’re not saying tomorrow we’re going to transform the world,” Mr. Crowley concluded. “It’s a puzzle with many pieces, but the long-term impact is really all of these pieces fitting together so that, over time, we can reduce the burden STIs have on the population.”
 

Implications for real-world change

H. Hunter Handsfield, MD, professor emeritus of medicine for the Center for AIDS and STD at the University of Washington, Seattle, said in an interview that this report essentially is a response to evolving societal changes, new and emerging means of social engagement, and increased focus on racial/ethnic disparities. “These features have all come to the forefront of health care and general policy discussions in recent years,” said Dr. Handsfield, who was not part of the committee that developed the NAS report.

Greater scrutiny on public health infrastructure and its relationship with health disparities in the United States makes the publication of these new recommendations especially appropriate during this era of enhanced focus on social justice. Although the report features the tone and quality needed to bolster bipartisan support, said Dr. Handsfield, it’s hard to predict whether such support will come to fruition in today’s political environment.

In terms of the effects the recommendations may have on STI rates, Dr. Handsfield noted that cherry-picking elements from the report to direct policy may result in its having only a trivial impact. “The report is really an appropriate and necessary response, and almost all the recommendations made can be helpful,” he said, “but for true effectiveness, all the elements need to be implemented to drive policy and funding.”

A version of this article first appeared on Medscape.com.

Approximately 68 million cases of sexually transmitted infections are reported in the United States each year, yet antiquated approaches to STI prevention, in addition to health care inequities and lack of funding, have substantially prevented providers and officials from curbing the spread. In response to rising case numbers, the National Academies of Sciences, Engineering, and Medicine released a report this week with recommendations to modernize the nation’s STI surveillance and monitoring systems, increase the capabilities of the STI workforce, and address structural barriers to STI prevention and access to care.

Given the rising rates of STIs and the urgent, unmet need for prevention and treatment, the Centers for Disease Control and Prevention’s National Association of County and City Health Officials commissioned the National Academies to develop actionable recommendations to control STIs. The new report marks a long road toward the public’s willingness to discuss STDs, or what a 1997 Institute of Medicine report described as a “hidden epidemic” that had been largely neglected in public discourse.

Jeffrey Crowley, MPH, committee member and an author of the new National Academies report, said in an interview that, despite the increased openness to discuss STIs in today’s society, STD rates since the late 1990s have gotten much worse. Lack of appropriate governmental funding for research and drug development, structural inequities, and persisting stigmatization are key drivers for rising rates, explained Mr. Crowley.
 

Addressing structural barriers to STI prevention

Playing a prominent role in the National Academies report are issues of structural and institutional barriers to STI prevention and care. In the report, the authors argued that a policy-based approach should seek to promote sexual health and eliminate structural racism and inequities to drive improvements in STI management.

“We think it’s these structural factors that are central to all the inequities that play out,” said Mr. Crowley, “and they either don’t get any attention or, if they do get attention, people don’t really speak concretely enough about how we address them.”

The concrete steps, as outlined in the report, begin with addressing factors that involve the health care industry at large. Automatic STI screening as part of routine visits, alerts in electronic health records that remind clinicians to screen patients, and reminders to test patients can be initial low-cost actions health care systems can take to improve STI testing, particularly in marginalized communities. Mr. Crowley noted that greater evidence is needed to support further steps to address structural factors that contribute to barriers in STI screening and treatment access.

Given the complexities inherent in structural barriers to STI care, the report calls on a whole-government response, in partnership with affected communities, to normalize discussions involving sexual well-being. “We have to ask ourselves how we can build healthier communities and how can we integrate sexual health into that dialogue in a way that improves our response to STI prevention and control,” Mr. Crowley explained.
 

Harnessing AI and dating apps

The report also addresses the power of artificial intelligence to predict STI rates and to discover trends in risk factors, both of which may improve STI surveillance and assist in the development of tailored interventions. The report calls for policy that will enable companies and the government to capitalize on AI to evaluate large collections of data in EHRs, insurance claims databases, social media, search engines, and even dating apps.

In particular, dating apps could be an avenue through which the public and private sectors could improve STI prevention, diagnosis, and treatment. “People want to focus on this idea of whether these apps increase transmission risk,” said Mr. Crowley. “But we would say that this is asking the wrong question, because these technologies are not going away.” He noted that private and public enterprises could work together to leverage these technologies to increase awareness of prevention and testing.
 

Unifying the STI/HIV and COVID-19 workforce

The report also recommends that the nation unify the STI/HIV workforce with the COVID-19 workforce. Given the high levels of expertise in these professional working groups, the report suggests unification could potentially address both the current crisis and possible future disease outbreaks. Combining COVID-19 response teams with underresourced STI/HIV programs may also improve the delivery of STI testing, considering that STI testing programs have had to compete for resources during the pandemic.

Addressing stigma

The National Academies report also addresses the ongoing issue of stigma, which results from “blaming” individuals and the choices they make so as to create shame, embarrassment, and discrimination. Because of stigma, sexually active people may be unwilling to seek recommended screening, which can lead to delays in diagnosis and treatment and can increase the risk for negative health outcomes.

“As a nation, we’ve almost focused too intently on individual-level factors in a way that’s driven stigma and really hasn’t been helpful for combating the problem,” said Mr. Crowley. He added that, instead of focusing solely on individual-level choices, the nation should instead work to reframe sexual health as a key aspect of overall physical, mental, and emotional well-being. Doing so could create more opportunities to address structural barriers to STI prevention and ensure that more prevention and screening services are available in stigma-free environments.

“I know what we’re recommending is ambitious, but it’s not too big to be achieved, and we’re not saying tomorrow we’re going to transform the world,” Mr. Crowley concluded. “It’s a puzzle with many pieces, but the long-term impact is really all of these pieces fitting together so that, over time, we can reduce the burden STIs have on the population.”
 

Implications for real-world change

H. Hunter Handsfield, MD, professor emeritus of medicine for the Center for AIDS and STD at the University of Washington, Seattle, said in an interview that this report essentially is a response to evolving societal changes, new and emerging means of social engagement, and increased focus on racial/ethnic disparities. “These features have all come to the forefront of health care and general policy discussions in recent years,” said Dr. Handsfield, who was not part of the committee that developed the NAS report.

Greater scrutiny on public health infrastructure and its relationship with health disparities in the United States makes the publication of these new recommendations especially appropriate during this era of enhanced focus on social justice. Although the report features the tone and quality needed to bolster bipartisan support, said Dr. Handsfield, it’s hard to predict whether such support will come to fruition in today’s political environment.

In terms of the effects the recommendations may have on STI rates, Dr. Handsfield noted that cherry-picking elements from the report to direct policy may result in its having only a trivial impact. “The report is really an appropriate and necessary response, and almost all the recommendations made can be helpful,” he said, “but for true effectiveness, all the elements need to be implemented to drive policy and funding.”

A version of this article first appeared on Medscape.com.

Approximately 68 million cases of sexually transmitted infections are reported in the United States each year, yet antiquated approaches to STI prevention, in addition to health care inequities and lack of funding, have substantially prevented providers and officials from curbing the spread. In response to rising case numbers, the National Academies of Sciences, Engineering, and Medicine released a report this week with recommendations to modernize the nation’s STI surveillance and monitoring systems, increase the capabilities of the STI workforce, and address structural barriers to STI prevention and access to care.

Given the rising rates of STIs and the urgent, unmet need for prevention and treatment, the Centers for Disease Control and Prevention’s National Association of County and City Health Officials commissioned the National Academies to develop actionable recommendations to control STIs. The new report marks a long road toward the public’s willingness to discuss STDs, or what a 1997 Institute of Medicine report described as a “hidden epidemic” that had been largely neglected in public discourse.

Jeffrey Crowley, MPH, committee member and an author of the new National Academies report, said in an interview that, despite the increased openness to discuss STIs in today’s society, STD rates since the late 1990s have gotten much worse. Lack of appropriate governmental funding for research and drug development, structural inequities, and persisting stigmatization are key drivers for rising rates, explained Mr. Crowley.
 

Addressing structural barriers to STI prevention

Playing a prominent role in the National Academies report are issues of structural and institutional barriers to STI prevention and care. In the report, the authors argued that a policy-based approach should seek to promote sexual health and eliminate structural racism and inequities to drive improvements in STI management.

“We think it’s these structural factors that are central to all the inequities that play out,” said Mr. Crowley, “and they either don’t get any attention or, if they do get attention, people don’t really speak concretely enough about how we address them.”

The concrete steps, as outlined in the report, begin with addressing factors that involve the health care industry at large. Automatic STI screening as part of routine visits, alerts in electronic health records that remind clinicians to screen patients, and reminders to test patients can be initial low-cost actions health care systems can take to improve STI testing, particularly in marginalized communities. Mr. Crowley noted that greater evidence is needed to support further steps to address structural factors that contribute to barriers in STI screening and treatment access.

Given the complexities inherent in structural barriers to STI care, the report calls on a whole-government response, in partnership with affected communities, to normalize discussions involving sexual well-being. “We have to ask ourselves how we can build healthier communities and how can we integrate sexual health into that dialogue in a way that improves our response to STI prevention and control,” Mr. Crowley explained.
 

Harnessing AI and dating apps

The report also addresses the power of artificial intelligence to predict STI rates and to discover trends in risk factors, both of which may improve STI surveillance and assist in the development of tailored interventions. The report calls for policy that will enable companies and the government to capitalize on AI to evaluate large collections of data in EHRs, insurance claims databases, social media, search engines, and even dating apps.

In particular, dating apps could be an avenue through which the public and private sectors could improve STI prevention, diagnosis, and treatment. “People want to focus on this idea of whether these apps increase transmission risk,” said Mr. Crowley. “But we would say that this is asking the wrong question, because these technologies are not going away.” He noted that private and public enterprises could work together to leverage these technologies to increase awareness of prevention and testing.
 

Unifying the STI/HIV and COVID-19 workforce

The report also recommends that the nation unify the STI/HIV workforce with the COVID-19 workforce. Given the high levels of expertise in these professional working groups, the report suggests unification could potentially address both the current crisis and possible future disease outbreaks. Combining COVID-19 response teams with underresourced STI/HIV programs may also improve the delivery of STI testing, considering that STI testing programs have had to compete for resources during the pandemic.

Addressing stigma

The National Academies report also addresses the ongoing issue of stigma, which results from “blaming” individuals and the choices they make so as to create shame, embarrassment, and discrimination. Because of stigma, sexually active people may be unwilling to seek recommended screening, which can lead to delays in diagnosis and treatment and can increase the risk for negative health outcomes.

“As a nation, we’ve almost focused too intently on individual-level factors in a way that’s driven stigma and really hasn’t been helpful for combating the problem,” said Mr. Crowley. He added that, instead of focusing solely on individual-level choices, the nation should instead work to reframe sexual health as a key aspect of overall physical, mental, and emotional well-being. Doing so could create more opportunities to address structural barriers to STI prevention and ensure that more prevention and screening services are available in stigma-free environments.

“I know what we’re recommending is ambitious, but it’s not too big to be achieved, and we’re not saying tomorrow we’re going to transform the world,” Mr. Crowley concluded. “It’s a puzzle with many pieces, but the long-term impact is really all of these pieces fitting together so that, over time, we can reduce the burden STIs have on the population.”
 

Implications for real-world change

H. Hunter Handsfield, MD, professor emeritus of medicine for the Center for AIDS and STD at the University of Washington, Seattle, said in an interview that this report essentially is a response to evolving societal changes, new and emerging means of social engagement, and increased focus on racial/ethnic disparities. “These features have all come to the forefront of health care and general policy discussions in recent years,” said Dr. Handsfield, who was not part of the committee that developed the NAS report.

Greater scrutiny on public health infrastructure and its relationship with health disparities in the United States makes the publication of these new recommendations especially appropriate during this era of enhanced focus on social justice. Although the report features the tone and quality needed to bolster bipartisan support, said Dr. Handsfield, it’s hard to predict whether such support will come to fruition in today’s political environment.

In terms of the effects the recommendations may have on STI rates, Dr. Handsfield noted that cherry-picking elements from the report to direct policy may result in its having only a trivial impact. “The report is really an appropriate and necessary response, and almost all the recommendations made can be helpful,” he said, “but for true effectiveness, all the elements need to be implemented to drive policy and funding.”

A version of this article first appeared on Medscape.com.

The KRAS inhibitor adagrasib produced a high disease control rate in patients with advanced or metastatic non–small cell lung cancer (NSCLC), according to data from the KRYSTAL-1 study.

An objective response rate was seen in 45% of patients, with a further 51% achieving stable disease, for a disease control rate of 96%.

“The vast majority of patients had significant tumor shrinkage,” said study investigator Gregory J. Riely, MD, PhD, when presenting the results at the European Lung Cancer Virtual Congress 2021 (Abstract 990_PR).

Dr. Riely, vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center in New York, noted that just 6 of the 70 patients in this phase 1/2 trial showed evidence of measurable tumor growth.

“This new way of targeting an oncogene may very well represent an evolutionary step forward in the management of lung cancer patients, akin to when we first had EGFR inhibitors,” Alastair Greystoke, MBChB, PhD, said in his discussion of the trial.

Dr. Greystoke, a clinical senior lecturer and honorary consultant in medical oncology at Newcastle (England) University, observed that the availability of KRAS-targeting agents could have a large potential impact on clinical practice. They could add another 14% of patients with NSCLC to the list of those who are eligible for molecularly-targeted therapy.

“It may be that soon, almost half our patients with lung adenocarcinoma will have a potential targetable abnormality,” Dr. Greystoke said.
 

Data confirm KRAS as a therapeutic target

Adagrasib is now the second drug to show promise as an inhibitor of KRAS G12C. In a phase 2 trial, the KRAS inhibitor sotorasib produced a response rate of 37%, a median response duration of 10 months, and a median progression-free survival of 6.8 months in patients with NSCLC.

Data on response duration and progression-free survival are not yet available for adagrasib. However, the duration of response extended past 11 months in four of the six patients who achieved a partial response to adagrasib in the phase 1/1b portion of the KRYSTAL-1 trial.

“What we’ve seen from this data, and data with other agents, is that responses are very heterogeneous,” Dr. Greystoke observed. “A small number of patients do not respond at all. In some patients, responses are short-lived, whilst in other patients, responses are long and still ongoing.”
 

KRYSTAL-1 study design and safety

KRYSTAL-1 is an ongoing phase 1/2 study designed to assess the safety and clinical activity of adagrasib in patients with advanced solid tumors that have a KRAS G12C mutation, including NSCLC.

Dr. Riely reported data on 79 patients with advanced or metastatic NSCLC who had progressed despite being treated with chemotherapy and immunotherapy. Of these, 18 patients had participated in the phase 1/1b dose-escalation and dose-expansion phase of the study, and 61 had participated in the phase 2 portion. Adagrasib was given at a twice-daily dose of 600 mg.

The patients’ median age was 65 years, 85% were White, and 57% were women. Almost all (95%) were current or former smokers, which is unsurprising since the KRAS G12C mutation is rarely seen in never-smokers. Almost all patients had nonsquamous histology (96%) and had received PD-1 or PD-L1 inhibitors (92%).

Treatment-related adverse events of any grade occurred in 85% of patients, and 30% of patients had grade 3-4 events. The most frequent treatment-related grade 3-4 adverse events were fatigue (6%), increased ALT or AST (each 5%), QT prolongation (3%), anemia (2%), nausea (2%), and vomiting (2%).

Two grade 5 adverse events were recorded – a case of pneumonitis in a patient with recurrent pneumonitis and one case of cardiac failure. Adverse events led to discontinuation in 4.5% of patients.
 

Greater effect seen with co-mutation

KRAS is commonly co-mutated, so the investigators performed an exploratory analysis to see if the presence of other mutations – STK11, KEAP1, and TP53 – might affect the results of adagrasib.

A greater objective response rate was seen in patients with the STK11 mutation than in those without it (64% and 33%, respectively). STK11 is associated with poorer responses to immune checkpoint inhibitors.

“We hypothesized that adagrasib treatment recruits T cells into the tumor and that T-cell infiltration may reverse STK11-mediated immune suppression,” Dr. Riely said. This theory seemed to be borne out with further analyses, though Dr. Greystoke raised doubts. There was no sign of STK11 mutations having any effect on response rates with adagrasib in preclinical studies.

Patients with KEAP1 as a co-mutation had a lower response rate than that of those without it (36% and 48%, respectively), which is in keeping with what might be expected. KEAP1 is known to be associated to a poor response to chemotherapy and immunotherapy.

“I think this data is very provocative but needs to be confirmed in larger cohorts,” Dr. Greystoke said. It could mean that adagrasib has the potential to turn a “cold tumor, hot,” enabling the use of immunotherapies.

A new cohort has been included in the KRYSTAL-1 study to further evaluate how having both the KRAS G12C and STK11 mutations may affect treatment with adagrasib.

Data could support drug combination

The adagrasib data lend support to the combination of KRAS G12C inhibitors with other molecularly-targeted treatments for NSCLC, Dr. Greystoke said, such as with tyrosine kinase inhibitors or immunotherapies. He noted that high steady-state levels of adagrasib were detected in the blood, and these levels were well above those needed for potential efficacy.

“This gives us confidence that if we do need to drop the dose below the recommended phase 2 dose to allow potential combinations with a small-molecule inhibitor due to overlapping toxicity or overlapping pharmacokinetics, that it is safe to do and shouldn’t [have an] impact on efficacy,” Dr. Greystoke said. “Overall, all this information will help us drive forward the next round of clinical trials of probably a combination of treatments.”

The KRYSTAL-1 study is supported by Mirati Therapeutics, Inc. Dr. Riely disclosed relationships with Mirati Therapeutics, Merck, Novartis, Pfizer, Takeda, and Roche. Dr. Greystoke was not involved in the study but disclosed relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Lilly, Takeda, and Roche.

The KRAS inhibitor adagrasib produced a high disease control rate in patients with advanced or metastatic non–small cell lung cancer (NSCLC), according to data from the KRYSTAL-1 study.

An objective response rate was seen in 45% of patients, with a further 51% achieving stable disease, for a disease control rate of 96%.

“The vast majority of patients had significant tumor shrinkage,” said study investigator Gregory J. Riely, MD, PhD, when presenting the results at the European Lung Cancer Virtual Congress 2021 (Abstract 990_PR).

Dr. Riely, vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center in New York, noted that just 6 of the 70 patients in this phase 1/2 trial showed evidence of measurable tumor growth.

“This new way of targeting an oncogene may very well represent an evolutionary step forward in the management of lung cancer patients, akin to when we first had EGFR inhibitors,” Alastair Greystoke, MBChB, PhD, said in his discussion of the trial.

Dr. Greystoke, a clinical senior lecturer and honorary consultant in medical oncology at Newcastle (England) University, observed that the availability of KRAS-targeting agents could have a large potential impact on clinical practice. They could add another 14% of patients with NSCLC to the list of those who are eligible for molecularly-targeted therapy.

“It may be that soon, almost half our patients with lung adenocarcinoma will have a potential targetable abnormality,” Dr. Greystoke said.
 

Data confirm KRAS as a therapeutic target

Adagrasib is now the second drug to show promise as an inhibitor of KRAS G12C. In a phase 2 trial, the KRAS inhibitor sotorasib produced a response rate of 37%, a median response duration of 10 months, and a median progression-free survival of 6.8 months in patients with NSCLC.

Data on response duration and progression-free survival are not yet available for adagrasib. However, the duration of response extended past 11 months in four of the six patients who achieved a partial response to adagrasib in the phase 1/1b portion of the KRYSTAL-1 trial.

“What we’ve seen from this data, and data with other agents, is that responses are very heterogeneous,” Dr. Greystoke observed. “A small number of patients do not respond at all. In some patients, responses are short-lived, whilst in other patients, responses are long and still ongoing.”
 

KRYSTAL-1 study design and safety

KRYSTAL-1 is an ongoing phase 1/2 study designed to assess the safety and clinical activity of adagrasib in patients with advanced solid tumors that have a KRAS G12C mutation, including NSCLC.

Dr. Riely reported data on 79 patients with advanced or metastatic NSCLC who had progressed despite being treated with chemotherapy and immunotherapy. Of these, 18 patients had participated in the phase 1/1b dose-escalation and dose-expansion phase of the study, and 61 had participated in the phase 2 portion. Adagrasib was given at a twice-daily dose of 600 mg.

The patients’ median age was 65 years, 85% were White, and 57% were women. Almost all (95%) were current or former smokers, which is unsurprising since the KRAS G12C mutation is rarely seen in never-smokers. Almost all patients had nonsquamous histology (96%) and had received PD-1 or PD-L1 inhibitors (92%).

Treatment-related adverse events of any grade occurred in 85% of patients, and 30% of patients had grade 3-4 events. The most frequent treatment-related grade 3-4 adverse events were fatigue (6%), increased ALT or AST (each 5%), QT prolongation (3%), anemia (2%), nausea (2%), and vomiting (2%).

Two grade 5 adverse events were recorded – a case of pneumonitis in a patient with recurrent pneumonitis and one case of cardiac failure. Adverse events led to discontinuation in 4.5% of patients.
 

Greater effect seen with co-mutation

KRAS is commonly co-mutated, so the investigators performed an exploratory analysis to see if the presence of other mutations – STK11, KEAP1, and TP53 – might affect the results of adagrasib.

A greater objective response rate was seen in patients with the STK11 mutation than in those without it (64% and 33%, respectively). STK11 is associated with poorer responses to immune checkpoint inhibitors.

“We hypothesized that adagrasib treatment recruits T cells into the tumor and that T-cell infiltration may reverse STK11-mediated immune suppression,” Dr. Riely said. This theory seemed to be borne out with further analyses, though Dr. Greystoke raised doubts. There was no sign of STK11 mutations having any effect on response rates with adagrasib in preclinical studies.

Patients with KEAP1 as a co-mutation had a lower response rate than that of those without it (36% and 48%, respectively), which is in keeping with what might be expected. KEAP1 is known to be associated to a poor response to chemotherapy and immunotherapy.

“I think this data is very provocative but needs to be confirmed in larger cohorts,” Dr. Greystoke said. It could mean that adagrasib has the potential to turn a “cold tumor, hot,” enabling the use of immunotherapies.

A new cohort has been included in the KRYSTAL-1 study to further evaluate how having both the KRAS G12C and STK11 mutations may affect treatment with adagrasib.

Data could support drug combination

The adagrasib data lend support to the combination of KRAS G12C inhibitors with other molecularly-targeted treatments for NSCLC, Dr. Greystoke said, such as with tyrosine kinase inhibitors or immunotherapies. He noted that high steady-state levels of adagrasib were detected in the blood, and these levels were well above those needed for potential efficacy.

“This gives us confidence that if we do need to drop the dose below the recommended phase 2 dose to allow potential combinations with a small-molecule inhibitor due to overlapping toxicity or overlapping pharmacokinetics, that it is safe to do and shouldn’t [have an] impact on efficacy,” Dr. Greystoke said. “Overall, all this information will help us drive forward the next round of clinical trials of probably a combination of treatments.”

The KRYSTAL-1 study is supported by Mirati Therapeutics, Inc. Dr. Riely disclosed relationships with Mirati Therapeutics, Merck, Novartis, Pfizer, Takeda, and Roche. Dr. Greystoke was not involved in the study but disclosed relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Lilly, Takeda, and Roche.

The KRAS inhibitor adagrasib produced a high disease control rate in patients with advanced or metastatic non–small cell lung cancer (NSCLC), according to data from the KRYSTAL-1 study.

An objective response rate was seen in 45% of patients, with a further 51% achieving stable disease, for a disease control rate of 96%.

“The vast majority of patients had significant tumor shrinkage,” said study investigator Gregory J. Riely, MD, PhD, when presenting the results at the European Lung Cancer Virtual Congress 2021 (Abstract 990_PR).

Dr. Riely, vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center in New York, noted that just 6 of the 70 patients in this phase 1/2 trial showed evidence of measurable tumor growth.

“This new way of targeting an oncogene may very well represent an evolutionary step forward in the management of lung cancer patients, akin to when we first had EGFR inhibitors,” Alastair Greystoke, MBChB, PhD, said in his discussion of the trial.

Dr. Greystoke, a clinical senior lecturer and honorary consultant in medical oncology at Newcastle (England) University, observed that the availability of KRAS-targeting agents could have a large potential impact on clinical practice. They could add another 14% of patients with NSCLC to the list of those who are eligible for molecularly-targeted therapy.

“It may be that soon, almost half our patients with lung adenocarcinoma will have a potential targetable abnormality,” Dr. Greystoke said.
 

Data confirm KRAS as a therapeutic target

Adagrasib is now the second drug to show promise as an inhibitor of KRAS G12C. In a phase 2 trial, the KRAS inhibitor sotorasib produced a response rate of 37%, a median response duration of 10 months, and a median progression-free survival of 6.8 months in patients with NSCLC.

Data on response duration and progression-free survival are not yet available for adagrasib. However, the duration of response extended past 11 months in four of the six patients who achieved a partial response to adagrasib in the phase 1/1b portion of the KRYSTAL-1 trial.

“What we’ve seen from this data, and data with other agents, is that responses are very heterogeneous,” Dr. Greystoke observed. “A small number of patients do not respond at all. In some patients, responses are short-lived, whilst in other patients, responses are long and still ongoing.”
 

KRYSTAL-1 study design and safety

KRYSTAL-1 is an ongoing phase 1/2 study designed to assess the safety and clinical activity of adagrasib in patients with advanced solid tumors that have a KRAS G12C mutation, including NSCLC.

Dr. Riely reported data on 79 patients with advanced or metastatic NSCLC who had progressed despite being treated with chemotherapy and immunotherapy. Of these, 18 patients had participated in the phase 1/1b dose-escalation and dose-expansion phase of the study, and 61 had participated in the phase 2 portion. Adagrasib was given at a twice-daily dose of 600 mg.

The patients’ median age was 65 years, 85% were White, and 57% were women. Almost all (95%) were current or former smokers, which is unsurprising since the KRAS G12C mutation is rarely seen in never-smokers. Almost all patients had nonsquamous histology (96%) and had received PD-1 or PD-L1 inhibitors (92%).

Treatment-related adverse events of any grade occurred in 85% of patients, and 30% of patients had grade 3-4 events. The most frequent treatment-related grade 3-4 adverse events were fatigue (6%), increased ALT or AST (each 5%), QT prolongation (3%), anemia (2%), nausea (2%), and vomiting (2%).

Two grade 5 adverse events were recorded – a case of pneumonitis in a patient with recurrent pneumonitis and one case of cardiac failure. Adverse events led to discontinuation in 4.5% of patients.
 

Greater effect seen with co-mutation

KRAS is commonly co-mutated, so the investigators performed an exploratory analysis to see if the presence of other mutations – STK11, KEAP1, and TP53 – might affect the results of adagrasib.

A greater objective response rate was seen in patients with the STK11 mutation than in those without it (64% and 33%, respectively). STK11 is associated with poorer responses to immune checkpoint inhibitors.

“We hypothesized that adagrasib treatment recruits T cells into the tumor and that T-cell infiltration may reverse STK11-mediated immune suppression,” Dr. Riely said. This theory seemed to be borne out with further analyses, though Dr. Greystoke raised doubts. There was no sign of STK11 mutations having any effect on response rates with adagrasib in preclinical studies.

Patients with KEAP1 as a co-mutation had a lower response rate than that of those without it (36% and 48%, respectively), which is in keeping with what might be expected. KEAP1 is known to be associated to a poor response to chemotherapy and immunotherapy.

“I think this data is very provocative but needs to be confirmed in larger cohorts,” Dr. Greystoke said. It could mean that adagrasib has the potential to turn a “cold tumor, hot,” enabling the use of immunotherapies.

A new cohort has been included in the KRYSTAL-1 study to further evaluate how having both the KRAS G12C and STK11 mutations may affect treatment with adagrasib.

Data could support drug combination

The adagrasib data lend support to the combination of KRAS G12C inhibitors with other molecularly-targeted treatments for NSCLC, Dr. Greystoke said, such as with tyrosine kinase inhibitors or immunotherapies. He noted that high steady-state levels of adagrasib were detected in the blood, and these levels were well above those needed for potential efficacy.

“This gives us confidence that if we do need to drop the dose below the recommended phase 2 dose to allow potential combinations with a small-molecule inhibitor due to overlapping toxicity or overlapping pharmacokinetics, that it is safe to do and shouldn’t [have an] impact on efficacy,” Dr. Greystoke said. “Overall, all this information will help us drive forward the next round of clinical trials of probably a combination of treatments.”

The KRYSTAL-1 study is supported by Mirati Therapeutics, Inc. Dr. Riely disclosed relationships with Mirati Therapeutics, Merck, Novartis, Pfizer, Takeda, and Roche. Dr. Greystoke was not involved in the study but disclosed relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Lilly, Takeda, and Roche.

Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.

peterschreiber_media/iStock/Getty Images

In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.

The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.

Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.

None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.

“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.

Antibody responses

In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.

The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.

Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.

The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.

Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.

Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.

peterschreiber_media/iStock/Getty Images

In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.

The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.

Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.

None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.

“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.

Antibody responses

In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.

The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.

Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.

The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.

Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.

Two reports support the safety and immunogenicity of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMDs) and represent the first available data on such patients.

peterschreiber_media/iStock/Getty Images

In an observational cohort study published in Annals of the Rheumatic Diseases, Caoilfhionn M. Connolly, MD, of Johns Hopkins University, Baltimore, and colleagues reviewed data from 325 adults with RMDs who received the first dose of SARS-CoV-2 mRNA vaccine during the period of Dec. 17, 2020, to Feb. 11, 2021. Of these, 51% received the Pfizer/BioNTech vaccine and 49% received the Moderna vaccine.

The patients, who were invited to participate on social media, were aged 34-54 years, 96% were women, and 89% were White. Inflammatory arthritis was the most common RMD condition (38%), followed by systemic lupus erythematosus (28%) and overlap connective tissue disease (19%). The patients were using a range of immunomodulatory treatment regimens, including nonbiologic disease modifying antirheumatic drugs (DMARDs) in 44%, biologics in 19%, and combination therapy in 37%.

Overall, 89% of patients reported localized symptoms of pain, swelling, and erythema, and 69% reported systemic symptoms. Fatigue was the most common systemic symptom, and 7.4% reported severe fatigue.

None of the patients experienced allergic reactions requiring epinephrine, and 3% reported new infections that required treatment.

“These early, reassuring results may ameliorate concern among patients and provide guidance for rheumatology providers in critical discussions regarding vaccine hesitancy or refusal,” they concluded.

Antibody responses

In another study published in Annals of the Rheumatic Diseases by the same group of researchers, antibody responses against the receptor binding domain of the SARS-CoV-2 spike protein were seen in 74% of 123 adults with an RMD at 18-26 days after receiving a first dose of SARS-CoV-2 mRNA vaccine (52% Pfizer vaccine and 48% Moderna) between Jan. 8, 2021, and Feb. 12, 2021.

The most common diagnoses in these patients were inflammatory arthritis (28%), systemic lupus erythematosus (20%), and Sjögren’s syndrome (13%). A total of 28% of participants reported taking no immunomodulatory agents, 19% reported nonbiologic DMARDs, 14% reported biologic DMARDs, and 19% reported combination therapy.

Although no differences appeared based on disease groups or overall categories of immunomodulatory therapies, patients whose treatment included mycophenolate or rituximab were significantly less likely to develop antibody responses than were patients not taking these medications (P = .001 and P = .04, respectively). Although rituximab and methotrexate have been associated with reduced responses to vaccines such as the flu vaccine, methotrexate was not associated with reduced vaccine response in this study. A total of 94% of patients taking a tumor necrosis factor inhibitor had detectable antibodies.

The studies’ findings were limited by several factors including a lack of longer-term safety data; the small, nonrandomized sample of mainly white women; limited information on immunomodulatory drug dosage and timing; lack of serial antibody measurements; use of an enzyme immunoassay designed to detect antibody response after natural infection; and the inclusion of data only on the first dose of a two-dose vaccine series, the researchers noted. However, the data should provide additional reassurance to RMD patients and their health care teams about vaccination against COVID-19, they said.

Both studies were supported by the Ben-Dov family. In addition, the studies were supported by grants to various study authors from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Transplantation and Immunology Research Network of the American Society of Transplantation. One author disclosed financial relationships with Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, and Thermo Fisher Scientific. The other researchers had no financial conflicts to disclose.

The medical community may have paused during the COVID-19 pandemic, but commercial payers kept pushing forward with new coverage restrictions, expanding the number of services and procedures requiring prior authorization (PA) and restricting covered drugs. As 2020 closed and with 2021 barely underway, the American Gastroenterological Association has been holding discussions with major payers to stop implementation of policies restricting gastroenterologists’ ability to prescribe the most appropriate drugs for their patients’ clinical situations.

The Government Affairs Committee’s Coverage and Reimbursement Subcommittee (CRS) works with commercial payers on issues affecting gastroenterologists and identifies outside experts on the policy subject when necessary. The subcommittee recently worked with UnitedHealthcare on a coverage policy change to make Inflictra (infliximab-dyyb) and Avsola (infliximab-axxq) its preferred products and move Remicade (infliximab) and Renflexis (infliximab-abda) to its nonpreferred list, as announced in UnitedHealthcare’s Medical benefit specialty drug update bulletin. The CRS identified Sundeep Singh, MD, an inflammatory bowel disease specialist from Stanford (Calif.) University, to engage in discussion with UnitedHealthcare on behalf of AGA and lead a multisociety effort with the North American Society For Pediatric Gastroenterology, Hepatology & Nutrition; the American Society for Gastrointestinal Endoscopy; and the American College of Gastroenterology.

After conversations with our physician experts, UnitedHealthcare agreed to notify its medical directors to allow pediatric patients 16 years and younger and currently on a nonpreferred product, such as Remicade, to remain on it if that is the recommendation of the treating physician. Adult patients meeting the following conditions may be allowed to remain on nonpreferred products, but will require the prescribing provider to request a review and a determination will be made on a case-by-case basis:

• Adult patients currently on induction of Remicade for less than 18 months will not be required to switch.
• Adult patients who are having a flare of active disease, who are, therefore, not stable, will not be required to switch.

AGA experts are a vital part of CRS’s work with commercial payers. Dr. Singh and his fellow IBD experts who participated in discussion with UnitedHealthcare helped the payer understand why its original policy implementing nonmedical switching without exceptions was harmful to patients. Dr. Singh had this to say about his experience with the process:

“Thanks to the coordinated efforts between AGA, NASPGHAN, ACG, ASGE, and UnitedHealthcare, we were able to reconcile the policy and knowledge gaps to protect our patients with inflammatory bowel disease. While there are significant cost savings associated with biosimilar use, we wanted to temper the health plan’s initial enthusiasm with the potential costs in patients whose clinical and economic outcomes are not certain yet. As we anticipate other health plans will implement similar policies, this effort may provide a road map for the future.”

The CRS also works with pharmacy benefit management organizations. The AGA joined the ASGE and ACG to ask Express Scripts to not exclude coverage of brand colonoscopy preparations such as Suprep, Clenpiq, and Plenvu. The formulary currently plans to cover only generic products for colon cleansing beginning April 1, 2021, primarily 4-liter polyethylene glycol electrolyte solutions (PEG-ELS).

Clinical representatives and staff from AGA, ACG, and ASGE participated in a fruitful discussion with the leadership of Express Scripts and presented several key discussion points in favor of keeping coverage of brand colonoscopy bowel preparations in addition to PEG-ELS. The multisociety group presented views from practicing gastroenterologists as well as from academicians about the safety and benefits of low-volume preparations for a quality screening colonoscopic exam especially in certain patient populations. Limiting choices of bowel preparations will deter patients from undergoing screening colonoscopies, which have been proven to prevent colorectal cancers. After the multisociety group pointed out the need to individualize the choice of bowel preparation to ensure safety and tolerability, Express Scripts will hopefully agree with the significance of having options for our patients. It was clear that the importance of patient preference and clinical appropriateness for different bowel preparation options was heard by the Express Scripts representatives, so we await their decision with hope.

The AGA is working to address issues with commercial payers, but to be effective we need to hear your experiences. We know commercial payers continue to develop increasingly restrictive PA policies and coverage conditions for procedures and drugs. Reach out to the AGA via the AGA Community, Twitter, or via email to Leslie Narramore, the director of regulatory affairs at AGA, at [email protected] to let us know what’s happening.

Seven options to consider if your PA has been rejected or claim has been denied

• Ask for the credentials of the payer representative who initially denied the request. Even when payer representatives are physicians, they are often not gastroenterologists. Ask to speak with a representative actively practicing gastroenterology.
• Ask to record your conversation with the payer representative for documentation purposes.
• Ask to speak directly to the payer’s medical director.
• Bring the complaint to the payer’s attention on social media. Using social media to bring attention to a denial can sometimes elicit quick, personal outreach from the payer to address the issue.
• Let the AGA know what’s happening. Reach out to the AGA via the AGA Community, via Twitter, or by emailing Leslie Narramore, the director of regulatory affairs at AGA ([email protected]).
• File a complaint with the State Insurance Commissioner. State Insurance Commissioners are responsible for regulating the insurance industry in their state and can investigate to ensure the laws in their state are being followed and providers and patients are being treated fairly. While insurance law and regulation are established at the state level, the insurance commissioners are members of the National Association of Insurance Commissioners (NAIC), which allows them to coordinate insurance regulation among the states and territories. Find out your state’s complaint process because many state insurance commissioners have on online complaint forms. Keep records of all interactions with the insurance company to document that you have attempted to resolve the matter with the payer first.
• File a complaint at the federal level for states without an external review process. If your state doesn’t have an external review process that meets the minimum consumer protection standards, the federal government’s Department of Health & Human Services oversees an external review process for health insurance companies in your state. See www.healthcare.gov/appeal-insurance-company-decision/external-review/ for more information. In states where the federal government oversees the process, insurance companies may choose to participate in an HHS-administered process or contract with independent review organizations. If your plan doesn’t participate in a state or HHS-Administered Federal External Review Process, your health plan must contract with an independent review organization.

Dr. Guha is with the University of Texas Health Science Center in Houston. Dr. Upchurch is with Adena Health System in Chillicothe, Ohio. Both are AGA Coverage and Reimbursement Subcommittee members. The authors have no conflicts to declare.

The medical community may have paused during the COVID-19 pandemic, but commercial payers kept pushing forward with new coverage restrictions, expanding the number of services and procedures requiring prior authorization (PA) and restricting covered drugs. As 2020 closed and with 2021 barely underway, the American Gastroenterological Association has been holding discussions with major payers to stop implementation of policies restricting gastroenterologists’ ability to prescribe the most appropriate drugs for their patients’ clinical situations.

The Government Affairs Committee’s Coverage and Reimbursement Subcommittee (CRS) works with commercial payers on issues affecting gastroenterologists and identifies outside experts on the policy subject when necessary. The subcommittee recently worked with UnitedHealthcare on a coverage policy change to make Inflictra (infliximab-dyyb) and Avsola (infliximab-axxq) its preferred products and move Remicade (infliximab) and Renflexis (infliximab-abda) to its nonpreferred list, as announced in UnitedHealthcare’s Medical benefit specialty drug update bulletin. The CRS identified Sundeep Singh, MD, an inflammatory bowel disease specialist from Stanford (Calif.) University, to engage in discussion with UnitedHealthcare on behalf of AGA and lead a multisociety effort with the North American Society For Pediatric Gastroenterology, Hepatology & Nutrition; the American Society for Gastrointestinal Endoscopy; and the American College of Gastroenterology.

After conversations with our physician experts, UnitedHealthcare agreed to notify its medical directors to allow pediatric patients 16 years and younger and currently on a nonpreferred product, such as Remicade, to remain on it if that is the recommendation of the treating physician. Adult patients meeting the following conditions may be allowed to remain on nonpreferred products, but will require the prescribing provider to request a review and a determination will be made on a case-by-case basis:

• Adult patients currently on induction of Remicade for less than 18 months will not be required to switch.
• Adult patients who are having a flare of active disease, who are, therefore, not stable, will not be required to switch.

AGA experts are a vital part of CRS’s work with commercial payers. Dr. Singh and his fellow IBD experts who participated in discussion with UnitedHealthcare helped the payer understand why its original policy implementing nonmedical switching without exceptions was harmful to patients. Dr. Singh had this to say about his experience with the process:

“Thanks to the coordinated efforts between AGA, NASPGHAN, ACG, ASGE, and UnitedHealthcare, we were able to reconcile the policy and knowledge gaps to protect our patients with inflammatory bowel disease. While there are significant cost savings associated with biosimilar use, we wanted to temper the health plan’s initial enthusiasm with the potential costs in patients whose clinical and economic outcomes are not certain yet. As we anticipate other health plans will implement similar policies, this effort may provide a road map for the future.”

The CRS also works with pharmacy benefit management organizations. The AGA joined the ASGE and ACG to ask Express Scripts to not exclude coverage of brand colonoscopy preparations such as Suprep, Clenpiq, and Plenvu. The formulary currently plans to cover only generic products for colon cleansing beginning April 1, 2021, primarily 4-liter polyethylene glycol electrolyte solutions (PEG-ELS).

Clinical representatives and staff from AGA, ACG, and ASGE participated in a fruitful discussion with the leadership of Express Scripts and presented several key discussion points in favor of keeping coverage of brand colonoscopy bowel preparations in addition to PEG-ELS. The multisociety group presented views from practicing gastroenterologists as well as from academicians about the safety and benefits of low-volume preparations for a quality screening colonoscopic exam especially in certain patient populations. Limiting choices of bowel preparations will deter patients from undergoing screening colonoscopies, which have been proven to prevent colorectal cancers. After the multisociety group pointed out the need to individualize the choice of bowel preparation to ensure safety and tolerability, Express Scripts will hopefully agree with the significance of having options for our patients. It was clear that the importance of patient preference and clinical appropriateness for different bowel preparation options was heard by the Express Scripts representatives, so we await their decision with hope.

The AGA is working to address issues with commercial payers, but to be effective we need to hear your experiences. We know commercial payers continue to develop increasingly restrictive PA policies and coverage conditions for procedures and drugs. Reach out to the AGA via the AGA Community, Twitter, or via email to Leslie Narramore, the director of regulatory affairs at AGA, at [email protected] to let us know what’s happening.

Seven options to consider if your PA has been rejected or claim has been denied

• Ask for the credentials of the payer representative who initially denied the request. Even when payer representatives are physicians, they are often not gastroenterologists. Ask to speak with a representative actively practicing gastroenterology.
• Ask to record your conversation with the payer representative for documentation purposes.
• Ask to speak directly to the payer’s medical director.
• Bring the complaint to the payer’s attention on social media. Using social media to bring attention to a denial can sometimes elicit quick, personal outreach from the payer to address the issue.
• Let the AGA know what’s happening. Reach out to the AGA via the AGA Community, via Twitter, or by emailing Leslie Narramore, the director of regulatory affairs at AGA ([email protected]).
• File a complaint with the State Insurance Commissioner. State Insurance Commissioners are responsible for regulating the insurance industry in their state and can investigate to ensure the laws in their state are being followed and providers and patients are being treated fairly. While insurance law and regulation are established at the state level, the insurance commissioners are members of the National Association of Insurance Commissioners (NAIC), which allows them to coordinate insurance regulation among the states and territories. Find out your state’s complaint process because many state insurance commissioners have on online complaint forms. Keep records of all interactions with the insurance company to document that you have attempted to resolve the matter with the payer first.
• File a complaint at the federal level for states without an external review process. If your state doesn’t have an external review process that meets the minimum consumer protection standards, the federal government’s Department of Health & Human Services oversees an external review process for health insurance companies in your state. See www.healthcare.gov/appeal-insurance-company-decision/external-review/ for more information. In states where the federal government oversees the process, insurance companies may choose to participate in an HHS-administered process or contract with independent review organizations. If your plan doesn’t participate in a state or HHS-Administered Federal External Review Process, your health plan must contract with an independent review organization.

Dr. Guha is with the University of Texas Health Science Center in Houston. Dr. Upchurch is with Adena Health System in Chillicothe, Ohio. Both are AGA Coverage and Reimbursement Subcommittee members. The authors have no conflicts to declare.

The medical community may have paused during the COVID-19 pandemic, but commercial payers kept pushing forward with new coverage restrictions, expanding the number of services and procedures requiring prior authorization (PA) and restricting covered drugs. As 2020 closed and with 2021 barely underway, the American Gastroenterological Association has been holding discussions with major payers to stop implementation of policies restricting gastroenterologists’ ability to prescribe the most appropriate drugs for their patients’ clinical situations.

The Government Affairs Committee’s Coverage and Reimbursement Subcommittee (CRS) works with commercial payers on issues affecting gastroenterologists and identifies outside experts on the policy subject when necessary. The subcommittee recently worked with UnitedHealthcare on a coverage policy change to make Inflictra (infliximab-dyyb) and Avsola (infliximab-axxq) its preferred products and move Remicade (infliximab) and Renflexis (infliximab-abda) to its nonpreferred list, as announced in UnitedHealthcare’s Medical benefit specialty drug update bulletin. The CRS identified Sundeep Singh, MD, an inflammatory bowel disease specialist from Stanford (Calif.) University, to engage in discussion with UnitedHealthcare on behalf of AGA and lead a multisociety effort with the North American Society For Pediatric Gastroenterology, Hepatology & Nutrition; the American Society for Gastrointestinal Endoscopy; and the American College of Gastroenterology.

After conversations with our physician experts, UnitedHealthcare agreed to notify its medical directors to allow pediatric patients 16 years and younger and currently on a nonpreferred product, such as Remicade, to remain on it if that is the recommendation of the treating physician. Adult patients meeting the following conditions may be allowed to remain on nonpreferred products, but will require the prescribing provider to request a review and a determination will be made on a case-by-case basis:

• Adult patients currently on induction of Remicade for less than 18 months will not be required to switch.
• Adult patients who are having a flare of active disease, who are, therefore, not stable, will not be required to switch.

AGA experts are a vital part of CRS’s work with commercial payers. Dr. Singh and his fellow IBD experts who participated in discussion with UnitedHealthcare helped the payer understand why its original policy implementing nonmedical switching without exceptions was harmful to patients. Dr. Singh had this to say about his experience with the process:

“Thanks to the coordinated efforts between AGA, NASPGHAN, ACG, ASGE, and UnitedHealthcare, we were able to reconcile the policy and knowledge gaps to protect our patients with inflammatory bowel disease. While there are significant cost savings associated with biosimilar use, we wanted to temper the health plan’s initial enthusiasm with the potential costs in patients whose clinical and economic outcomes are not certain yet. As we anticipate other health plans will implement similar policies, this effort may provide a road map for the future.”

The CRS also works with pharmacy benefit management organizations. The AGA joined the ASGE and ACG to ask Express Scripts to not exclude coverage of brand colonoscopy preparations such as Suprep, Clenpiq, and Plenvu. The formulary currently plans to cover only generic products for colon cleansing beginning April 1, 2021, primarily 4-liter polyethylene glycol electrolyte solutions (PEG-ELS).

Clinical representatives and staff from AGA, ACG, and ASGE participated in a fruitful discussion with the leadership of Express Scripts and presented several key discussion points in favor of keeping coverage of brand colonoscopy bowel preparations in addition to PEG-ELS. The multisociety group presented views from practicing gastroenterologists as well as from academicians about the safety and benefits of low-volume preparations for a quality screening colonoscopic exam especially in certain patient populations. Limiting choices of bowel preparations will deter patients from undergoing screening colonoscopies, which have been proven to prevent colorectal cancers. After the multisociety group pointed out the need to individualize the choice of bowel preparation to ensure safety and tolerability, Express Scripts will hopefully agree with the significance of having options for our patients. It was clear that the importance of patient preference and clinical appropriateness for different bowel preparation options was heard by the Express Scripts representatives, so we await their decision with hope.

The AGA is working to address issues with commercial payers, but to be effective we need to hear your experiences. We know commercial payers continue to develop increasingly restrictive PA policies and coverage conditions for procedures and drugs. Reach out to the AGA via the AGA Community, Twitter, or via email to Leslie Narramore, the director of regulatory affairs at AGA, at [email protected] to let us know what’s happening.

Seven options to consider if your PA has been rejected or claim has been denied

• Ask for the credentials of the payer representative who initially denied the request. Even when payer representatives are physicians, they are often not gastroenterologists. Ask to speak with a representative actively practicing gastroenterology.
• Ask to record your conversation with the payer representative for documentation purposes.
• Ask to speak directly to the payer’s medical director.
• Bring the complaint to the payer’s attention on social media. Using social media to bring attention to a denial can sometimes elicit quick, personal outreach from the payer to address the issue.
• Let the AGA know what’s happening. Reach out to the AGA via the AGA Community, via Twitter, or by emailing Leslie Narramore, the director of regulatory affairs at AGA ([email protected]).
• File a complaint with the State Insurance Commissioner. State Insurance Commissioners are responsible for regulating the insurance industry in their state and can investigate to ensure the laws in their state are being followed and providers and patients are being treated fairly. While insurance law and regulation are established at the state level, the insurance commissioners are members of the National Association of Insurance Commissioners (NAIC), which allows them to coordinate insurance regulation among the states and territories. Find out your state’s complaint process because many state insurance commissioners have on online complaint forms. Keep records of all interactions with the insurance company to document that you have attempted to resolve the matter with the payer first.
• File a complaint at the federal level for states without an external review process. If your state doesn’t have an external review process that meets the minimum consumer protection standards, the federal government’s Department of Health & Human Services oversees an external review process for health insurance companies in your state. See www.healthcare.gov/appeal-insurance-company-decision/external-review/ for more information. In states where the federal government oversees the process, insurance companies may choose to participate in an HHS-administered process or contract with independent review organizations. If your plan doesn’t participate in a state or HHS-Administered Federal External Review Process, your health plan must contract with an independent review organization.

Dr. Guha is with the University of Texas Health Science Center in Houston. Dr. Upchurch is with Adena Health System in Chillicothe, Ohio. Both are AGA Coverage and Reimbursement Subcommittee members. The authors have no conflicts to declare.

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community to seek advice from colleagues about therapy and disease management options, best practices, and diagnoses. The following is a preview of a recent popular clinical discussion:

From John Fang, MD: Update on feeding tubes: Indications and troubleshooting complications.

Gastroenterologists are uniquely positioned to manage individuals with feeding tubes as their training underscores principles in digestion, nutrition support, and enteral tube placement. Adequate management of individuals with feeding tubes and, importantly, the complications that arise from feeding tube use and placement require both right education and experience. Therefore, gastroenterologists are well suited to both place and manage individuals with feeding tubes in the long term.

Questions:

1. Are gastroenterologist best suited for placement and management of feeding tubes (vs. interventional radiology or surgery)?

2. Are gastroenterologists adequately trained place and manage feeding tubes?

3. What are the most difficult complication(s) of feeding tubes to manage?

The conversation stems from the February In Focus article from The New Gastroenterologist, “Update on feeding tubes: Indications and troubleshooting complications.”

See how AGA members responded and join the discussion: https://community.gastro.org/posts/23639.

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community to seek advice from colleagues about therapy and disease management options, best practices, and diagnoses. The following is a preview of a recent popular clinical discussion:

From John Fang, MD: Update on feeding tubes: Indications and troubleshooting complications.

Gastroenterologists are uniquely positioned to manage individuals with feeding tubes as their training underscores principles in digestion, nutrition support, and enteral tube placement. Adequate management of individuals with feeding tubes and, importantly, the complications that arise from feeding tube use and placement require both right education and experience. Therefore, gastroenterologists are well suited to both place and manage individuals with feeding tubes in the long term.

Questions:

1. Are gastroenterologist best suited for placement and management of feeding tubes (vs. interventional radiology or surgery)?

2. Are gastroenterologists adequately trained place and manage feeding tubes?

3. What are the most difficult complication(s) of feeding tubes to manage?

The conversation stems from the February In Focus article from The New Gastroenterologist, “Update on feeding tubes: Indications and troubleshooting complications.”

See how AGA members responded and join the discussion: https://community.gastro.org/posts/23639.

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community to seek advice from colleagues about therapy and disease management options, best practices, and diagnoses. The following is a preview of a recent popular clinical discussion:

From John Fang, MD: Update on feeding tubes: Indications and troubleshooting complications.

Gastroenterologists are uniquely positioned to manage individuals with feeding tubes as their training underscores principles in digestion, nutrition support, and enteral tube placement. Adequate management of individuals with feeding tubes and, importantly, the complications that arise from feeding tube use and placement require both right education and experience. Therefore, gastroenterologists are well suited to both place and manage individuals with feeding tubes in the long term.

Questions:

1. Are gastroenterologist best suited for placement and management of feeding tubes (vs. interventional radiology or surgery)?

2. Are gastroenterologists adequately trained place and manage feeding tubes?

3. What are the most difficult complication(s) of feeding tubes to manage?

The conversation stems from the February In Focus article from The New Gastroenterologist, “Update on feeding tubes: Indications and troubleshooting complications.”

See how AGA members responded and join the discussion: https://community.gastro.org/posts/23639.

An international panel of mood disorder experts has published guidance on how to safely and effectively use ketamine and esketamine to treat adults with treatment-resistant depression (TRD).

“Ketamine and esketamine are the first rapid-onset treatments for adults with TRD, and there was an international need for best-practice guidance on the deft and safe implementation of ketamine and esketamine at the point of care, as none previously existed,” first author Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said in an interview.

“This need has only been amplified by the significant increase in the number of clinics and centers providing this treatment,” added Dr. McIntyre, head of the mood disorders psychopharmacology unit.

Their article was published online March 17 in the American Journal of Psychiatry.
 

Insufficient evidence of long-term efficacy

As reported by this news organization, the U.S. Food and Drug Administration (FDA) approved esketamine nasal spray (Spravato) for TRD in March 2019.

In August 2020, the FDA updated the approval to include adults with major depression and suicidal thoughts or actions.

To provide clinical guidance, Dr. McIntyre and colleagues synthesized the available literature on the efficacy, safety, and tolerability of ketamine and esketamine for TRD.

The evidence, they note, supports the rapid-onset (within 1-2 days) efficacy of esketamine and ketamine in TRD.

The strongest evidence of efficacy is for intranasal esketamine and intravenous ketamine. There is insufficient evidence for oral, subcutaneous, or intramuscular ketamine for TRD, they report.

Intranasal esketamine demonstrates efficacy, safety, and tolerability for up to 1 year in adults with TRD. Evidence for long-term efficacy, safety, and tolerability of intravenous ketamine for patients with TRD is insufficient, the group notes.

They also note that esketamine is approved in the United States for major depression in association with suicidal ideation or behavior and that it has been proven to reduce suicide completion.

Safety concerns with ketamine and esketamine identified in the literature include, but are not limited to, psychiatric, neurologic/cognitive, genitourinary, and hemodynamic effects.
 

Implementation checklist

The group has developed an “implementation checklist” for use of ketamine/esketamine in clinical practice.

Starting with patient selection, they note that appropriate patients are those with a confirmed diagnosis of TRD for whom psychosis and other conditions that would significantly affect the risk-benefit ratio have been ruled out.

They suggest that a physical examination and monitoring of vital signs be undertaken during treatment and during posttreatment surveillance. A urine drug screen should be considered if appropriate.

The group advises that esketamine and ketamine be administered only in settings with multidisciplinary personnel, including, but not limited to, those with expertise in the assessment of mood disorders.

Clinics should be equipped with appropriate cardiorespiratory monitoring and be capable of psychiatric assessment of dissociation and psychotomimetic effects.

Depressive symptoms should be measured, and the authors suggest assessing for anxiety, cognitive function, well-being, and psychosocial function.

Patients should be monitored immediately after treatment to ensure cardiorespiratory stability, clear sensorium, and attenuation of dissociative and psychotomimetic effects.

The United States and some other countries require a risk evaluation and mitigation strategy (REMS) when administering esketamine. Regarding the REMS, it is advised that all patients be monitored for a minimum of 2 hours before discharge.

Patients should arrange for reliable transportation for each appointment, and they should be advised not to operate motor vehicles or hazardous machinery without at least one night of sleep.

“The rate of treatment-resistant depression as well as suicide is extraordinary and rising in many parts of the world, only worsened by COVID-19,” said Dr. McIntyre.

“Clinicians of different professional backgrounds have been interested in ketamine/esketamine, and we are extraordinarily pleased to see our international guidelines published,” he added.
 

‘Extremely useful’

Reached for comment, Alan Schatzberg, MD, professor of psychiatry and behavioral sciences at Stanford (Calif.) University, said this document “puts a lot of information in one place as far as what we know and what we don’t know right now, and that’s helpful. I think it’s an attempt to have a kind of a somewhat objective review of the literature, and it’s in a good journal.”

The article, Dr. Schatzberg added, “could be extremely useful for someone who is considering whether ketamine is useful for a patient or what they can tell a patient about ketamine, that is, about how long they might need, is it going to work, will it continue to work, and the level of data we have either on benefits or side effects.”

The research had no specific funding. The original article contains a complete list of author disclosures. Dr. Schatzberg has received grant support from Janssen; has served as a consultant for Alkermes, Avanir, Brain Resource, Bracket, Compass, Delpor, Epiodyne, GLG, Jazz, Janssen Pharmaceuticals, Lundbeck/Takeda, McKinsey and Company, Merck, Myriad Genetics, Neuronetics, Owl Analytics, Pfizer, Sage, Sunovion, and Xhale; holds equity in Corcept (cofounder), Delpor, Dermira, Epiodyne, Gilead, Incyte Genetics, Intersect ENT, Madrigal, Merck, Owl Analytics, Seattle Genetics, Titan, and Xhale; and is listed as an inventor on patents for pharmacogenetics and antiglucocorticoid use in the prediction of antidepressant response.

A version of this article first appeared on Medscape.com.

An international panel of mood disorder experts has published guidance on how to safely and effectively use ketamine and esketamine to treat adults with treatment-resistant depression (TRD).

“Ketamine and esketamine are the first rapid-onset treatments for adults with TRD, and there was an international need for best-practice guidance on the deft and safe implementation of ketamine and esketamine at the point of care, as none previously existed,” first author Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said in an interview.

“This need has only been amplified by the significant increase in the number of clinics and centers providing this treatment,” added Dr. McIntyre, head of the mood disorders psychopharmacology unit.

Their article was published online March 17 in the American Journal of Psychiatry.
 

Insufficient evidence of long-term efficacy

As reported by this news organization, the U.S. Food and Drug Administration (FDA) approved esketamine nasal spray (Spravato) for TRD in March 2019.

In August 2020, the FDA updated the approval to include adults with major depression and suicidal thoughts or actions.

To provide clinical guidance, Dr. McIntyre and colleagues synthesized the available literature on the efficacy, safety, and tolerability of ketamine and esketamine for TRD.

The evidence, they note, supports the rapid-onset (within 1-2 days) efficacy of esketamine and ketamine in TRD.

The strongest evidence of efficacy is for intranasal esketamine and intravenous ketamine. There is insufficient evidence for oral, subcutaneous, or intramuscular ketamine for TRD, they report.

Intranasal esketamine demonstrates efficacy, safety, and tolerability for up to 1 year in adults with TRD. Evidence for long-term efficacy, safety, and tolerability of intravenous ketamine for patients with TRD is insufficient, the group notes.

They also note that esketamine is approved in the United States for major depression in association with suicidal ideation or behavior and that it has been proven to reduce suicide completion.

Safety concerns with ketamine and esketamine identified in the literature include, but are not limited to, psychiatric, neurologic/cognitive, genitourinary, and hemodynamic effects.
 

Implementation checklist

The group has developed an “implementation checklist” for use of ketamine/esketamine in clinical practice.

Starting with patient selection, they note that appropriate patients are those with a confirmed diagnosis of TRD for whom psychosis and other conditions that would significantly affect the risk-benefit ratio have been ruled out.

They suggest that a physical examination and monitoring of vital signs be undertaken during treatment and during posttreatment surveillance. A urine drug screen should be considered if appropriate.

The group advises that esketamine and ketamine be administered only in settings with multidisciplinary personnel, including, but not limited to, those with expertise in the assessment of mood disorders.

Clinics should be equipped with appropriate cardiorespiratory monitoring and be capable of psychiatric assessment of dissociation and psychotomimetic effects.

Depressive symptoms should be measured, and the authors suggest assessing for anxiety, cognitive function, well-being, and psychosocial function.

Patients should be monitored immediately after treatment to ensure cardiorespiratory stability, clear sensorium, and attenuation of dissociative and psychotomimetic effects.

The United States and some other countries require a risk evaluation and mitigation strategy (REMS) when administering esketamine. Regarding the REMS, it is advised that all patients be monitored for a minimum of 2 hours before discharge.

Patients should arrange for reliable transportation for each appointment, and they should be advised not to operate motor vehicles or hazardous machinery without at least one night of sleep.

“The rate of treatment-resistant depression as well as suicide is extraordinary and rising in many parts of the world, only worsened by COVID-19,” said Dr. McIntyre.

“Clinicians of different professional backgrounds have been interested in ketamine/esketamine, and we are extraordinarily pleased to see our international guidelines published,” he added.
 

‘Extremely useful’

Reached for comment, Alan Schatzberg, MD, professor of psychiatry and behavioral sciences at Stanford (Calif.) University, said this document “puts a lot of information in one place as far as what we know and what we don’t know right now, and that’s helpful. I think it’s an attempt to have a kind of a somewhat objective review of the literature, and it’s in a good journal.”

The article, Dr. Schatzberg added, “could be extremely useful for someone who is considering whether ketamine is useful for a patient or what they can tell a patient about ketamine, that is, about how long they might need, is it going to work, will it continue to work, and the level of data we have either on benefits or side effects.”

The research had no specific funding. The original article contains a complete list of author disclosures. Dr. Schatzberg has received grant support from Janssen; has served as a consultant for Alkermes, Avanir, Brain Resource, Bracket, Compass, Delpor, Epiodyne, GLG, Jazz, Janssen Pharmaceuticals, Lundbeck/Takeda, McKinsey and Company, Merck, Myriad Genetics, Neuronetics, Owl Analytics, Pfizer, Sage, Sunovion, and Xhale; holds equity in Corcept (cofounder), Delpor, Dermira, Epiodyne, Gilead, Incyte Genetics, Intersect ENT, Madrigal, Merck, Owl Analytics, Seattle Genetics, Titan, and Xhale; and is listed as an inventor on patents for pharmacogenetics and antiglucocorticoid use in the prediction of antidepressant response.

A version of this article first appeared on Medscape.com.

An international panel of mood disorder experts has published guidance on how to safely and effectively use ketamine and esketamine to treat adults with treatment-resistant depression (TRD).

“Ketamine and esketamine are the first rapid-onset treatments for adults with TRD, and there was an international need for best-practice guidance on the deft and safe implementation of ketamine and esketamine at the point of care, as none previously existed,” first author Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said in an interview.

“This need has only been amplified by the significant increase in the number of clinics and centers providing this treatment,” added Dr. McIntyre, head of the mood disorders psychopharmacology unit.

Their article was published online March 17 in the American Journal of Psychiatry.
 

Insufficient evidence of long-term efficacy

As reported by this news organization, the U.S. Food and Drug Administration (FDA) approved esketamine nasal spray (Spravato) for TRD in March 2019.

In August 2020, the FDA updated the approval to include adults with major depression and suicidal thoughts or actions.

To provide clinical guidance, Dr. McIntyre and colleagues synthesized the available literature on the efficacy, safety, and tolerability of ketamine and esketamine for TRD.

The evidence, they note, supports the rapid-onset (within 1-2 days) efficacy of esketamine and ketamine in TRD.

The strongest evidence of efficacy is for intranasal esketamine and intravenous ketamine. There is insufficient evidence for oral, subcutaneous, or intramuscular ketamine for TRD, they report.

Intranasal esketamine demonstrates efficacy, safety, and tolerability for up to 1 year in adults with TRD. Evidence for long-term efficacy, safety, and tolerability of intravenous ketamine for patients with TRD is insufficient, the group notes.

They also note that esketamine is approved in the United States for major depression in association with suicidal ideation or behavior and that it has been proven to reduce suicide completion.

Safety concerns with ketamine and esketamine identified in the literature include, but are not limited to, psychiatric, neurologic/cognitive, genitourinary, and hemodynamic effects.
 

Implementation checklist

The group has developed an “implementation checklist” for use of ketamine/esketamine in clinical practice.

Starting with patient selection, they note that appropriate patients are those with a confirmed diagnosis of TRD for whom psychosis and other conditions that would significantly affect the risk-benefit ratio have been ruled out.

They suggest that a physical examination and monitoring of vital signs be undertaken during treatment and during posttreatment surveillance. A urine drug screen should be considered if appropriate.

The group advises that esketamine and ketamine be administered only in settings with multidisciplinary personnel, including, but not limited to, those with expertise in the assessment of mood disorders.

Clinics should be equipped with appropriate cardiorespiratory monitoring and be capable of psychiatric assessment of dissociation and psychotomimetic effects.

Depressive symptoms should be measured, and the authors suggest assessing for anxiety, cognitive function, well-being, and psychosocial function.

Patients should be monitored immediately after treatment to ensure cardiorespiratory stability, clear sensorium, and attenuation of dissociative and psychotomimetic effects.

The United States and some other countries require a risk evaluation and mitigation strategy (REMS) when administering esketamine. Regarding the REMS, it is advised that all patients be monitored for a minimum of 2 hours before discharge.

Patients should arrange for reliable transportation for each appointment, and they should be advised not to operate motor vehicles or hazardous machinery without at least one night of sleep.

“The rate of treatment-resistant depression as well as suicide is extraordinary and rising in many parts of the world, only worsened by COVID-19,” said Dr. McIntyre.

“Clinicians of different professional backgrounds have been interested in ketamine/esketamine, and we are extraordinarily pleased to see our international guidelines published,” he added.
 

‘Extremely useful’

Reached for comment, Alan Schatzberg, MD, professor of psychiatry and behavioral sciences at Stanford (Calif.) University, said this document “puts a lot of information in one place as far as what we know and what we don’t know right now, and that’s helpful. I think it’s an attempt to have a kind of a somewhat objective review of the literature, and it’s in a good journal.”

The article, Dr. Schatzberg added, “could be extremely useful for someone who is considering whether ketamine is useful for a patient or what they can tell a patient about ketamine, that is, about how long they might need, is it going to work, will it continue to work, and the level of data we have either on benefits or side effects.”

The research had no specific funding. The original article contains a complete list of author disclosures. Dr. Schatzberg has received grant support from Janssen; has served as a consultant for Alkermes, Avanir, Brain Resource, Bracket, Compass, Delpor, Epiodyne, GLG, Jazz, Janssen Pharmaceuticals, Lundbeck/Takeda, McKinsey and Company, Merck, Myriad Genetics, Neuronetics, Owl Analytics, Pfizer, Sage, Sunovion, and Xhale; holds equity in Corcept (cofounder), Delpor, Dermira, Epiodyne, Gilead, Incyte Genetics, Intersect ENT, Madrigal, Merck, Owl Analytics, Seattle Genetics, Titan, and Xhale; and is listed as an inventor on patents for pharmacogenetics and antiglucocorticoid use in the prediction of antidepressant response.

A version of this article first appeared on Medscape.com.

Weekly injections with the GLP-1 receptor agonist semaglutide helped people maintain, and even increase, their initial weight loss on the agent when they continued treatment beyond 20 weeks in results from an international, multicenter trial with 803 randomized subjects.

The study “reflects what we always see in practice, that when people lose weight their body then fights to regain it. The results underscore this” by showing what happens when people stop the drug, Domenica M. Rubino, MD, reported at the annual meeting of the Endocrine Society.

The STEP 4 study began with 902 obese or higher-risk people with an average body mass index of about 38 kg/m² who underwent a 20-week, open-label, run-in phase of weekly subcutaneous injections of semaglutide (Ozempic), during which all subjects gradually up-titrated to the study’s maintenance dosage of 2.4 mg/week and allowing investigators to weed out intolerant, noncompliant, or nonresponsive people. After this phase excluded 99 subjects from continuing, and documented that the remaining 803 patients had already lost an average of 11% of their starting weight, the core of the study kicked in by randomizing them 2:1 to either maintain their weekly semaglutide injections for another 48 weeks or change to placebo injections.

After 48 more weeks, the 535 people who continued active semaglutide treatment lost on average an additional 8% of their weight. Meanwhile, the 268 who switched to placebo gained 7% of the weight they had reached at the 20-week point, for a significant between-group weight-loss difference of about 15% for the study’s primary endpoint. Those maintained on semaglutide for the full 68 weeks had a cumulative average weight loss of about 17%, compared with when they first began treatment, Dr. Rubino said. Concurrently with her report, the results also appeared in an article published online in JAMA.

“It’s reassuring that people who remain on this treatment can sustain weight losses of 15%, and in some cases 20% or more. That’s huge,” Dr. Rubino said in an interview. . After 68 weeks, 40% of the people who maintained their semaglutide treatment had lost at least 20% of their weight, compared with when they first started treatment.

“Preventing weight regain following initial weight loss is a well-known major challenge for people who lose weight,” commented John Clark III, MD, PhD, a weight management specialist at the University of Texas Southwestern Medical Center in Dallas who was not involved with the study. The findings from STEP 4 will be “helpful to have a discussion [with weight-loss patients] about the risks and benefits of continuing to take this medication longer than just a few months and if they want to continue taking the medication after they reach their goal weight,” Dr. Clark noted in an interview. “This new information reinforces that treatment continues to be effective after the short term.”

“This is obesity 101. If a treatment is provided that targets mechanisms of obesity, and then the treatment stops, we should not be surprised that weight regain occurs,” commented Ania M. Jastreboff, MD, PhD, codirector of the Yale Center for Weight Management in New Haven, Conn. “It’s tragic to see patients who, after successful weight loss, suffer regain because the treatment by which they lost weight stopped,” she said in an interview.

The STEP 4 study ran at 73 centers in 10 countries during 2018-2020. It enrolled adults without diabetes and with a BMI of at least 30, or at least 27 if they also had at least one weight-related comorbidity such as hypertension, dyslipidemia, or obstructive sleep apnea. Participants averaged about 47 years of age, almost 80% were women, and about 84% were White, including 8% of Hispanic or Latinx ethnicity.

The adverse-event profile was consistent with findings from trials where semaglutide treated hyperglycemia in patients with type 2 diabetes (semaglutide at a maximum once-weekly dosage of 1 mg has Food and Drug Administration approval for controlling hyperglycemia in patients with type 2 diabetes), as well results from other semaglutide studies and from studies of other agents in the GLP-1 receptor agonist class.

In STEP 4 9% of patients who received semaglutide during the randomized phase and 7% of those randomized to placebo had a serious adverse reaction, and about 2% of those in both treatment arms stopped treatment because of an adverse event. The most common adverse events on semaglutide were gastrointestinal, with diarrhea in 14%, nausea in 14%, constipation in 12%, and vomiting in 10%.

These GI effects are often mitigated by slower dose escalation, eating smaller amounts of food at a time, and not eating beyond the point of feeling full, noted Dr. Jastreboff.

The STEP 4 results follow prior reports from three other large trials – STEP 1, STEP 2, and STEP 3 – that studied the weight-loss effects of weekly semaglutide treatment in adults using varying enrollment criteria and treatment designs. “We’ve seen very consistent results [across all four studies] for efficacy and safety,” said Dr. Rubino, who owns and directs the Washington Center for Weight Management & Research in Arlington, Va.

NovoNordisk, the company that markets semaglutide, submitted data from all four studies to the FDA late last year in an application for a new label for a weight loss indication at the 2.4-mg/week dosage. The company has said it expects an agency decision by June 2021.

Dr. Rubino has been an adviser and consultant to and a speaker on behalf of Novo Nordisk, and she has also been an investigator for studies sponsored by AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr. Clark had no disclosures. Dr. Jastreboff is consultant for and has received research funding from NovoNordisk, and she has also been a consultant to and/or received research from Eli Lilly and Boehringer Ingelheim.

[email protected]

Weekly injections with the GLP-1 receptor agonist semaglutide helped people maintain, and even increase, their initial weight loss on the agent when they continued treatment beyond 20 weeks in results from an international, multicenter trial with 803 randomized subjects.

The study “reflects what we always see in practice, that when people lose weight their body then fights to regain it. The results underscore this” by showing what happens when people stop the drug, Domenica M. Rubino, MD, reported at the annual meeting of the Endocrine Society.

The STEP 4 study began with 902 obese or higher-risk people with an average body mass index of about 38 kg/m² who underwent a 20-week, open-label, run-in phase of weekly subcutaneous injections of semaglutide (Ozempic), during which all subjects gradually up-titrated to the study’s maintenance dosage of 2.4 mg/week and allowing investigators to weed out intolerant, noncompliant, or nonresponsive people. After this phase excluded 99 subjects from continuing, and documented that the remaining 803 patients had already lost an average of 11% of their starting weight, the core of the study kicked in by randomizing them 2:1 to either maintain their weekly semaglutide injections for another 48 weeks or change to placebo injections.

After 48 more weeks, the 535 people who continued active semaglutide treatment lost on average an additional 8% of their weight. Meanwhile, the 268 who switched to placebo gained 7% of the weight they had reached at the 20-week point, for a significant between-group weight-loss difference of about 15% for the study’s primary endpoint. Those maintained on semaglutide for the full 68 weeks had a cumulative average weight loss of about 17%, compared with when they first began treatment, Dr. Rubino said. Concurrently with her report, the results also appeared in an article published online in JAMA.

“It’s reassuring that people who remain on this treatment can sustain weight losses of 15%, and in some cases 20% or more. That’s huge,” Dr. Rubino said in an interview. . After 68 weeks, 40% of the people who maintained their semaglutide treatment had lost at least 20% of their weight, compared with when they first started treatment.

“Preventing weight regain following initial weight loss is a well-known major challenge for people who lose weight,” commented John Clark III, MD, PhD, a weight management specialist at the University of Texas Southwestern Medical Center in Dallas who was not involved with the study. The findings from STEP 4 will be “helpful to have a discussion [with weight-loss patients] about the risks and benefits of continuing to take this medication longer than just a few months and if they want to continue taking the medication after they reach their goal weight,” Dr. Clark noted in an interview. “This new information reinforces that treatment continues to be effective after the short term.”

“This is obesity 101. If a treatment is provided that targets mechanisms of obesity, and then the treatment stops, we should not be surprised that weight regain occurs,” commented Ania M. Jastreboff, MD, PhD, codirector of the Yale Center for Weight Management in New Haven, Conn. “It’s tragic to see patients who, after successful weight loss, suffer regain because the treatment by which they lost weight stopped,” she said in an interview.

The STEP 4 study ran at 73 centers in 10 countries during 2018-2020. It enrolled adults without diabetes and with a BMI of at least 30, or at least 27 if they also had at least one weight-related comorbidity such as hypertension, dyslipidemia, or obstructive sleep apnea. Participants averaged about 47 years of age, almost 80% were women, and about 84% were White, including 8% of Hispanic or Latinx ethnicity.

The adverse-event profile was consistent with findings from trials where semaglutide treated hyperglycemia in patients with type 2 diabetes (semaglutide at a maximum once-weekly dosage of 1 mg has Food and Drug Administration approval for controlling hyperglycemia in patients with type 2 diabetes), as well results from other semaglutide studies and from studies of other agents in the GLP-1 receptor agonist class.

In STEP 4 9% of patients who received semaglutide during the randomized phase and 7% of those randomized to placebo had a serious adverse reaction, and about 2% of those in both treatment arms stopped treatment because of an adverse event. The most common adverse events on semaglutide were gastrointestinal, with diarrhea in 14%, nausea in 14%, constipation in 12%, and vomiting in 10%.

These GI effects are often mitigated by slower dose escalation, eating smaller amounts of food at a time, and not eating beyond the point of feeling full, noted Dr. Jastreboff.

The STEP 4 results follow prior reports from three other large trials – STEP 1, STEP 2, and STEP 3 – that studied the weight-loss effects of weekly semaglutide treatment in adults using varying enrollment criteria and treatment designs. “We’ve seen very consistent results [across all four studies] for efficacy and safety,” said Dr. Rubino, who owns and directs the Washington Center for Weight Management & Research in Arlington, Va.

NovoNordisk, the company that markets semaglutide, submitted data from all four studies to the FDA late last year in an application for a new label for a weight loss indication at the 2.4-mg/week dosage. The company has said it expects an agency decision by June 2021.

Dr. Rubino has been an adviser and consultant to and a speaker on behalf of Novo Nordisk, and she has also been an investigator for studies sponsored by AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr. Clark had no disclosures. Dr. Jastreboff is consultant for and has received research funding from NovoNordisk, and she has also been a consultant to and/or received research from Eli Lilly and Boehringer Ingelheim.

[email protected]

Weekly injections with the GLP-1 receptor agonist semaglutide helped people maintain, and even increase, their initial weight loss on the agent when they continued treatment beyond 20 weeks in results from an international, multicenter trial with 803 randomized subjects.

The study “reflects what we always see in practice, that when people lose weight their body then fights to regain it. The results underscore this” by showing what happens when people stop the drug, Domenica M. Rubino, MD, reported at the annual meeting of the Endocrine Society.

The STEP 4 study began with 902 obese or higher-risk people with an average body mass index of about 38 kg/m² who underwent a 20-week, open-label, run-in phase of weekly subcutaneous injections of semaglutide (Ozempic), during which all subjects gradually up-titrated to the study’s maintenance dosage of 2.4 mg/week and allowing investigators to weed out intolerant, noncompliant, or nonresponsive people. After this phase excluded 99 subjects from continuing, and documented that the remaining 803 patients had already lost an average of 11% of their starting weight, the core of the study kicked in by randomizing them 2:1 to either maintain their weekly semaglutide injections for another 48 weeks or change to placebo injections.

After 48 more weeks, the 535 people who continued active semaglutide treatment lost on average an additional 8% of their weight. Meanwhile, the 268 who switched to placebo gained 7% of the weight they had reached at the 20-week point, for a significant between-group weight-loss difference of about 15% for the study’s primary endpoint. Those maintained on semaglutide for the full 68 weeks had a cumulative average weight loss of about 17%, compared with when they first began treatment, Dr. Rubino said. Concurrently with her report, the results also appeared in an article published online in JAMA.

“It’s reassuring that people who remain on this treatment can sustain weight losses of 15%, and in some cases 20% or more. That’s huge,” Dr. Rubino said in an interview. . After 68 weeks, 40% of the people who maintained their semaglutide treatment had lost at least 20% of their weight, compared with when they first started treatment.

“Preventing weight regain following initial weight loss is a well-known major challenge for people who lose weight,” commented John Clark III, MD, PhD, a weight management specialist at the University of Texas Southwestern Medical Center in Dallas who was not involved with the study. The findings from STEP 4 will be “helpful to have a discussion [with weight-loss patients] about the risks and benefits of continuing to take this medication longer than just a few months and if they want to continue taking the medication after they reach their goal weight,” Dr. Clark noted in an interview. “This new information reinforces that treatment continues to be effective after the short term.”

“This is obesity 101. If a treatment is provided that targets mechanisms of obesity, and then the treatment stops, we should not be surprised that weight regain occurs,” commented Ania M. Jastreboff, MD, PhD, codirector of the Yale Center for Weight Management in New Haven, Conn. “It’s tragic to see patients who, after successful weight loss, suffer regain because the treatment by which they lost weight stopped,” she said in an interview.

The STEP 4 study ran at 73 centers in 10 countries during 2018-2020. It enrolled adults without diabetes and with a BMI of at least 30, or at least 27 if they also had at least one weight-related comorbidity such as hypertension, dyslipidemia, or obstructive sleep apnea. Participants averaged about 47 years of age, almost 80% were women, and about 84% were White, including 8% of Hispanic or Latinx ethnicity.

The adverse-event profile was consistent with findings from trials where semaglutide treated hyperglycemia in patients with type 2 diabetes (semaglutide at a maximum once-weekly dosage of 1 mg has Food and Drug Administration approval for controlling hyperglycemia in patients with type 2 diabetes), as well results from other semaglutide studies and from studies of other agents in the GLP-1 receptor agonist class.

In STEP 4 9% of patients who received semaglutide during the randomized phase and 7% of those randomized to placebo had a serious adverse reaction, and about 2% of those in both treatment arms stopped treatment because of an adverse event. The most common adverse events on semaglutide were gastrointestinal, with diarrhea in 14%, nausea in 14%, constipation in 12%, and vomiting in 10%.

These GI effects are often mitigated by slower dose escalation, eating smaller amounts of food at a time, and not eating beyond the point of feeling full, noted Dr. Jastreboff.

The STEP 4 results follow prior reports from three other large trials – STEP 1, STEP 2, and STEP 3 – that studied the weight-loss effects of weekly semaglutide treatment in adults using varying enrollment criteria and treatment designs. “We’ve seen very consistent results [across all four studies] for efficacy and safety,” said Dr. Rubino, who owns and directs the Washington Center for Weight Management & Research in Arlington, Va.

NovoNordisk, the company that markets semaglutide, submitted data from all four studies to the FDA late last year in an application for a new label for a weight loss indication at the 2.4-mg/week dosage. The company has said it expects an agency decision by June 2021.

Dr. Rubino has been an adviser and consultant to and a speaker on behalf of Novo Nordisk, and she has also been an investigator for studies sponsored by AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr. Clark had no disclosures. Dr. Jastreboff is consultant for and has received research funding from NovoNordisk, and she has also been a consultant to and/or received research from Eli Lilly and Boehringer Ingelheim.

[email protected]

For pregnant women, just half a cup of coffee a day may reduce neonatal birth size and body weight, according to a prospective study involving more than 2,500 women.

kjekol/thinkstock

That’s only 50 mg of a caffeine day, which falls below the upper threshold of 200 mg set by the American College of Obstetricians and Gynecologists, lead author Jessica Gleason, PhD, MPH, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md, and colleagues reported.

“Systematic reviews and meta-analyses have reported that maternal caffeine consumption, even in doses lower than 200 mg, is associated with a higher risk for low birth weight, small for gestational age (SGA), and fetal growth restriction, suggesting there may be no safe amount of caffeine during pregnancy,” the investigators wrote in JAMA Network Open.

Findings to date have been inconsistent, with a 2014 meta-analysis reporting contrary or null results in four out of nine studies.

Dr. Gleason and colleagues suggested that such discrepancies may be caused by uncontrolled confounding factors in some of the studies, such as smoking, as well as the inadequacy of self-reporting, which fails to incorporate variations in caffeine content between beverages, or differences in rates of metabolism between individuals.

“To our knowledge, no studies have examined the association between caffeine intake and neonatal anthropometric measures beyond weight, length, and head circumference, and few have analyzed plasma concentrations of caffeine and its metabolites or genetic variations in the rate of metabolism associated with neonatal size,” the investigators wrote.

Dr. Gleason and colleagues set out to address this knowledge gap with a prospective cohort study, including 2,055 nonsmoking women with low risk of birth defects who presented at 12 centers between 2009 and 2013. Mean participant age was 28.3 years and mean body mass index was 23.6. Races and ethnicities were represented almost evenly even across four groups: Hispanic (28.2%), White (27.4%), Black (25.2%), and Asian/Pacific Islander (19.2%). Rate of caffeine metabolism was defined by the single-nucleotide variant rs762551 (CYP1A2*1F), according to which, slightly more women had slow metabolism (52.7%) than fast metabolism (47.3%).

Women were enrolled at 8-13 weeks’ gestational age, at which time they underwent interviews and blood draws, allowing for measurement of caffeine and paraxanthine plasma levels, as well as self-reported caffeine consumption during the preceding week.

Over the course of six visits, fetal growth was observed via ultrasound. Medical records were used to determine birth weights and neonatal anthropometric measures, including fat and skin fold mass, body length, and circumferences of the thigh, arm, abdomen, and head.

Neonatal measurements were compared with plasma levels of caffeine and paraxanthine, both continuously and as quartiles (Q1, ≤ 28.3 ng/mL; Q2, 28.4-157.1 ng/mL; Q3, 157.2-658.8 ng/mL; Q4, > 658.8 ng/mL). Comparisons were also made with self-reported caffeine intake.

Women who reported drinking 1-50 mg of caffeine per day had neonates with smaller subscapular skin folds (beta = –0.14 mm; 95% confidence interval, –0.27 to -–0.01 mm), while those who reported more than 50 mg per day had newborns with lower birth weight (beta = –66 g; 95% CI, –121 to –10 g), and smaller circumferences of mid-upper thigh (beta = –0.32 cm; 95% CI, –0.55 to –0.09 cm), anterior thigh skin fold (beta = –0.24 mm; 95% CI, –0.47 to -.01 mm), and mid-upper arm (beta = –0.17 cm; 95% CI, –0.31 to –0.02 cm).

Caffeine plasma concentrations supported these findings.

Compared with women who had caffeine plasma concentrations in the lowest quartile, those in the highest quartile gave birth to neonates with shorter length (beta = –0.44 cm; P = .04 for trend) and lower body weight (beta = –84.3 g; P = .04 for trend), as well as smaller mid-upper arm circumference (beta = -0.25 cm; P = .02 for trend), mid-upper thigh circumference (beta = –0.29 cm; P = .07 for trend), and head circumference (beta = –0.28 cm; P < .001 for trend). A comparison of lower and upper paraxanthine quartiles revealed the similar trends, as did analyses of continuous measures.

“Our results suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine may be associated with decreased fetal growth,” the investigators concluded.

Sarah W. Prager, MD, of the University of Washington, Seattle, suggested that the findings “do not demonstrate that caffeine has a clinically meaningful negative clinical impact on newborn size and weight.”

She noted that there was no difference in the rate of SGA between plasma caffeine quartiles, and that most patients were thin, which may not accurately represent the U.S. population.

“Based on these new data, my take home message to patients would be that increasing amounts of caffeine can have a small but real impact on the size of their baby at birth, though it is unlikely to result in a diagnosis of SGA,” she said. “Pregnant patients may want to limit caffeine intake even more than the ACOG recommendation of 200 mg per day.”

According to Robert M. Silver, MD, of the University of Utah Health Sciences Center, Salt Lake City, “data from this study are of high quality, owing to the prospective cohort design, large numbers, assessment of biomarkers, and sophisticated analyses.”

Still, he urged a cautious interpretation from a clinical perspective.

“It is important to not overreact to these data,” he said. “The decrease in fetal growth associated with caffeine is small and may prove to be clinically meaningless. Accordingly, clinical recommendations regarding caffeine intake during pregnancy should not be modified solely based on this study.”

Dr. Silver suggested that the findings deserve additional investigation.

“These observations warrant further research about the effects of caffeine exposure during pregnancy,” he said. “Ideally, studies should assess the effect of caffeine exposure on fetal growth in various pregnancy epochs as well as on neonatal and childhood growth.”

The study was funded by the Intramural Research Program of the NICHD. Dr. Gerlanc is an employee of The Prospective Group, which was contracted to provide statistical support.

For pregnant women, just half a cup of coffee a day may reduce neonatal birth size and body weight, according to a prospective study involving more than 2,500 women.

kjekol/thinkstock

That’s only 50 mg of a caffeine day, which falls below the upper threshold of 200 mg set by the American College of Obstetricians and Gynecologists, lead author Jessica Gleason, PhD, MPH, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md, and colleagues reported.

“Systematic reviews and meta-analyses have reported that maternal caffeine consumption, even in doses lower than 200 mg, is associated with a higher risk for low birth weight, small for gestational age (SGA), and fetal growth restriction, suggesting there may be no safe amount of caffeine during pregnancy,” the investigators wrote in JAMA Network Open.

Findings to date have been inconsistent, with a 2014 meta-analysis reporting contrary or null results in four out of nine studies.

Dr. Gleason and colleagues suggested that such discrepancies may be caused by uncontrolled confounding factors in some of the studies, such as smoking, as well as the inadequacy of self-reporting, which fails to incorporate variations in caffeine content between beverages, or differences in rates of metabolism between individuals.

“To our knowledge, no studies have examined the association between caffeine intake and neonatal anthropometric measures beyond weight, length, and head circumference, and few have analyzed plasma concentrations of caffeine and its metabolites or genetic variations in the rate of metabolism associated with neonatal size,” the investigators wrote.

Dr. Gleason and colleagues set out to address this knowledge gap with a prospective cohort study, including 2,055 nonsmoking women with low risk of birth defects who presented at 12 centers between 2009 and 2013. Mean participant age was 28.3 years and mean body mass index was 23.6. Races and ethnicities were represented almost evenly even across four groups: Hispanic (28.2%), White (27.4%), Black (25.2%), and Asian/Pacific Islander (19.2%). Rate of caffeine metabolism was defined by the single-nucleotide variant rs762551 (CYP1A2*1F), according to which, slightly more women had slow metabolism (52.7%) than fast metabolism (47.3%).

Women were enrolled at 8-13 weeks’ gestational age, at which time they underwent interviews and blood draws, allowing for measurement of caffeine and paraxanthine plasma levels, as well as self-reported caffeine consumption during the preceding week.

Over the course of six visits, fetal growth was observed via ultrasound. Medical records were used to determine birth weights and neonatal anthropometric measures, including fat and skin fold mass, body length, and circumferences of the thigh, arm, abdomen, and head.

Neonatal measurements were compared with plasma levels of caffeine and paraxanthine, both continuously and as quartiles (Q1, ≤ 28.3 ng/mL; Q2, 28.4-157.1 ng/mL; Q3, 157.2-658.8 ng/mL; Q4, > 658.8 ng/mL). Comparisons were also made with self-reported caffeine intake.

Women who reported drinking 1-50 mg of caffeine per day had neonates with smaller subscapular skin folds (beta = –0.14 mm; 95% confidence interval, –0.27 to -–0.01 mm), while those who reported more than 50 mg per day had newborns with lower birth weight (beta = –66 g; 95% CI, –121 to –10 g), and smaller circumferences of mid-upper thigh (beta = –0.32 cm; 95% CI, –0.55 to –0.09 cm), anterior thigh skin fold (beta = –0.24 mm; 95% CI, –0.47 to -.01 mm), and mid-upper arm (beta = –0.17 cm; 95% CI, –0.31 to –0.02 cm).

Caffeine plasma concentrations supported these findings.

Compared with women who had caffeine plasma concentrations in the lowest quartile, those in the highest quartile gave birth to neonates with shorter length (beta = –0.44 cm; P = .04 for trend) and lower body weight (beta = –84.3 g; P = .04 for trend), as well as smaller mid-upper arm circumference (beta = -0.25 cm; P = .02 for trend), mid-upper thigh circumference (beta = –0.29 cm; P = .07 for trend), and head circumference (beta = –0.28 cm; P < .001 for trend). A comparison of lower and upper paraxanthine quartiles revealed the similar trends, as did analyses of continuous measures.

“Our results suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine may be associated with decreased fetal growth,” the investigators concluded.

Sarah W. Prager, MD, of the University of Washington, Seattle, suggested that the findings “do not demonstrate that caffeine has a clinically meaningful negative clinical impact on newborn size and weight.”

She noted that there was no difference in the rate of SGA between plasma caffeine quartiles, and that most patients were thin, which may not accurately represent the U.S. population.

“Based on these new data, my take home message to patients would be that increasing amounts of caffeine can have a small but real impact on the size of their baby at birth, though it is unlikely to result in a diagnosis of SGA,” she said. “Pregnant patients may want to limit caffeine intake even more than the ACOG recommendation of 200 mg per day.”

According to Robert M. Silver, MD, of the University of Utah Health Sciences Center, Salt Lake City, “data from this study are of high quality, owing to the prospective cohort design, large numbers, assessment of biomarkers, and sophisticated analyses.”

Still, he urged a cautious interpretation from a clinical perspective.

“It is important to not overreact to these data,” he said. “The decrease in fetal growth associated with caffeine is small and may prove to be clinically meaningless. Accordingly, clinical recommendations regarding caffeine intake during pregnancy should not be modified solely based on this study.”

Dr. Silver suggested that the findings deserve additional investigation.

“These observations warrant further research about the effects of caffeine exposure during pregnancy,” he said. “Ideally, studies should assess the effect of caffeine exposure on fetal growth in various pregnancy epochs as well as on neonatal and childhood growth.”

The study was funded by the Intramural Research Program of the NICHD. Dr. Gerlanc is an employee of The Prospective Group, which was contracted to provide statistical support.

For pregnant women, just half a cup of coffee a day may reduce neonatal birth size and body weight, according to a prospective study involving more than 2,500 women.

kjekol/thinkstock

That’s only 50 mg of a caffeine day, which falls below the upper threshold of 200 mg set by the American College of Obstetricians and Gynecologists, lead author Jessica Gleason, PhD, MPH, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md, and colleagues reported.

“Systematic reviews and meta-analyses have reported that maternal caffeine consumption, even in doses lower than 200 mg, is associated with a higher risk for low birth weight, small for gestational age (SGA), and fetal growth restriction, suggesting there may be no safe amount of caffeine during pregnancy,” the investigators wrote in JAMA Network Open.

Findings to date have been inconsistent, with a 2014 meta-analysis reporting contrary or null results in four out of nine studies.

Dr. Gleason and colleagues suggested that such discrepancies may be caused by uncontrolled confounding factors in some of the studies, such as smoking, as well as the inadequacy of self-reporting, which fails to incorporate variations in caffeine content between beverages, or differences in rates of metabolism between individuals.

“To our knowledge, no studies have examined the association between caffeine intake and neonatal anthropometric measures beyond weight, length, and head circumference, and few have analyzed plasma concentrations of caffeine and its metabolites or genetic variations in the rate of metabolism associated with neonatal size,” the investigators wrote.

Dr. Gleason and colleagues set out to address this knowledge gap with a prospective cohort study, including 2,055 nonsmoking women with low risk of birth defects who presented at 12 centers between 2009 and 2013. Mean participant age was 28.3 years and mean body mass index was 23.6. Races and ethnicities were represented almost evenly even across four groups: Hispanic (28.2%), White (27.4%), Black (25.2%), and Asian/Pacific Islander (19.2%). Rate of caffeine metabolism was defined by the single-nucleotide variant rs762551 (CYP1A2*1F), according to which, slightly more women had slow metabolism (52.7%) than fast metabolism (47.3%).

Women were enrolled at 8-13 weeks’ gestational age, at which time they underwent interviews and blood draws, allowing for measurement of caffeine and paraxanthine plasma levels, as well as self-reported caffeine consumption during the preceding week.

Over the course of six visits, fetal growth was observed via ultrasound. Medical records were used to determine birth weights and neonatal anthropometric measures, including fat and skin fold mass, body length, and circumferences of the thigh, arm, abdomen, and head.

Neonatal measurements were compared with plasma levels of caffeine and paraxanthine, both continuously and as quartiles (Q1, ≤ 28.3 ng/mL; Q2, 28.4-157.1 ng/mL; Q3, 157.2-658.8 ng/mL; Q4, > 658.8 ng/mL). Comparisons were also made with self-reported caffeine intake.

Women who reported drinking 1-50 mg of caffeine per day had neonates with smaller subscapular skin folds (beta = –0.14 mm; 95% confidence interval, –0.27 to -–0.01 mm), while those who reported more than 50 mg per day had newborns with lower birth weight (beta = –66 g; 95% CI, –121 to –10 g), and smaller circumferences of mid-upper thigh (beta = –0.32 cm; 95% CI, –0.55 to –0.09 cm), anterior thigh skin fold (beta = –0.24 mm; 95% CI, –0.47 to -.01 mm), and mid-upper arm (beta = –0.17 cm; 95% CI, –0.31 to –0.02 cm).

Caffeine plasma concentrations supported these findings.

Compared with women who had caffeine plasma concentrations in the lowest quartile, those in the highest quartile gave birth to neonates with shorter length (beta = –0.44 cm; P = .04 for trend) and lower body weight (beta = –84.3 g; P = .04 for trend), as well as smaller mid-upper arm circumference (beta = -0.25 cm; P = .02 for trend), mid-upper thigh circumference (beta = –0.29 cm; P = .07 for trend), and head circumference (beta = –0.28 cm; P < .001 for trend). A comparison of lower and upper paraxanthine quartiles revealed the similar trends, as did analyses of continuous measures.

“Our results suggest that caffeine consumption during pregnancy, even at levels much lower than the recommended 200 mg per day of caffeine may be associated with decreased fetal growth,” the investigators concluded.

Sarah W. Prager, MD, of the University of Washington, Seattle, suggested that the findings “do not demonstrate that caffeine has a clinically meaningful negative clinical impact on newborn size and weight.”

She noted that there was no difference in the rate of SGA between plasma caffeine quartiles, and that most patients were thin, which may not accurately represent the U.S. population.

“Based on these new data, my take home message to patients would be that increasing amounts of caffeine can have a small but real impact on the size of their baby at birth, though it is unlikely to result in a diagnosis of SGA,” she said. “Pregnant patients may want to limit caffeine intake even more than the ACOG recommendation of 200 mg per day.”

According to Robert M. Silver, MD, of the University of Utah Health Sciences Center, Salt Lake City, “data from this study are of high quality, owing to the prospective cohort design, large numbers, assessment of biomarkers, and sophisticated analyses.”

Still, he urged a cautious interpretation from a clinical perspective.

“It is important to not overreact to these data,” he said. “The decrease in fetal growth associated with caffeine is small and may prove to be clinically meaningless. Accordingly, clinical recommendations regarding caffeine intake during pregnancy should not be modified solely based on this study.”

Dr. Silver suggested that the findings deserve additional investigation.

“These observations warrant further research about the effects of caffeine exposure during pregnancy,” he said. “Ideally, studies should assess the effect of caffeine exposure on fetal growth in various pregnancy epochs as well as on neonatal and childhood growth.”

The study was funded by the Intramural Research Program of the NICHD. Dr. Gerlanc is an employee of The Prospective Group, which was contracted to provide statistical support.

The Food and Drug Administration has approved rilonacept (Arcalyst) to treat recurrent pericarditis and reduce the risk for recurrence in adults and children 12 years and older.

Approval of the weekly subcutaneous injection offers patients the first and only FDA-approved therapy for recurrent pericarditis, the agency said in a release.

Recurrent pericarditis is characterized by a remitting relapsing inflammation of the pericardium, and therapeutic options have been limited to NSAIDs, colchicine, and corticosteroids.

Rilonacept is a recombinant fusion protein that blocks interleukin-1 alpha and interleukin-1 beta signaling. It is already approved by the FDA to treat a group of rare inherited inflammatory diseases called cryopyrin-associated periodic syndromes.

The new indication is based on the pivotal phase 3 RHAPSODY trial in 86 patients with acute symptoms of recurrent pericarditis and systemic inflammation. After randomization, pericarditis recurred in 2 of 30 patients (7%) treated with rilonacept and in 23 of 31 patients (74%) treated with placebo, representing a 96% reduction in the relative risk for recurrence with rilonacept.

Patients who received rilonacept were also pain free or had minimal pain on 98% of trial days, whereas those who received placebo had minimal or no pain on 46% of trial days.

The most common adverse effects of rilonacept are injection-site reactions and upper-respiratory tract infections.

Serious, life-threatening infections have been reported in patients taking rilonacept, according to the FDA. Patients with active or chronic infections should not take the drug.

The FDA label also advises that patients should avoid live vaccines while taking rilonacept and that it should be discontinued if a hypersensitivity reaction occurs.

The commercial launch is expected in April, according to the company.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved rilonacept (Arcalyst) to treat recurrent pericarditis and reduce the risk for recurrence in adults and children 12 years and older.

Approval of the weekly subcutaneous injection offers patients the first and only FDA-approved therapy for recurrent pericarditis, the agency said in a release.

Recurrent pericarditis is characterized by a remitting relapsing inflammation of the pericardium, and therapeutic options have been limited to NSAIDs, colchicine, and corticosteroids.

Rilonacept is a recombinant fusion protein that blocks interleukin-1 alpha and interleukin-1 beta signaling. It is already approved by the FDA to treat a group of rare inherited inflammatory diseases called cryopyrin-associated periodic syndromes.

The new indication is based on the pivotal phase 3 RHAPSODY trial in 86 patients with acute symptoms of recurrent pericarditis and systemic inflammation. After randomization, pericarditis recurred in 2 of 30 patients (7%) treated with rilonacept and in 23 of 31 patients (74%) treated with placebo, representing a 96% reduction in the relative risk for recurrence with rilonacept.

Patients who received rilonacept were also pain free or had minimal pain on 98% of trial days, whereas those who received placebo had minimal or no pain on 46% of trial days.

The most common adverse effects of rilonacept are injection-site reactions and upper-respiratory tract infections.

Serious, life-threatening infections have been reported in patients taking rilonacept, according to the FDA. Patients with active or chronic infections should not take the drug.

The FDA label also advises that patients should avoid live vaccines while taking rilonacept and that it should be discontinued if a hypersensitivity reaction occurs.

The commercial launch is expected in April, according to the company.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved rilonacept (Arcalyst) to treat recurrent pericarditis and reduce the risk for recurrence in adults and children 12 years and older.

Approval of the weekly subcutaneous injection offers patients the first and only FDA-approved therapy for recurrent pericarditis, the agency said in a release.

Recurrent pericarditis is characterized by a remitting relapsing inflammation of the pericardium, and therapeutic options have been limited to NSAIDs, colchicine, and corticosteroids.

Rilonacept is a recombinant fusion protein that blocks interleukin-1 alpha and interleukin-1 beta signaling. It is already approved by the FDA to treat a group of rare inherited inflammatory diseases called cryopyrin-associated periodic syndromes.

The new indication is based on the pivotal phase 3 RHAPSODY trial in 86 patients with acute symptoms of recurrent pericarditis and systemic inflammation. After randomization, pericarditis recurred in 2 of 30 patients (7%) treated with rilonacept and in 23 of 31 patients (74%) treated with placebo, representing a 96% reduction in the relative risk for recurrence with rilonacept.

Patients who received rilonacept were also pain free or had minimal pain on 98% of trial days, whereas those who received placebo had minimal or no pain on 46% of trial days.

The most common adverse effects of rilonacept are injection-site reactions and upper-respiratory tract infections.

Serious, life-threatening infections have been reported in patients taking rilonacept, according to the FDA. Patients with active or chronic infections should not take the drug.

The FDA label also advises that patients should avoid live vaccines while taking rilonacept and that it should be discontinued if a hypersensitivity reaction occurs.

The commercial launch is expected in April, according to the company.

A version of this article first appeared on Medscape.com.

Background: Beta-blockers are underutilized in patients with both COPD and established cardiovascular indications for beta-blocker therapy, despite evidence suggesting overall benefit. Prior observational studies have associated beta-blockers with improved outcomes in COPD in the absence of cardiovascular indications; however, this has not been previously evaluated in a randomized trial.

Importantly, this trial excluded patients with established indications for beta-blocker therapy, and study findings should not be applied to this population.

Bottom line: Metoprolol is not associated with increased risk of COPD exacerbations, but is associated with increased severity of COPD exacerbations in patients with moderate to severe COPD who have no established indications for beta-blockers.

Citation: Dransfield MT et al. Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142.

Dr. Gerstenberger is a hospitalist and clinical assistant professor of medicine at the University of Utah, Salt Lake City.

Background: Beta-blockers are underutilized in patients with both COPD and established cardiovascular indications for beta-blocker therapy, despite evidence suggesting overall benefit. Prior observational studies have associated beta-blockers with improved outcomes in COPD in the absence of cardiovascular indications; however, this has not been previously evaluated in a randomized trial.

Importantly, this trial excluded patients with established indications for beta-blocker therapy, and study findings should not be applied to this population.

Bottom line: Metoprolol is not associated with increased risk of COPD exacerbations, but is associated with increased severity of COPD exacerbations in patients with moderate to severe COPD who have no established indications for beta-blockers.

Citation: Dransfield MT et al. Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142.

Dr. Gerstenberger is a hospitalist and clinical assistant professor of medicine at the University of Utah, Salt Lake City.

Background: Beta-blockers are underutilized in patients with both COPD and established cardiovascular indications for beta-blocker therapy, despite evidence suggesting overall benefit. Prior observational studies have associated beta-blockers with improved outcomes in COPD in the absence of cardiovascular indications; however, this has not been previously evaluated in a randomized trial.

Importantly, this trial excluded patients with established indications for beta-blocker therapy, and study findings should not be applied to this population.

Bottom line: Metoprolol is not associated with increased risk of COPD exacerbations, but is associated with increased severity of COPD exacerbations in patients with moderate to severe COPD who have no established indications for beta-blockers.

Citation: Dransfield MT et al. Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142.

Dr. Gerstenberger is a hospitalist and clinical assistant professor of medicine at the University of Utah, Salt Lake City.