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Study affirms better breast cancer outcomes when chemo comes first
New efficacy and safety data from the monarchE study show that chemotherapy administered before treatment with abemaciclib and estrogen therapy, led to a clinically meaningful improvement in invasive disease-free survival and distant relapse-free survival for women with HR-positive, ERBB2-negative, node-positive, early breast cancer at high risk of recurrence.
The study was published earlier this year in JAMA Oncology.
Neoadjuvant chemotherapy is often provided to such patients in hopes of achieving breast-conserving surgery. Although pathologic complete response rates can be higher than 50% after chemotherapy treatment in triple-negative and ERBB2-positive breast cancer, most patients with HR-positive and ERBB2-negative breast cancer have residual tumor at surgery after neoadjuvant chemotherapy, which is associated with an increased risk of recurrence.
“To our knowledge, abemaciclib is the first agent added to standard adjuvant estrogen therapy that has been shown to reduce the risk of recurrence in patients with HR-positive, ERBB2-negative early breast cancer with residual disease after neoadjuvant chemotherapy,” wrote the authors, who were led by Miguel Martin, MD, PhD, Hospital General Universitario Gregorio Marañon, Spain.
In 2021, Food and Drug Administration approved abemaciclib (Verzenio, Lilly) with endocrine therapy for the treatment of HR-positive/ERBB2-negative, node-positive, high-risk early breast cancer. Their decision was based on data from the monarchE study.
The study is at odds with the previously published Penelope-B study, which found no benefit from treatment with the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) after 42.8 months of follow-up. The authors suggest that the disparate outcomes may be due to pharmacological differences between the two drugs as well as different dosing schedules: In monarchE, patients received abemaciclib on a continuous basis, while patients in Penelope-B received palbociclib for 21 days, followed by 7 days off. The treatment duration was 2 years in monarchE and 1 year in Penelope-B. Abemaciclib can be dosed continuously because it is a stronger inhibitor of CDK4 versus CDK6 compared to abemaciclib, and in vitro studies suggest that continuous dosing could be a key factor in creating profound inhibition of DNA synthesis.
The monarchE study included 5,637 patients who were randomized to receive standard of care estrogen therapy for 5 years with or without abemaciclib (150 mg, twice per day) for 2 years; 36.5% received abemaciclib. The mean age was 49.9 years; 70.8% were White, 22.8% Asian, and 2.7% Black.
The abemaciclib group had a clinically and statistically significant benefit in invasive disease-free survival (IDFS) (hazard ratio, 0.61; nominal P < .001) and distant relapse-free survival (DRFS) (HR, 0.61; nominal P < .001). At 2 years, DRFS was 89.5% in the abemaciclib group and 82.8% in the estrogen therapy–only group. IDFS was 87.2% and 80.6%, respectively. Patients who underwent neoadjuvant chemotherapy had a similar safety profile to the estrogen therapy–only group, although there was a higher incidence of treatment-emergent adverse events. The most common were diarrhea, infections, neutropenia, and fatigue. The most frequent grade treatment-emergent adverse events (of at least 3) were neutropenia and leucopenia.
The researchers noted that patients who underwent neoadjuvant chemotherapy had a worse prognosis than the intent-to-treat arm, as evidenced by a higher risk of 2-year recurrence (19% versus 11%). Exploratory subgroup analyses revealed that treatment with abemaciclib and estrogen therapy conferred IDFS and DRFS benefits regardless of the pathological tumor size and number of positive axillary lymph nodes.
The study was limited by the fact that it was open label, and the subgroup analyses were not powered to find statistically significant associations.
Dr. Martin has received grants from Eli Lilly, which funded monarchE.
New efficacy and safety data from the monarchE study show that chemotherapy administered before treatment with abemaciclib and estrogen therapy, led to a clinically meaningful improvement in invasive disease-free survival and distant relapse-free survival for women with HR-positive, ERBB2-negative, node-positive, early breast cancer at high risk of recurrence.
The study was published earlier this year in JAMA Oncology.
Neoadjuvant chemotherapy is often provided to such patients in hopes of achieving breast-conserving surgery. Although pathologic complete response rates can be higher than 50% after chemotherapy treatment in triple-negative and ERBB2-positive breast cancer, most patients with HR-positive and ERBB2-negative breast cancer have residual tumor at surgery after neoadjuvant chemotherapy, which is associated with an increased risk of recurrence.
“To our knowledge, abemaciclib is the first agent added to standard adjuvant estrogen therapy that has been shown to reduce the risk of recurrence in patients with HR-positive, ERBB2-negative early breast cancer with residual disease after neoadjuvant chemotherapy,” wrote the authors, who were led by Miguel Martin, MD, PhD, Hospital General Universitario Gregorio Marañon, Spain.
In 2021, Food and Drug Administration approved abemaciclib (Verzenio, Lilly) with endocrine therapy for the treatment of HR-positive/ERBB2-negative, node-positive, high-risk early breast cancer. Their decision was based on data from the monarchE study.
The study is at odds with the previously published Penelope-B study, which found no benefit from treatment with the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) after 42.8 months of follow-up. The authors suggest that the disparate outcomes may be due to pharmacological differences between the two drugs as well as different dosing schedules: In monarchE, patients received abemaciclib on a continuous basis, while patients in Penelope-B received palbociclib for 21 days, followed by 7 days off. The treatment duration was 2 years in monarchE and 1 year in Penelope-B. Abemaciclib can be dosed continuously because it is a stronger inhibitor of CDK4 versus CDK6 compared to abemaciclib, and in vitro studies suggest that continuous dosing could be a key factor in creating profound inhibition of DNA synthesis.
The monarchE study included 5,637 patients who were randomized to receive standard of care estrogen therapy for 5 years with or without abemaciclib (150 mg, twice per day) for 2 years; 36.5% received abemaciclib. The mean age was 49.9 years; 70.8% were White, 22.8% Asian, and 2.7% Black.
The abemaciclib group had a clinically and statistically significant benefit in invasive disease-free survival (IDFS) (hazard ratio, 0.61; nominal P < .001) and distant relapse-free survival (DRFS) (HR, 0.61; nominal P < .001). At 2 years, DRFS was 89.5% in the abemaciclib group and 82.8% in the estrogen therapy–only group. IDFS was 87.2% and 80.6%, respectively. Patients who underwent neoadjuvant chemotherapy had a similar safety profile to the estrogen therapy–only group, although there was a higher incidence of treatment-emergent adverse events. The most common were diarrhea, infections, neutropenia, and fatigue. The most frequent grade treatment-emergent adverse events (of at least 3) were neutropenia and leucopenia.
The researchers noted that patients who underwent neoadjuvant chemotherapy had a worse prognosis than the intent-to-treat arm, as evidenced by a higher risk of 2-year recurrence (19% versus 11%). Exploratory subgroup analyses revealed that treatment with abemaciclib and estrogen therapy conferred IDFS and DRFS benefits regardless of the pathological tumor size and number of positive axillary lymph nodes.
The study was limited by the fact that it was open label, and the subgroup analyses were not powered to find statistically significant associations.
Dr. Martin has received grants from Eli Lilly, which funded monarchE.
New efficacy and safety data from the monarchE study show that chemotherapy administered before treatment with abemaciclib and estrogen therapy, led to a clinically meaningful improvement in invasive disease-free survival and distant relapse-free survival for women with HR-positive, ERBB2-negative, node-positive, early breast cancer at high risk of recurrence.
The study was published earlier this year in JAMA Oncology.
Neoadjuvant chemotherapy is often provided to such patients in hopes of achieving breast-conserving surgery. Although pathologic complete response rates can be higher than 50% after chemotherapy treatment in triple-negative and ERBB2-positive breast cancer, most patients with HR-positive and ERBB2-negative breast cancer have residual tumor at surgery after neoadjuvant chemotherapy, which is associated with an increased risk of recurrence.
“To our knowledge, abemaciclib is the first agent added to standard adjuvant estrogen therapy that has been shown to reduce the risk of recurrence in patients with HR-positive, ERBB2-negative early breast cancer with residual disease after neoadjuvant chemotherapy,” wrote the authors, who were led by Miguel Martin, MD, PhD, Hospital General Universitario Gregorio Marañon, Spain.
In 2021, Food and Drug Administration approved abemaciclib (Verzenio, Lilly) with endocrine therapy for the treatment of HR-positive/ERBB2-negative, node-positive, high-risk early breast cancer. Their decision was based on data from the monarchE study.
The study is at odds with the previously published Penelope-B study, which found no benefit from treatment with the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) after 42.8 months of follow-up. The authors suggest that the disparate outcomes may be due to pharmacological differences between the two drugs as well as different dosing schedules: In monarchE, patients received abemaciclib on a continuous basis, while patients in Penelope-B received palbociclib for 21 days, followed by 7 days off. The treatment duration was 2 years in monarchE and 1 year in Penelope-B. Abemaciclib can be dosed continuously because it is a stronger inhibitor of CDK4 versus CDK6 compared to abemaciclib, and in vitro studies suggest that continuous dosing could be a key factor in creating profound inhibition of DNA synthesis.
The monarchE study included 5,637 patients who were randomized to receive standard of care estrogen therapy for 5 years with or without abemaciclib (150 mg, twice per day) for 2 years; 36.5% received abemaciclib. The mean age was 49.9 years; 70.8% were White, 22.8% Asian, and 2.7% Black.
The abemaciclib group had a clinically and statistically significant benefit in invasive disease-free survival (IDFS) (hazard ratio, 0.61; nominal P < .001) and distant relapse-free survival (DRFS) (HR, 0.61; nominal P < .001). At 2 years, DRFS was 89.5% in the abemaciclib group and 82.8% in the estrogen therapy–only group. IDFS was 87.2% and 80.6%, respectively. Patients who underwent neoadjuvant chemotherapy had a similar safety profile to the estrogen therapy–only group, although there was a higher incidence of treatment-emergent adverse events. The most common were diarrhea, infections, neutropenia, and fatigue. The most frequent grade treatment-emergent adverse events (of at least 3) were neutropenia and leucopenia.
The researchers noted that patients who underwent neoadjuvant chemotherapy had a worse prognosis than the intent-to-treat arm, as evidenced by a higher risk of 2-year recurrence (19% versus 11%). Exploratory subgroup analyses revealed that treatment with abemaciclib and estrogen therapy conferred IDFS and DRFS benefits regardless of the pathological tumor size and number of positive axillary lymph nodes.
The study was limited by the fact that it was open label, and the subgroup analyses were not powered to find statistically significant associations.
Dr. Martin has received grants from Eli Lilly, which funded monarchE.
FROM JAMA ONCOLOGY
Four commonly abused drugs linked with atrial fibrillation
Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.
While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.
“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.
Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.
The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.
Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.
“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”
In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.
At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).
“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.
Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
Causal mechanisms deserve a closer look
Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.
“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”
Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.
Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.
“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”
Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.
“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”
Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.
“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”
The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.
Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.
While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.
“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.
Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.
The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.
Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.
“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”
In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.
At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).
“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.
Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
Causal mechanisms deserve a closer look
Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.
“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”
Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.
Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.
“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”
Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.
“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”
Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.
“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”
The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.
Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.
While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.
“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.
Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.
The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.
Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.
“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”
In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.
At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).
“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.
Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
Causal mechanisms deserve a closer look
Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.
“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”
Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.
Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.
“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”
Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.
“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”
Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.
“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”
The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.
FROM EUROPEAN HEART JOURNAL
Durvalumab combinations show tentative promise in NSCLC
in patients with unresectable stage 3 non–small-cell lung cancer.
Combinations of the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab led to improved overall response rate and progression-free survival compared to durvalumab alone.
The findings support further study in a phase 3 clinical trial, according to the authors of the study recently published in the Journal of Clinical Oncology.
Durvalumab is the standard treatment following consolidation therapy of chemoradiotherapy in unresectable stage 3 non–small-cell lung cancer (NSCLC). Although it extended progression-free survival (PFS) and overall survival in the PACIFIC phase 3 study, some patients experience a recurrence, which has led to exploration of immunotherapy combinations.
Oleclumab inhibits the enzyme CD73, found on the surfaces of both tumor and immune cells. Its activity leads to an immunosuppressive effect in the tumor microenvironment, and preclinical studies have shown that it can have an additive antitumor effect when combined with PD-1 or PD-L1 inhibitors. A phase 1 study also suggested efficacy. Monalizumab blocks interactions between major histocompatibility complex-E (HLA-E) and an inhibitor receptor. A number of tumors overexpress HLA-E, triggering inhibitor signals that inhibit natural killer and CD8+ T cells.
“COAST was an interesting study that, although not definitive, suggested that the combination of durvalumab with oleclumab or with monalizumab was more effective than durvalumab alone in the consolidation setting after definitive concurrent chemoradiation for patients with stage 3 unresectable NSCLC,” said Nathan Pennell, MD, PhD, who wrote an accompanying editorial.
Despite the positive signal, Dr. Pennell expressed some skepticism that the combinations would pass a phase 3 test. He questioned the choice of response rate as the primary endpoint of the phase 2 study, and noted that the durvalumab arm had worse progression-free survival (PFS) than the previous PACIFIC trial. It could be that the clinical characteristics of the study population differed between the two trials, in which case the improved objective response rate (ORR) and PFS results should be encouraging. It’s also possible the COAST trial’s small sample size led to a mismatch between the control and treatment group despite randomization, in which case the findings may not be valid.
“These are the kinds of issues that keep drug developers up at night. There really is no way to know which scenario is correct without doing the larger trial. I do hope though that the phase 3 trials have robust biomarker analysis including PDL1 to make sure the arms are as well matched for known prognostic and predictive markers as possible,” said Dr. Pennell, who is vice chair of clinical research at Taussig Cancer Institute.
The study details
The researchers randomized 189 patients to durvalumab, durvalumab plus oleclumab, or durvalumab plus monalizumab between January 2019 and July 2020. After a median follow-up of 11.5 months, there was a higher confirmed objective response rate in the durvalumab plus oleclumab group (30.0%; 95% confidence interval, 18.8%-43.2%) and the durvalumab plus monalizumab group (35.5%; 95% CI, 23.7%-48.7%) versus durvalumab alone (17.9%; 95% CI, 9.6%-29.2%).
Compared to durvalumab alone, there was improved PFS in both durvalumab plus oleclumab (stratified hazard ratio, 0.44; 95% CI, 0.26-0.75) and durvalumab plus monalizumab (HR, 0.42; 95% CI, 0.24-0.72). At 12 months, PFS was 62.6% (95% CI, 48.1-74.2%) for durvalumab plus oleclumab, 72.7% (95% CI, 58.8-82.6%) for durvalumab plus monalizumab, and 33.9% (95% CI, 21.2-47.1%) for durvalumab alone.
The study was funded by AstraZeneca.
in patients with unresectable stage 3 non–small-cell lung cancer.
Combinations of the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab led to improved overall response rate and progression-free survival compared to durvalumab alone.
The findings support further study in a phase 3 clinical trial, according to the authors of the study recently published in the Journal of Clinical Oncology.
Durvalumab is the standard treatment following consolidation therapy of chemoradiotherapy in unresectable stage 3 non–small-cell lung cancer (NSCLC). Although it extended progression-free survival (PFS) and overall survival in the PACIFIC phase 3 study, some patients experience a recurrence, which has led to exploration of immunotherapy combinations.
Oleclumab inhibits the enzyme CD73, found on the surfaces of both tumor and immune cells. Its activity leads to an immunosuppressive effect in the tumor microenvironment, and preclinical studies have shown that it can have an additive antitumor effect when combined with PD-1 or PD-L1 inhibitors. A phase 1 study also suggested efficacy. Monalizumab blocks interactions between major histocompatibility complex-E (HLA-E) and an inhibitor receptor. A number of tumors overexpress HLA-E, triggering inhibitor signals that inhibit natural killer and CD8+ T cells.
“COAST was an interesting study that, although not definitive, suggested that the combination of durvalumab with oleclumab or with monalizumab was more effective than durvalumab alone in the consolidation setting after definitive concurrent chemoradiation for patients with stage 3 unresectable NSCLC,” said Nathan Pennell, MD, PhD, who wrote an accompanying editorial.
Despite the positive signal, Dr. Pennell expressed some skepticism that the combinations would pass a phase 3 test. He questioned the choice of response rate as the primary endpoint of the phase 2 study, and noted that the durvalumab arm had worse progression-free survival (PFS) than the previous PACIFIC trial. It could be that the clinical characteristics of the study population differed between the two trials, in which case the improved objective response rate (ORR) and PFS results should be encouraging. It’s also possible the COAST trial’s small sample size led to a mismatch between the control and treatment group despite randomization, in which case the findings may not be valid.
“These are the kinds of issues that keep drug developers up at night. There really is no way to know which scenario is correct without doing the larger trial. I do hope though that the phase 3 trials have robust biomarker analysis including PDL1 to make sure the arms are as well matched for known prognostic and predictive markers as possible,” said Dr. Pennell, who is vice chair of clinical research at Taussig Cancer Institute.
The study details
The researchers randomized 189 patients to durvalumab, durvalumab plus oleclumab, or durvalumab plus monalizumab between January 2019 and July 2020. After a median follow-up of 11.5 months, there was a higher confirmed objective response rate in the durvalumab plus oleclumab group (30.0%; 95% confidence interval, 18.8%-43.2%) and the durvalumab plus monalizumab group (35.5%; 95% CI, 23.7%-48.7%) versus durvalumab alone (17.9%; 95% CI, 9.6%-29.2%).
Compared to durvalumab alone, there was improved PFS in both durvalumab plus oleclumab (stratified hazard ratio, 0.44; 95% CI, 0.26-0.75) and durvalumab plus monalizumab (HR, 0.42; 95% CI, 0.24-0.72). At 12 months, PFS was 62.6% (95% CI, 48.1-74.2%) for durvalumab plus oleclumab, 72.7% (95% CI, 58.8-82.6%) for durvalumab plus monalizumab, and 33.9% (95% CI, 21.2-47.1%) for durvalumab alone.
The study was funded by AstraZeneca.
in patients with unresectable stage 3 non–small-cell lung cancer.
Combinations of the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab led to improved overall response rate and progression-free survival compared to durvalumab alone.
The findings support further study in a phase 3 clinical trial, according to the authors of the study recently published in the Journal of Clinical Oncology.
Durvalumab is the standard treatment following consolidation therapy of chemoradiotherapy in unresectable stage 3 non–small-cell lung cancer (NSCLC). Although it extended progression-free survival (PFS) and overall survival in the PACIFIC phase 3 study, some patients experience a recurrence, which has led to exploration of immunotherapy combinations.
Oleclumab inhibits the enzyme CD73, found on the surfaces of both tumor and immune cells. Its activity leads to an immunosuppressive effect in the tumor microenvironment, and preclinical studies have shown that it can have an additive antitumor effect when combined with PD-1 or PD-L1 inhibitors. A phase 1 study also suggested efficacy. Monalizumab blocks interactions between major histocompatibility complex-E (HLA-E) and an inhibitor receptor. A number of tumors overexpress HLA-E, triggering inhibitor signals that inhibit natural killer and CD8+ T cells.
“COAST was an interesting study that, although not definitive, suggested that the combination of durvalumab with oleclumab or with monalizumab was more effective than durvalumab alone in the consolidation setting after definitive concurrent chemoradiation for patients with stage 3 unresectable NSCLC,” said Nathan Pennell, MD, PhD, who wrote an accompanying editorial.
Despite the positive signal, Dr. Pennell expressed some skepticism that the combinations would pass a phase 3 test. He questioned the choice of response rate as the primary endpoint of the phase 2 study, and noted that the durvalumab arm had worse progression-free survival (PFS) than the previous PACIFIC trial. It could be that the clinical characteristics of the study population differed between the two trials, in which case the improved objective response rate (ORR) and PFS results should be encouraging. It’s also possible the COAST trial’s small sample size led to a mismatch between the control and treatment group despite randomization, in which case the findings may not be valid.
“These are the kinds of issues that keep drug developers up at night. There really is no way to know which scenario is correct without doing the larger trial. I do hope though that the phase 3 trials have robust biomarker analysis including PDL1 to make sure the arms are as well matched for known prognostic and predictive markers as possible,” said Dr. Pennell, who is vice chair of clinical research at Taussig Cancer Institute.
The study details
The researchers randomized 189 patients to durvalumab, durvalumab plus oleclumab, or durvalumab plus monalizumab between January 2019 and July 2020. After a median follow-up of 11.5 months, there was a higher confirmed objective response rate in the durvalumab plus oleclumab group (30.0%; 95% confidence interval, 18.8%-43.2%) and the durvalumab plus monalizumab group (35.5%; 95% CI, 23.7%-48.7%) versus durvalumab alone (17.9%; 95% CI, 9.6%-29.2%).
Compared to durvalumab alone, there was improved PFS in both durvalumab plus oleclumab (stratified hazard ratio, 0.44; 95% CI, 0.26-0.75) and durvalumab plus monalizumab (HR, 0.42; 95% CI, 0.24-0.72). At 12 months, PFS was 62.6% (95% CI, 48.1-74.2%) for durvalumab plus oleclumab, 72.7% (95% CI, 58.8-82.6%) for durvalumab plus monalizumab, and 33.9% (95% CI, 21.2-47.1%) for durvalumab alone.
The study was funded by AstraZeneca.
FROM JOURNAL OF CLINICAL ONCOLOGY
FDA approves new immunotherapy combo for liver cancer
(HCC), the most common type of liver cancer.
The new combination comprises a single dose of tremelimumab (Imjudo, AstraZeneca) followed by treatment with durvalumab (Imfinzi, AstraZeneca) in what is known as the STRIDE (single-tremelimumab regular-interval durvalumab) regimen.
This marks the first worldwide approval for tremelimumab, which is a CTLA-4 antibody.
The other drug in the combination, durvalumab, is an anti-PDL1 antibody and is already approved by the FDA for use in several tumor types, including lung cancer, bladder cancer, and biliary tract cancers.
The STRIDE regimen is composed of a single 300-mg dose of tremelimumab followed by durvalumab 1,500 mg given every 4 weeks.
This regimen was used in the HIMALAYA phase 3 trial, which was published in June 2022 in the New England Journal of Medicine.
Results from this trial showed that 30% of patients treated with that combination were still alive at 3 years, compared with 20% of patients who were treated with the standard regimen, sorafenib.
“In addition to this regimen demonstrating a favorable 3-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease,” commented the principal investigator of this trial, Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center, New York.
“Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival,” he commented in a press release from the drug’s manufacturer, AstraZeneca.
When the results from this trial were presented earlier this year at the ASCO Gastrointestinal Cancers meeting, the discussant for that abstract, Anthony B. El-Khoueiry, MD, from the University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, suggested that the STRIDE regimen offers a new first-line treatment option for patients with advanced HCC.
He also made several comments about the design of the HIMALAYA trial, which has a third treatment arm in which patients received durvalumab alone. Dr. El-Khoueiry noted that single-agent durvalumab was noninferior to sorafenib, but he added that no conclusions could be drawn about the STRIDE regimen in comparison with durvalumab as a single agent, because the trial was not powered for that.
The STRIDE regimen showed a lower risk of bleeding in comparison with combinations that include VEGF inhibitors (such as bevacizumab), he said, but he also pointed out that this trial excluded patients with main portal vein thrombosis, who are at high risk of bleeding.
Details of adverse events
In the NEJM article, the trialists report that grade 3/4 treatment-emergent adverse events occurred in 50.5% of patients with STRIDE, 37.1% with durvalumab alone, and 52.4% of patients with sorafenib.
The manufacturer noted that severe and fatal immune-mediated adverse reactions may occur, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic reactions, and others.
The company also noted that among the patients with unresectable HCC in the HIMALAYA study who received the STRIDE regimen, the most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.
Serious adverse reactions occurred in 41% of patients and included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%).
Fatal adverse reactions occurred in 8% of patients who received the combination, including death (1%), intracranial hemorrhage (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%).
Permanent discontinuation of the treatment regimen because of an adverse reaction occurred in 14% of patients.
A version of this article first appeared on Medscape.com.
(HCC), the most common type of liver cancer.
The new combination comprises a single dose of tremelimumab (Imjudo, AstraZeneca) followed by treatment with durvalumab (Imfinzi, AstraZeneca) in what is known as the STRIDE (single-tremelimumab regular-interval durvalumab) regimen.
This marks the first worldwide approval for tremelimumab, which is a CTLA-4 antibody.
The other drug in the combination, durvalumab, is an anti-PDL1 antibody and is already approved by the FDA for use in several tumor types, including lung cancer, bladder cancer, and biliary tract cancers.
The STRIDE regimen is composed of a single 300-mg dose of tremelimumab followed by durvalumab 1,500 mg given every 4 weeks.
This regimen was used in the HIMALAYA phase 3 trial, which was published in June 2022 in the New England Journal of Medicine.
Results from this trial showed that 30% of patients treated with that combination were still alive at 3 years, compared with 20% of patients who were treated with the standard regimen, sorafenib.
“In addition to this regimen demonstrating a favorable 3-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease,” commented the principal investigator of this trial, Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center, New York.
“Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival,” he commented in a press release from the drug’s manufacturer, AstraZeneca.
When the results from this trial were presented earlier this year at the ASCO Gastrointestinal Cancers meeting, the discussant for that abstract, Anthony B. El-Khoueiry, MD, from the University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, suggested that the STRIDE regimen offers a new first-line treatment option for patients with advanced HCC.
He also made several comments about the design of the HIMALAYA trial, which has a third treatment arm in which patients received durvalumab alone. Dr. El-Khoueiry noted that single-agent durvalumab was noninferior to sorafenib, but he added that no conclusions could be drawn about the STRIDE regimen in comparison with durvalumab as a single agent, because the trial was not powered for that.
The STRIDE regimen showed a lower risk of bleeding in comparison with combinations that include VEGF inhibitors (such as bevacizumab), he said, but he also pointed out that this trial excluded patients with main portal vein thrombosis, who are at high risk of bleeding.
Details of adverse events
In the NEJM article, the trialists report that grade 3/4 treatment-emergent adverse events occurred in 50.5% of patients with STRIDE, 37.1% with durvalumab alone, and 52.4% of patients with sorafenib.
The manufacturer noted that severe and fatal immune-mediated adverse reactions may occur, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic reactions, and others.
The company also noted that among the patients with unresectable HCC in the HIMALAYA study who received the STRIDE regimen, the most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.
Serious adverse reactions occurred in 41% of patients and included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%).
Fatal adverse reactions occurred in 8% of patients who received the combination, including death (1%), intracranial hemorrhage (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%).
Permanent discontinuation of the treatment regimen because of an adverse reaction occurred in 14% of patients.
A version of this article first appeared on Medscape.com.
(HCC), the most common type of liver cancer.
The new combination comprises a single dose of tremelimumab (Imjudo, AstraZeneca) followed by treatment with durvalumab (Imfinzi, AstraZeneca) in what is known as the STRIDE (single-tremelimumab regular-interval durvalumab) regimen.
This marks the first worldwide approval for tremelimumab, which is a CTLA-4 antibody.
The other drug in the combination, durvalumab, is an anti-PDL1 antibody and is already approved by the FDA for use in several tumor types, including lung cancer, bladder cancer, and biliary tract cancers.
The STRIDE regimen is composed of a single 300-mg dose of tremelimumab followed by durvalumab 1,500 mg given every 4 weeks.
This regimen was used in the HIMALAYA phase 3 trial, which was published in June 2022 in the New England Journal of Medicine.
Results from this trial showed that 30% of patients treated with that combination were still alive at 3 years, compared with 20% of patients who were treated with the standard regimen, sorafenib.
“In addition to this regimen demonstrating a favorable 3-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease,” commented the principal investigator of this trial, Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center, New York.
“Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival,” he commented in a press release from the drug’s manufacturer, AstraZeneca.
When the results from this trial were presented earlier this year at the ASCO Gastrointestinal Cancers meeting, the discussant for that abstract, Anthony B. El-Khoueiry, MD, from the University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, suggested that the STRIDE regimen offers a new first-line treatment option for patients with advanced HCC.
He also made several comments about the design of the HIMALAYA trial, which has a third treatment arm in which patients received durvalumab alone. Dr. El-Khoueiry noted that single-agent durvalumab was noninferior to sorafenib, but he added that no conclusions could be drawn about the STRIDE regimen in comparison with durvalumab as a single agent, because the trial was not powered for that.
The STRIDE regimen showed a lower risk of bleeding in comparison with combinations that include VEGF inhibitors (such as bevacizumab), he said, but he also pointed out that this trial excluded patients with main portal vein thrombosis, who are at high risk of bleeding.
Details of adverse events
In the NEJM article, the trialists report that grade 3/4 treatment-emergent adverse events occurred in 50.5% of patients with STRIDE, 37.1% with durvalumab alone, and 52.4% of patients with sorafenib.
The manufacturer noted that severe and fatal immune-mediated adverse reactions may occur, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, dermatologic reactions, and others.
The company also noted that among the patients with unresectable HCC in the HIMALAYA study who received the STRIDE regimen, the most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.
Serious adverse reactions occurred in 41% of patients and included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%).
Fatal adverse reactions occurred in 8% of patients who received the combination, including death (1%), intracranial hemorrhage (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%).
Permanent discontinuation of the treatment regimen because of an adverse reaction occurred in 14% of patients.
A version of this article first appeared on Medscape.com.
Drug repurposing ‘fast track’ to new medicines for obesity, diabetes
for these two conditions.
The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.
Their findings suggest that:
- Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.
- Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.
- Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.
- Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.
Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research during an oral session at the International Congress on Obesity, the biennial congress of the World Obesity Federation, in Melbourne.
“New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity,” senior coauthor Murray Cairns, PhD, said in a press release from the ICO.
“Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders,” said Dr. Cairns, from the school of biomedical sciences and pharmacy at the University of Newcastle.
Matchmaking between individual, their genetic traits, and drugs
Dr. Cairns and senior coauthor William Reay, PhD, also from the school of biomedical sciences and pharmacy, have cofounded a company called PolygenRx.
The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is “essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors.”
It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, “are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene,” Dr. Cairns explained in an email.
“Complex traits,” he noted, “are associated with thousands of [genetic] variants that are common in people and have a cumulative effect.”
For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.
“By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions with controls, these studies have revealed regions of the genome and genes associated with the condition,” Dr. Cairns noted.
The pharmagenic enrichment score integrates a person’s genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.
“We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless),” Dr. Cairns explained.
From the PES score, “we have an estimate of each individual’s likelihood of a positive response to said drug,” he noted. “We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants.”
With this research, “we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk” for obesity and type 2 diabetes.
“Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans,” he said.
Next steps: Raising funds for clinical trials
“We would like to progress some of these compounds to preclinical and clinical trials,” Dr. Cairns said, “but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates.”
The authors have reported no relevant financial relationships. Dr. Reay and Dr. Cairns are cofounders of PolygenRx.
A version of this article first appeared on Medscape.com.
for these two conditions.
The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.
Their findings suggest that:
- Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.
- Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.
- Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.
- Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.
Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research during an oral session at the International Congress on Obesity, the biennial congress of the World Obesity Federation, in Melbourne.
“New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity,” senior coauthor Murray Cairns, PhD, said in a press release from the ICO.
“Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders,” said Dr. Cairns, from the school of biomedical sciences and pharmacy at the University of Newcastle.
Matchmaking between individual, their genetic traits, and drugs
Dr. Cairns and senior coauthor William Reay, PhD, also from the school of biomedical sciences and pharmacy, have cofounded a company called PolygenRx.
The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is “essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors.”
It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, “are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene,” Dr. Cairns explained in an email.
“Complex traits,” he noted, “are associated with thousands of [genetic] variants that are common in people and have a cumulative effect.”
For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.
“By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions with controls, these studies have revealed regions of the genome and genes associated with the condition,” Dr. Cairns noted.
The pharmagenic enrichment score integrates a person’s genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.
“We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless),” Dr. Cairns explained.
From the PES score, “we have an estimate of each individual’s likelihood of a positive response to said drug,” he noted. “We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants.”
With this research, “we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk” for obesity and type 2 diabetes.
“Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans,” he said.
Next steps: Raising funds for clinical trials
“We would like to progress some of these compounds to preclinical and clinical trials,” Dr. Cairns said, “but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates.”
The authors have reported no relevant financial relationships. Dr. Reay and Dr. Cairns are cofounders of PolygenRx.
A version of this article first appeared on Medscape.com.
for these two conditions.
The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.
Their findings suggest that:
- Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.
- Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.
- Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.
- Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.
Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research during an oral session at the International Congress on Obesity, the biennial congress of the World Obesity Federation, in Melbourne.
“New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity,” senior coauthor Murray Cairns, PhD, said in a press release from the ICO.
“Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders,” said Dr. Cairns, from the school of biomedical sciences and pharmacy at the University of Newcastle.
Matchmaking between individual, their genetic traits, and drugs
Dr. Cairns and senior coauthor William Reay, PhD, also from the school of biomedical sciences and pharmacy, have cofounded a company called PolygenRx.
The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is “essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors.”
It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, “are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene,” Dr. Cairns explained in an email.
“Complex traits,” he noted, “are associated with thousands of [genetic] variants that are common in people and have a cumulative effect.”
For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.
“By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions with controls, these studies have revealed regions of the genome and genes associated with the condition,” Dr. Cairns noted.
The pharmagenic enrichment score integrates a person’s genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.
“We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless),” Dr. Cairns explained.
From the PES score, “we have an estimate of each individual’s likelihood of a positive response to said drug,” he noted. “We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants.”
With this research, “we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk” for obesity and type 2 diabetes.
“Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans,” he said.
Next steps: Raising funds for clinical trials
“We would like to progress some of these compounds to preclinical and clinical trials,” Dr. Cairns said, “but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates.”
The authors have reported no relevant financial relationships. Dr. Reay and Dr. Cairns are cofounders of PolygenRx.
A version of this article first appeared on Medscape.com.
FROM ICO 2022
JAK inhibitors show no excess cardiovascular safety signal in French nationwide cohort
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF THE RHEUMATIC DISEASES
Nonhormonal drug fezolinetant found safe for hot flashes in yearlong study
The drug fezolinetant, a selective neurokinin-3 receptor antagonist under investigation for treatment of menopausal vasomotor symptoms, showed acceptable long-term safety and tolerability during a 1-year phase 3 randomized controlled trial, according to data presented at the annual meeting of the North American Menopause Society. The study, called SKYLIGHT 4, examined fezolinetant treatment, especially in terms of endometrial health.
The findings mean that fezolinetant “may help bridge a gap in the management of vasomotor symptoms,” according to lead author Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
This study was an important step in fezolinetant’s path toward potential approval by the Food and Drug Administration for vasomotor symptoms.
”Moderate and severe vasomotor symptoms can adversely affect quality of life of those affected and result in sleep disruption as well as increased risk for heart disease and other high-risk medical problems,” Dr. Neal-Perry said. “Although menopausal hormone therapy significantly improves vasomotor symptoms, it may not be desired or it may not be safe for some women,” resulting in gaps in care and a need for targeted, nonhormonal therapies for hot flashes. A planned study will also assess the safety of the drug in patients with a diagnosis of hormone-sensitive cancer and disorders that increase the risk for blood clots.
”Fezolinetant has a low side effect profile, it is a nonhormonal option, and it is selective for the neurons that trigger and mediate hot flashes,” Dr. Neal-Perry said.
Hot flashes are caused by kisspeptin, neurokinin B, and dynorphin neurons located in the hypothalamus. Fezolinetant works by selectively blocking the neurokinin 3 receptor (NK3R), which regulates a person’s sense of temperature, Dr. Neal-Perry explained. Overactivation of NK3R, resulting from low estrogen levels, plays a role in the hot flashes and cold sweats women experience during menopause.
Drug development for hot flashes ”has been hampered by a lack of knowledge regarding the biological cause,” Dr. Neal-Perry said. “Now that we have a robust understanding of the basic biology of hot flashes, we can develop novel, highly effective, and targeted therapy.”
This safety study involved 1,830 women, ages 40-65, who were experiencing menopausal vasomotor symptoms and were randomly assigned to one of three arms for 52 weeks: 45 mg of fezolinetant, 30 mg of fezolinetant, or a placebo once daily.
The primary endpoints included the percentage of women with endometrial hyperplasia, the percentage of women with endometrial cancer, and the frequency and severity of treatment-emergent adverse events (TEAEs). To meet the primary safety endpoint, no more than 1% of participants could have hyperplasia or malignancy, with an upper confidence interval boundary not greater than 4%. Women who met prespecified criteria for their endometrial health to be assessed, underwent endometrial biopsies at baseline and at the end of the study. Three independent pathologists analyzed the tissue without knowledge of which study arm each sample came from. Among the 599 endometrial biopsy samples, 0.5% of the 203 participants taking 45 mg fezolinetant had hyperplasia while none of the women in the other two arms did. Among the 210 women taking 30 mg of fezolinetant, 0.5% had a malignancy; no malignancies occurred in the other two arms.
Overall adverse events were similar across all three arms, including rates of adverse events leading to discontinuation. The most common adverse events were headache and COVID-19. TEAEs related to the drug were 18.1% in the 45-mg arm, 15.4% in the 30-mg arm, and 17.4% in the placebo arm. Serious adverse events were similar across all three arms, and only 0.5% of participants in the 45-mg arm experienced drug-related serious adverse events, compared with none of the women in the 30-mg arm and 0.2% of women in the placebo group.
”The frequency of transaminase elevations was low, and these TEAEs were generally isolated, transient, and resolved on treatment or with discontinuation,” the authors reported.
The next steps for fezolinetant will be to assess its effect on mood and quality of life measures related to vasomotor symptoms, Dr. Neal-Perry said.
Samantha Dunham, MD, a NAMS-certified menopause practitioner and an associate professor of obstetrics and gynecology at New York University, suggested the drug’s safety in the study is encouraging.
”As a medication that treats menopausal symptoms, the study confirmed there are no issues with the endometrium, or lining of the uterus, not that one would expect issues given the mechanism of action,” Dr. Dunham, also codirector of NYU Langone’s Center for Midlife Health and Menopause, said in an interview. Dr. Dunham was not involved in the study.
”Earlier versions of medication in this class have caused liver enzyme elevation.” The trial of this medication showed that there were only transient elevations in liver enzymes, which resolved upon cessation of the medication. Dr. Dunham said. ”If the medicine proves to be safe over long periods of time in different populations, this will be a very significant medication for treating menopausal vasomotor symptoms.”
The research was funded by Astellas Pharma. Dr. Dunham had no disclosures. Dr. Neal-Perry is a scientific advisory board member for Astellas and Ferring Pharmaceuticals, and has received research funding from Merck and Overa.
The drug fezolinetant, a selective neurokinin-3 receptor antagonist under investigation for treatment of menopausal vasomotor symptoms, showed acceptable long-term safety and tolerability during a 1-year phase 3 randomized controlled trial, according to data presented at the annual meeting of the North American Menopause Society. The study, called SKYLIGHT 4, examined fezolinetant treatment, especially in terms of endometrial health.
The findings mean that fezolinetant “may help bridge a gap in the management of vasomotor symptoms,” according to lead author Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
This study was an important step in fezolinetant’s path toward potential approval by the Food and Drug Administration for vasomotor symptoms.
”Moderate and severe vasomotor symptoms can adversely affect quality of life of those affected and result in sleep disruption as well as increased risk for heart disease and other high-risk medical problems,” Dr. Neal-Perry said. “Although menopausal hormone therapy significantly improves vasomotor symptoms, it may not be desired or it may not be safe for some women,” resulting in gaps in care and a need for targeted, nonhormonal therapies for hot flashes. A planned study will also assess the safety of the drug in patients with a diagnosis of hormone-sensitive cancer and disorders that increase the risk for blood clots.
”Fezolinetant has a low side effect profile, it is a nonhormonal option, and it is selective for the neurons that trigger and mediate hot flashes,” Dr. Neal-Perry said.
Hot flashes are caused by kisspeptin, neurokinin B, and dynorphin neurons located in the hypothalamus. Fezolinetant works by selectively blocking the neurokinin 3 receptor (NK3R), which regulates a person’s sense of temperature, Dr. Neal-Perry explained. Overactivation of NK3R, resulting from low estrogen levels, plays a role in the hot flashes and cold sweats women experience during menopause.
Drug development for hot flashes ”has been hampered by a lack of knowledge regarding the biological cause,” Dr. Neal-Perry said. “Now that we have a robust understanding of the basic biology of hot flashes, we can develop novel, highly effective, and targeted therapy.”
This safety study involved 1,830 women, ages 40-65, who were experiencing menopausal vasomotor symptoms and were randomly assigned to one of three arms for 52 weeks: 45 mg of fezolinetant, 30 mg of fezolinetant, or a placebo once daily.
The primary endpoints included the percentage of women with endometrial hyperplasia, the percentage of women with endometrial cancer, and the frequency and severity of treatment-emergent adverse events (TEAEs). To meet the primary safety endpoint, no more than 1% of participants could have hyperplasia or malignancy, with an upper confidence interval boundary not greater than 4%. Women who met prespecified criteria for their endometrial health to be assessed, underwent endometrial biopsies at baseline and at the end of the study. Three independent pathologists analyzed the tissue without knowledge of which study arm each sample came from. Among the 599 endometrial biopsy samples, 0.5% of the 203 participants taking 45 mg fezolinetant had hyperplasia while none of the women in the other two arms did. Among the 210 women taking 30 mg of fezolinetant, 0.5% had a malignancy; no malignancies occurred in the other two arms.
Overall adverse events were similar across all three arms, including rates of adverse events leading to discontinuation. The most common adverse events were headache and COVID-19. TEAEs related to the drug were 18.1% in the 45-mg arm, 15.4% in the 30-mg arm, and 17.4% in the placebo arm. Serious adverse events were similar across all three arms, and only 0.5% of participants in the 45-mg arm experienced drug-related serious adverse events, compared with none of the women in the 30-mg arm and 0.2% of women in the placebo group.
”The frequency of transaminase elevations was low, and these TEAEs were generally isolated, transient, and resolved on treatment or with discontinuation,” the authors reported.
The next steps for fezolinetant will be to assess its effect on mood and quality of life measures related to vasomotor symptoms, Dr. Neal-Perry said.
Samantha Dunham, MD, a NAMS-certified menopause practitioner and an associate professor of obstetrics and gynecology at New York University, suggested the drug’s safety in the study is encouraging.
”As a medication that treats menopausal symptoms, the study confirmed there are no issues with the endometrium, or lining of the uterus, not that one would expect issues given the mechanism of action,” Dr. Dunham, also codirector of NYU Langone’s Center for Midlife Health and Menopause, said in an interview. Dr. Dunham was not involved in the study.
”Earlier versions of medication in this class have caused liver enzyme elevation.” The trial of this medication showed that there were only transient elevations in liver enzymes, which resolved upon cessation of the medication. Dr. Dunham said. ”If the medicine proves to be safe over long periods of time in different populations, this will be a very significant medication for treating menopausal vasomotor symptoms.”
The research was funded by Astellas Pharma. Dr. Dunham had no disclosures. Dr. Neal-Perry is a scientific advisory board member for Astellas and Ferring Pharmaceuticals, and has received research funding from Merck and Overa.
The drug fezolinetant, a selective neurokinin-3 receptor antagonist under investigation for treatment of menopausal vasomotor symptoms, showed acceptable long-term safety and tolerability during a 1-year phase 3 randomized controlled trial, according to data presented at the annual meeting of the North American Menopause Society. The study, called SKYLIGHT 4, examined fezolinetant treatment, especially in terms of endometrial health.
The findings mean that fezolinetant “may help bridge a gap in the management of vasomotor symptoms,” according to lead author Genevieve Neal-Perry, MD, PhD, chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.
This study was an important step in fezolinetant’s path toward potential approval by the Food and Drug Administration for vasomotor symptoms.
”Moderate and severe vasomotor symptoms can adversely affect quality of life of those affected and result in sleep disruption as well as increased risk for heart disease and other high-risk medical problems,” Dr. Neal-Perry said. “Although menopausal hormone therapy significantly improves vasomotor symptoms, it may not be desired or it may not be safe for some women,” resulting in gaps in care and a need for targeted, nonhormonal therapies for hot flashes. A planned study will also assess the safety of the drug in patients with a diagnosis of hormone-sensitive cancer and disorders that increase the risk for blood clots.
”Fezolinetant has a low side effect profile, it is a nonhormonal option, and it is selective for the neurons that trigger and mediate hot flashes,” Dr. Neal-Perry said.
Hot flashes are caused by kisspeptin, neurokinin B, and dynorphin neurons located in the hypothalamus. Fezolinetant works by selectively blocking the neurokinin 3 receptor (NK3R), which regulates a person’s sense of temperature, Dr. Neal-Perry explained. Overactivation of NK3R, resulting from low estrogen levels, plays a role in the hot flashes and cold sweats women experience during menopause.
Drug development for hot flashes ”has been hampered by a lack of knowledge regarding the biological cause,” Dr. Neal-Perry said. “Now that we have a robust understanding of the basic biology of hot flashes, we can develop novel, highly effective, and targeted therapy.”
This safety study involved 1,830 women, ages 40-65, who were experiencing menopausal vasomotor symptoms and were randomly assigned to one of three arms for 52 weeks: 45 mg of fezolinetant, 30 mg of fezolinetant, or a placebo once daily.
The primary endpoints included the percentage of women with endometrial hyperplasia, the percentage of women with endometrial cancer, and the frequency and severity of treatment-emergent adverse events (TEAEs). To meet the primary safety endpoint, no more than 1% of participants could have hyperplasia or malignancy, with an upper confidence interval boundary not greater than 4%. Women who met prespecified criteria for their endometrial health to be assessed, underwent endometrial biopsies at baseline and at the end of the study. Three independent pathologists analyzed the tissue without knowledge of which study arm each sample came from. Among the 599 endometrial biopsy samples, 0.5% of the 203 participants taking 45 mg fezolinetant had hyperplasia while none of the women in the other two arms did. Among the 210 women taking 30 mg of fezolinetant, 0.5% had a malignancy; no malignancies occurred in the other two arms.
Overall adverse events were similar across all three arms, including rates of adverse events leading to discontinuation. The most common adverse events were headache and COVID-19. TEAEs related to the drug were 18.1% in the 45-mg arm, 15.4% in the 30-mg arm, and 17.4% in the placebo arm. Serious adverse events were similar across all three arms, and only 0.5% of participants in the 45-mg arm experienced drug-related serious adverse events, compared with none of the women in the 30-mg arm and 0.2% of women in the placebo group.
”The frequency of transaminase elevations was low, and these TEAEs were generally isolated, transient, and resolved on treatment or with discontinuation,” the authors reported.
The next steps for fezolinetant will be to assess its effect on mood and quality of life measures related to vasomotor symptoms, Dr. Neal-Perry said.
Samantha Dunham, MD, a NAMS-certified menopause practitioner and an associate professor of obstetrics and gynecology at New York University, suggested the drug’s safety in the study is encouraging.
”As a medication that treats menopausal symptoms, the study confirmed there are no issues with the endometrium, or lining of the uterus, not that one would expect issues given the mechanism of action,” Dr. Dunham, also codirector of NYU Langone’s Center for Midlife Health and Menopause, said in an interview. Dr. Dunham was not involved in the study.
”Earlier versions of medication in this class have caused liver enzyme elevation.” The trial of this medication showed that there were only transient elevations in liver enzymes, which resolved upon cessation of the medication. Dr. Dunham said. ”If the medicine proves to be safe over long periods of time in different populations, this will be a very significant medication for treating menopausal vasomotor symptoms.”
The research was funded by Astellas Pharma. Dr. Dunham had no disclosures. Dr. Neal-Perry is a scientific advisory board member for Astellas and Ferring Pharmaceuticals, and has received research funding from Merck and Overa.
FROM NAMS 2022
VTE prophylaxis overused in low-risk hospitalized patients
A majority of hospitalized patients at low risk for venous thromboembolism were unnecessarily treated with medication, based on data from more than 400 individuals.
Prevention of venous thromboembolism (VTE) is important, and current guidelines from the American College of Chest Physicians suggest that patients with high or moderate risk for VTE be treated with mechanical prophylaxis, and that pharmacological prophylaxis is not recommended for patients at high risk for bleeding, said Hui Chong Lau, MD, in a presentation at the annual meeting of the American College of Chest Physicians (CHEST).
However, the nature of VTE prophylaxis using a risk assessment score has not been explored, said Dr. Lau, a third-year resident in internal medicine at Crozer-Chester Medical Center, Upland, Penn.
Low-molecular-weight heparin (LWMH) and intermittent pneumatic compression are often used to reduce VTE risk during hospitalization, but for patients with low VTE risk, prophylaxis is not necessarily recommended, he said. In fact, overuse of chemical prophylaxis in low-risk patients can increase bleeding risk and contribute to patient discomfort in the form of additional needle sticks while hospitalized, Dr. Lau said in the presentation.
“We wanted to see how well physicians in the hospital used a risk assessment model to stratify patients,” and how well the patients were assigned to the correct prophylaxis, he explained.
Dr. Lau and colleagues reviewed data from 469 adult patients hospitalized at a single medical center who were hospitalized between January 2021 and June 2021. The researchers retrospectively performed risk assessment using the Padua prediction score. A score of less than 4 was considered low risk for VTE, and a score of 4 or higher was considered high risk.
In the study population, 180 patients were identified as low risk and 289 were considered high risk.
Based on the Padua score, 95% of the patients at high risk were on the correct prophylaxis, Dr. Lau said.
A total of 193 high-risk patients were on heparin. However, many of these patients had good kidney function, and could have been treated with enoxaparin instead; “this would have spared them two needle sticks per day,” Dr. Lau noted.
Of the 180 low-risk patients, 168 (93.3%) were on chemical prophylaxis, and should have been on mechanical prophylaxis, he said. Only 10 patients (5%) who were considered low risk were placed on mechanical prophylaxis.
Overall, 3.6% of all patients who received chemical VTE prophylaxis developed bleeding.
The results were limited by the retrospective design and use of data from a single center. However, the findings emphasize the need for better attention to VTE risk when considering prophylaxis, said Dr. Lau. “We have to have risk assessment every day,” during a hospital stay, and adjust treatment accordingly, he said.
he concluded.
Additional research is needed to better understand the potential consequences of overusing chemical VTE, including not only bleeding risk, but also financial costs and patient discomfort, he said.
The study received no outside funding. The researchers had no financial conflicts to disclose.
A majority of hospitalized patients at low risk for venous thromboembolism were unnecessarily treated with medication, based on data from more than 400 individuals.
Prevention of venous thromboembolism (VTE) is important, and current guidelines from the American College of Chest Physicians suggest that patients with high or moderate risk for VTE be treated with mechanical prophylaxis, and that pharmacological prophylaxis is not recommended for patients at high risk for bleeding, said Hui Chong Lau, MD, in a presentation at the annual meeting of the American College of Chest Physicians (CHEST).
However, the nature of VTE prophylaxis using a risk assessment score has not been explored, said Dr. Lau, a third-year resident in internal medicine at Crozer-Chester Medical Center, Upland, Penn.
Low-molecular-weight heparin (LWMH) and intermittent pneumatic compression are often used to reduce VTE risk during hospitalization, but for patients with low VTE risk, prophylaxis is not necessarily recommended, he said. In fact, overuse of chemical prophylaxis in low-risk patients can increase bleeding risk and contribute to patient discomfort in the form of additional needle sticks while hospitalized, Dr. Lau said in the presentation.
“We wanted to see how well physicians in the hospital used a risk assessment model to stratify patients,” and how well the patients were assigned to the correct prophylaxis, he explained.
Dr. Lau and colleagues reviewed data from 469 adult patients hospitalized at a single medical center who were hospitalized between January 2021 and June 2021. The researchers retrospectively performed risk assessment using the Padua prediction score. A score of less than 4 was considered low risk for VTE, and a score of 4 or higher was considered high risk.
In the study population, 180 patients were identified as low risk and 289 were considered high risk.
Based on the Padua score, 95% of the patients at high risk were on the correct prophylaxis, Dr. Lau said.
A total of 193 high-risk patients were on heparin. However, many of these patients had good kidney function, and could have been treated with enoxaparin instead; “this would have spared them two needle sticks per day,” Dr. Lau noted.
Of the 180 low-risk patients, 168 (93.3%) were on chemical prophylaxis, and should have been on mechanical prophylaxis, he said. Only 10 patients (5%) who were considered low risk were placed on mechanical prophylaxis.
Overall, 3.6% of all patients who received chemical VTE prophylaxis developed bleeding.
The results were limited by the retrospective design and use of data from a single center. However, the findings emphasize the need for better attention to VTE risk when considering prophylaxis, said Dr. Lau. “We have to have risk assessment every day,” during a hospital stay, and adjust treatment accordingly, he said.
he concluded.
Additional research is needed to better understand the potential consequences of overusing chemical VTE, including not only bleeding risk, but also financial costs and patient discomfort, he said.
The study received no outside funding. The researchers had no financial conflicts to disclose.
A majority of hospitalized patients at low risk for venous thromboembolism were unnecessarily treated with medication, based on data from more than 400 individuals.
Prevention of venous thromboembolism (VTE) is important, and current guidelines from the American College of Chest Physicians suggest that patients with high or moderate risk for VTE be treated with mechanical prophylaxis, and that pharmacological prophylaxis is not recommended for patients at high risk for bleeding, said Hui Chong Lau, MD, in a presentation at the annual meeting of the American College of Chest Physicians (CHEST).
However, the nature of VTE prophylaxis using a risk assessment score has not been explored, said Dr. Lau, a third-year resident in internal medicine at Crozer-Chester Medical Center, Upland, Penn.
Low-molecular-weight heparin (LWMH) and intermittent pneumatic compression are often used to reduce VTE risk during hospitalization, but for patients with low VTE risk, prophylaxis is not necessarily recommended, he said. In fact, overuse of chemical prophylaxis in low-risk patients can increase bleeding risk and contribute to patient discomfort in the form of additional needle sticks while hospitalized, Dr. Lau said in the presentation.
“We wanted to see how well physicians in the hospital used a risk assessment model to stratify patients,” and how well the patients were assigned to the correct prophylaxis, he explained.
Dr. Lau and colleagues reviewed data from 469 adult patients hospitalized at a single medical center who were hospitalized between January 2021 and June 2021. The researchers retrospectively performed risk assessment using the Padua prediction score. A score of less than 4 was considered low risk for VTE, and a score of 4 or higher was considered high risk.
In the study population, 180 patients were identified as low risk and 289 were considered high risk.
Based on the Padua score, 95% of the patients at high risk were on the correct prophylaxis, Dr. Lau said.
A total of 193 high-risk patients were on heparin. However, many of these patients had good kidney function, and could have been treated with enoxaparin instead; “this would have spared them two needle sticks per day,” Dr. Lau noted.
Of the 180 low-risk patients, 168 (93.3%) were on chemical prophylaxis, and should have been on mechanical prophylaxis, he said. Only 10 patients (5%) who were considered low risk were placed on mechanical prophylaxis.
Overall, 3.6% of all patients who received chemical VTE prophylaxis developed bleeding.
The results were limited by the retrospective design and use of data from a single center. However, the findings emphasize the need for better attention to VTE risk when considering prophylaxis, said Dr. Lau. “We have to have risk assessment every day,” during a hospital stay, and adjust treatment accordingly, he said.
he concluded.
Additional research is needed to better understand the potential consequences of overusing chemical VTE, including not only bleeding risk, but also financial costs and patient discomfort, he said.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM CHEST 2022
Rapid point-of-care test could help avoid inappropriate antibiotic prescribing
The fingerstick test, FebriDx, works by detecting myxovirus resistance protein A, which the body generates in response to viral infections, and C-reactive protein (CRP), which is associated with systemic bacterial or viral infection.
In a study of 520 adults and children with symptoms of acute respiratory illness who were treated in outpatient settings, the test correctly classified bacterial infections 93.2% of the time (95% confidence interval [CI], 84.9-97.0). The negative predictive value (NPV), or probability that a person with a negative test result was truly free of a bacterial infection, was 98.7% (95% CI, 96.9-99.4).
The findings of the study, which was sponsored by the test’s manufacturer, were published in JAMA Network Open).
The ability to rule out a bacterial cause “may provide clinicians with reassurance to withhold antibiotics when supported by the clinical assessment,” the researchers wrote.
They added that the ability to identify infections that may benefit from antibiotics and confidently rule out those that will not “is essential to optimizing clinical management and addressing global antimicrobial resistance.”
FDA concerned about false negative viral infection results
FebriDx has been cleared for sale in the United Kingdom, Europe, Canada, United Arab Emirates, Brazil, and Australia, according to the manufacturer, Australia-based Lumos Diagnostics.
However, the product is not available in the United States, where the Food and Drug Administration denied marketing clearance in July. In a news release, Lumos said the FDA determined that FebriDx did not demonstrate “substantial equivalence” to a predicate device and expressed concern that false negative viral infection results could lead to missed cases of COVID-19.
In the newly published study, FebriDx identified individuals with viral infections 70.3% of the time (95% CI, 64.8-75.2). The probability that a person who tested negative for a viral infection was truly negative was 66.7% (95%CI, 60.8-72.1).
The study included patients with respiratory symptoms and recent fever who were enrolled from October 2019 to April 2021 at nine emergency departments, six urgent care clinics, and five primary care clinics in the United States. All patients were tested with FebriDx and underwent separate laboratory testing to determine a final diagnosis.
In addition, researchers recruited a control group of 120 individuals without symptoms.
Among 496 symptomatic individuals who had a final diagnosis, 73 (14.7%) were classified as having a response associated with a bacterial infection, 296 (59.7%) as having a viral-associated response, and 127 (25.6%) as negative.
FebriDx correctly ruled out a bacterial infection 88.4% of the time (95% CI, 85.0-91.1). The probability that a patient with a positive result for bacterial infection actually had a bacterial infection was 58.1% (95%CI, 49.1-66.7).
The findings bolster those of a previous study on the same test. This research included 220 patients who reported having a fever within the prior 3 days or had a measurable fever at the time of enrollment. In that study, the test correctly identified bacterial infections 85% of the time and correctly ruled out bacterial infection 93% of the time, with a NPV of 97%.
Too early to say test will be useful in practice
The idea of a test to guide the prescribing of antibiotics isn’t new, according to an expert who was not involved in FebriDx research.
Noah Ivers, MD, PhD, a family physician and associate professor at the University of Toronto who studies strategies to optimize primary care delivery, said, “many such point-of-care tests have been tried” to detect biomarkers such as CRP or procalcitonin, which is associated with bacterial infections.
Such tests have looked good in initial studies, he said, but when trialed in urgent care clinics, primary care clinics, or emergency departments, “they tend run into implementation challenges or simply lack of effects, or both.
“So, while I am happy at the news of this result, it’s too early to say with any certainty that it will prove useful in practice,” he added.
Meanwhile, Dr. Ivers said it’s “crucial that people understand that most illnesses are likely to be viral” and therefore not helped by antibiotics. When antibiotics are needed for outpatients, he said, “5 days is usually ample.”
The study was funded by Lumos Diagnostics. Among the 15 study authors, 6 had conflicts of interest disclosures, reporting ties to Inflammatix, Medical College of Wisconsin, Siemens, Technomics Research, and Lumos Diagnostics. Dr. Ivers reported no relevant financial interests.
The fingerstick test, FebriDx, works by detecting myxovirus resistance protein A, which the body generates in response to viral infections, and C-reactive protein (CRP), which is associated with systemic bacterial or viral infection.
In a study of 520 adults and children with symptoms of acute respiratory illness who were treated in outpatient settings, the test correctly classified bacterial infections 93.2% of the time (95% confidence interval [CI], 84.9-97.0). The negative predictive value (NPV), or probability that a person with a negative test result was truly free of a bacterial infection, was 98.7% (95% CI, 96.9-99.4).
The findings of the study, which was sponsored by the test’s manufacturer, were published in JAMA Network Open).
The ability to rule out a bacterial cause “may provide clinicians with reassurance to withhold antibiotics when supported by the clinical assessment,” the researchers wrote.
They added that the ability to identify infections that may benefit from antibiotics and confidently rule out those that will not “is essential to optimizing clinical management and addressing global antimicrobial resistance.”
FDA concerned about false negative viral infection results
FebriDx has been cleared for sale in the United Kingdom, Europe, Canada, United Arab Emirates, Brazil, and Australia, according to the manufacturer, Australia-based Lumos Diagnostics.
However, the product is not available in the United States, where the Food and Drug Administration denied marketing clearance in July. In a news release, Lumos said the FDA determined that FebriDx did not demonstrate “substantial equivalence” to a predicate device and expressed concern that false negative viral infection results could lead to missed cases of COVID-19.
In the newly published study, FebriDx identified individuals with viral infections 70.3% of the time (95% CI, 64.8-75.2). The probability that a person who tested negative for a viral infection was truly negative was 66.7% (95%CI, 60.8-72.1).
The study included patients with respiratory symptoms and recent fever who were enrolled from October 2019 to April 2021 at nine emergency departments, six urgent care clinics, and five primary care clinics in the United States. All patients were tested with FebriDx and underwent separate laboratory testing to determine a final diagnosis.
In addition, researchers recruited a control group of 120 individuals without symptoms.
Among 496 symptomatic individuals who had a final diagnosis, 73 (14.7%) were classified as having a response associated with a bacterial infection, 296 (59.7%) as having a viral-associated response, and 127 (25.6%) as negative.
FebriDx correctly ruled out a bacterial infection 88.4% of the time (95% CI, 85.0-91.1). The probability that a patient with a positive result for bacterial infection actually had a bacterial infection was 58.1% (95%CI, 49.1-66.7).
The findings bolster those of a previous study on the same test. This research included 220 patients who reported having a fever within the prior 3 days or had a measurable fever at the time of enrollment. In that study, the test correctly identified bacterial infections 85% of the time and correctly ruled out bacterial infection 93% of the time, with a NPV of 97%.
Too early to say test will be useful in practice
The idea of a test to guide the prescribing of antibiotics isn’t new, according to an expert who was not involved in FebriDx research.
Noah Ivers, MD, PhD, a family physician and associate professor at the University of Toronto who studies strategies to optimize primary care delivery, said, “many such point-of-care tests have been tried” to detect biomarkers such as CRP or procalcitonin, which is associated with bacterial infections.
Such tests have looked good in initial studies, he said, but when trialed in urgent care clinics, primary care clinics, or emergency departments, “they tend run into implementation challenges or simply lack of effects, or both.
“So, while I am happy at the news of this result, it’s too early to say with any certainty that it will prove useful in practice,” he added.
Meanwhile, Dr. Ivers said it’s “crucial that people understand that most illnesses are likely to be viral” and therefore not helped by antibiotics. When antibiotics are needed for outpatients, he said, “5 days is usually ample.”
The study was funded by Lumos Diagnostics. Among the 15 study authors, 6 had conflicts of interest disclosures, reporting ties to Inflammatix, Medical College of Wisconsin, Siemens, Technomics Research, and Lumos Diagnostics. Dr. Ivers reported no relevant financial interests.
The fingerstick test, FebriDx, works by detecting myxovirus resistance protein A, which the body generates in response to viral infections, and C-reactive protein (CRP), which is associated with systemic bacterial or viral infection.
In a study of 520 adults and children with symptoms of acute respiratory illness who were treated in outpatient settings, the test correctly classified bacterial infections 93.2% of the time (95% confidence interval [CI], 84.9-97.0). The negative predictive value (NPV), or probability that a person with a negative test result was truly free of a bacterial infection, was 98.7% (95% CI, 96.9-99.4).
The findings of the study, which was sponsored by the test’s manufacturer, were published in JAMA Network Open).
The ability to rule out a bacterial cause “may provide clinicians with reassurance to withhold antibiotics when supported by the clinical assessment,” the researchers wrote.
They added that the ability to identify infections that may benefit from antibiotics and confidently rule out those that will not “is essential to optimizing clinical management and addressing global antimicrobial resistance.”
FDA concerned about false negative viral infection results
FebriDx has been cleared for sale in the United Kingdom, Europe, Canada, United Arab Emirates, Brazil, and Australia, according to the manufacturer, Australia-based Lumos Diagnostics.
However, the product is not available in the United States, where the Food and Drug Administration denied marketing clearance in July. In a news release, Lumos said the FDA determined that FebriDx did not demonstrate “substantial equivalence” to a predicate device and expressed concern that false negative viral infection results could lead to missed cases of COVID-19.
In the newly published study, FebriDx identified individuals with viral infections 70.3% of the time (95% CI, 64.8-75.2). The probability that a person who tested negative for a viral infection was truly negative was 66.7% (95%CI, 60.8-72.1).
The study included patients with respiratory symptoms and recent fever who were enrolled from October 2019 to April 2021 at nine emergency departments, six urgent care clinics, and five primary care clinics in the United States. All patients were tested with FebriDx and underwent separate laboratory testing to determine a final diagnosis.
In addition, researchers recruited a control group of 120 individuals without symptoms.
Among 496 symptomatic individuals who had a final diagnosis, 73 (14.7%) were classified as having a response associated with a bacterial infection, 296 (59.7%) as having a viral-associated response, and 127 (25.6%) as negative.
FebriDx correctly ruled out a bacterial infection 88.4% of the time (95% CI, 85.0-91.1). The probability that a patient with a positive result for bacterial infection actually had a bacterial infection was 58.1% (95%CI, 49.1-66.7).
The findings bolster those of a previous study on the same test. This research included 220 patients who reported having a fever within the prior 3 days or had a measurable fever at the time of enrollment. In that study, the test correctly identified bacterial infections 85% of the time and correctly ruled out bacterial infection 93% of the time, with a NPV of 97%.
Too early to say test will be useful in practice
The idea of a test to guide the prescribing of antibiotics isn’t new, according to an expert who was not involved in FebriDx research.
Noah Ivers, MD, PhD, a family physician and associate professor at the University of Toronto who studies strategies to optimize primary care delivery, said, “many such point-of-care tests have been tried” to detect biomarkers such as CRP or procalcitonin, which is associated with bacterial infections.
Such tests have looked good in initial studies, he said, but when trialed in urgent care clinics, primary care clinics, or emergency departments, “they tend run into implementation challenges or simply lack of effects, or both.
“So, while I am happy at the news of this result, it’s too early to say with any certainty that it will prove useful in practice,” he added.
Meanwhile, Dr. Ivers said it’s “crucial that people understand that most illnesses are likely to be viral” and therefore not helped by antibiotics. When antibiotics are needed for outpatients, he said, “5 days is usually ample.”
The study was funded by Lumos Diagnostics. Among the 15 study authors, 6 had conflicts of interest disclosures, reporting ties to Inflammatix, Medical College of Wisconsin, Siemens, Technomics Research, and Lumos Diagnostics. Dr. Ivers reported no relevant financial interests.
FROM JAMA NETWORK OPEN
Apixaban outmatches rivaroxaban in patients with AFib and valvular heart disease
Compared with rivaroxaban, apixaban cut risks nearly in half, suggesting that clinicians should consider these new data when choosing an anticoagulant, reported lead author Ghadeer K. Dawwas, PhD, of the University of Pennsylvania, Philadelphia, and colleagues.
In the new retrospective study involving almost 20,000 patients, Dr. Dawwas and her colleagues “emulated a target trial” using private insurance claims from Optum’s deidentified Clinformatics Data Mart Database. The cohort was narrowed from a screened population of 58,210 patients with concurrent AFib and VHD to 9,947 new apixaban users who could be closely matched with 9,947 new rivaroxaban users. Covariates included provider specialty, type of VHD, demographic characteristics, measures of health care use, baseline use of medications, and baseline comorbidities.
The primary effectiveness outcome was a composite of systemic embolism and ischemic stroke, while the primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
“Although several ongoing trials aim to compare apixaban with warfarin in patients with AFib and VHD, none of these trials will directly compare apixaban and rivaroxaban,” the investigators wrote. Their report is in Annals of Internal Medicine.
Dr. Dawwas and colleagues previously showed that direct oral anticoagulants (DOACs) were safer and more effective than warfarin in the same patient population. Comparing apixaban and rivaroxaban – the two most common DOACs – was the next logical step, Dr. Dawwas said in an interview.
Study results
Compared with rivaroxaban, patients who received apixaban had a 43% reduced risk of stroke or embolism (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40-0.80). Apixaban’s ability to protect against bleeding appeared even more pronounced, with a 49% reduced risk over rivaroxaban (HR, 0.51; 95% CI, 0.41-0.62).
Comparing the two agents on an absolute basis, apixaban reduced risk of embolism or stroke by 0.2% within the first 6 months of treatment initiation, and 1.1% within the first year of initiation. At the same time points, absolute risk reductions for bleeding were 1.2% and 1.9%, respectively.
The investigators noted that their results held consistent in an alternative analysis that considered separate types of VHD.
“Based on the results from our analysis, we showed that apixaban is effective and safe in patients with atrial fibrillation and valvular heart diseases,” Dr. Dawwas said.
Head-to-head trial needed to change practice
Christopher M. Bianco, DO, associate professor of medicine at West Virginia University Heart and Vascular Institute, Morgantown, said the findings “add to the growing body of literature,” but “a head-to-head trial would be necessary to make a definitive change to clinical practice.”
Dr. Bianco, who recently conducted a retrospective analysis of apixaban and rivaroxaban that found no difference in safety and efficacy among a different patient population, said these kinds of studies are helpful in generating hypotheses, but they can’t account for all relevant clinical factors.
“There are just so many things that go into the decision-making process of [prescribing] apixaban and rivaroxaban,” he said. “Even though [Dr. Dawwas and colleagues] used propensity matching, you’re never going to be able to sort that out with a retrospective analysis.”
Specifically, Dr. Bianco noted that the findings did not include dose data. This is a key gap, he said, considering how often real-world datasets have shown that providers underdose DOACs for a number of unaccountable reasons, and how frequently patients exhibit poor adherence.
The study also lacked detail concerning the degree of renal dysfunction, which can determine drug eligibility, Dr. Bianco said. Furthermore, attempts to stratify patients based on thrombosis and bleeding risk were likely “insufficient,” he added.
Dr. Bianco also cautioned that the investigators defined valvular heart disease as any valve-related disease of any severity. In contrast, previous studies have generally restricted valvular heart disease to patients with mitral stenosis or prosthetic valves.
“This is definitely not the traditional definition of valvular heart disease, so the title is a little bit misleading in that sense, although they certainly do disclose that in the methods,” Dr. Bianco said.
On a more positive note, he highlighted the size of the patient population, and the real-world data, which included many patients who would be excluded from clinical trials.
More broadly, the study helps drive research forward, Dr. Bianco concluded; namely, by attracting financial support for a more powerful head-to-head trial that drug makers are unlikely to fund due to inherent market risk.
This study was supported by the National Institutes of Health. The investigators disclosed additional relationships with Takeda, Spark, Sanofi, and others. Dr. Bianco disclosed no conflicts of interest.
Compared with rivaroxaban, apixaban cut risks nearly in half, suggesting that clinicians should consider these new data when choosing an anticoagulant, reported lead author Ghadeer K. Dawwas, PhD, of the University of Pennsylvania, Philadelphia, and colleagues.
In the new retrospective study involving almost 20,000 patients, Dr. Dawwas and her colleagues “emulated a target trial” using private insurance claims from Optum’s deidentified Clinformatics Data Mart Database. The cohort was narrowed from a screened population of 58,210 patients with concurrent AFib and VHD to 9,947 new apixaban users who could be closely matched with 9,947 new rivaroxaban users. Covariates included provider specialty, type of VHD, demographic characteristics, measures of health care use, baseline use of medications, and baseline comorbidities.
The primary effectiveness outcome was a composite of systemic embolism and ischemic stroke, while the primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
“Although several ongoing trials aim to compare apixaban with warfarin in patients with AFib and VHD, none of these trials will directly compare apixaban and rivaroxaban,” the investigators wrote. Their report is in Annals of Internal Medicine.
Dr. Dawwas and colleagues previously showed that direct oral anticoagulants (DOACs) were safer and more effective than warfarin in the same patient population. Comparing apixaban and rivaroxaban – the two most common DOACs – was the next logical step, Dr. Dawwas said in an interview.
Study results
Compared with rivaroxaban, patients who received apixaban had a 43% reduced risk of stroke or embolism (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40-0.80). Apixaban’s ability to protect against bleeding appeared even more pronounced, with a 49% reduced risk over rivaroxaban (HR, 0.51; 95% CI, 0.41-0.62).
Comparing the two agents on an absolute basis, apixaban reduced risk of embolism or stroke by 0.2% within the first 6 months of treatment initiation, and 1.1% within the first year of initiation. At the same time points, absolute risk reductions for bleeding were 1.2% and 1.9%, respectively.
The investigators noted that their results held consistent in an alternative analysis that considered separate types of VHD.
“Based on the results from our analysis, we showed that apixaban is effective and safe in patients with atrial fibrillation and valvular heart diseases,” Dr. Dawwas said.
Head-to-head trial needed to change practice
Christopher M. Bianco, DO, associate professor of medicine at West Virginia University Heart and Vascular Institute, Morgantown, said the findings “add to the growing body of literature,” but “a head-to-head trial would be necessary to make a definitive change to clinical practice.”
Dr. Bianco, who recently conducted a retrospective analysis of apixaban and rivaroxaban that found no difference in safety and efficacy among a different patient population, said these kinds of studies are helpful in generating hypotheses, but they can’t account for all relevant clinical factors.
“There are just so many things that go into the decision-making process of [prescribing] apixaban and rivaroxaban,” he said. “Even though [Dr. Dawwas and colleagues] used propensity matching, you’re never going to be able to sort that out with a retrospective analysis.”
Specifically, Dr. Bianco noted that the findings did not include dose data. This is a key gap, he said, considering how often real-world datasets have shown that providers underdose DOACs for a number of unaccountable reasons, and how frequently patients exhibit poor adherence.
The study also lacked detail concerning the degree of renal dysfunction, which can determine drug eligibility, Dr. Bianco said. Furthermore, attempts to stratify patients based on thrombosis and bleeding risk were likely “insufficient,” he added.
Dr. Bianco also cautioned that the investigators defined valvular heart disease as any valve-related disease of any severity. In contrast, previous studies have generally restricted valvular heart disease to patients with mitral stenosis or prosthetic valves.
“This is definitely not the traditional definition of valvular heart disease, so the title is a little bit misleading in that sense, although they certainly do disclose that in the methods,” Dr. Bianco said.
On a more positive note, he highlighted the size of the patient population, and the real-world data, which included many patients who would be excluded from clinical trials.
More broadly, the study helps drive research forward, Dr. Bianco concluded; namely, by attracting financial support for a more powerful head-to-head trial that drug makers are unlikely to fund due to inherent market risk.
This study was supported by the National Institutes of Health. The investigators disclosed additional relationships with Takeda, Spark, Sanofi, and others. Dr. Bianco disclosed no conflicts of interest.
Compared with rivaroxaban, apixaban cut risks nearly in half, suggesting that clinicians should consider these new data when choosing an anticoagulant, reported lead author Ghadeer K. Dawwas, PhD, of the University of Pennsylvania, Philadelphia, and colleagues.
In the new retrospective study involving almost 20,000 patients, Dr. Dawwas and her colleagues “emulated a target trial” using private insurance claims from Optum’s deidentified Clinformatics Data Mart Database. The cohort was narrowed from a screened population of 58,210 patients with concurrent AFib and VHD to 9,947 new apixaban users who could be closely matched with 9,947 new rivaroxaban users. Covariates included provider specialty, type of VHD, demographic characteristics, measures of health care use, baseline use of medications, and baseline comorbidities.
The primary effectiveness outcome was a composite of systemic embolism and ischemic stroke, while the primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
“Although several ongoing trials aim to compare apixaban with warfarin in patients with AFib and VHD, none of these trials will directly compare apixaban and rivaroxaban,” the investigators wrote. Their report is in Annals of Internal Medicine.
Dr. Dawwas and colleagues previously showed that direct oral anticoagulants (DOACs) were safer and more effective than warfarin in the same patient population. Comparing apixaban and rivaroxaban – the two most common DOACs – was the next logical step, Dr. Dawwas said in an interview.
Study results
Compared with rivaroxaban, patients who received apixaban had a 43% reduced risk of stroke or embolism (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40-0.80). Apixaban’s ability to protect against bleeding appeared even more pronounced, with a 49% reduced risk over rivaroxaban (HR, 0.51; 95% CI, 0.41-0.62).
Comparing the two agents on an absolute basis, apixaban reduced risk of embolism or stroke by 0.2% within the first 6 months of treatment initiation, and 1.1% within the first year of initiation. At the same time points, absolute risk reductions for bleeding were 1.2% and 1.9%, respectively.
The investigators noted that their results held consistent in an alternative analysis that considered separate types of VHD.
“Based on the results from our analysis, we showed that apixaban is effective and safe in patients with atrial fibrillation and valvular heart diseases,” Dr. Dawwas said.
Head-to-head trial needed to change practice
Christopher M. Bianco, DO, associate professor of medicine at West Virginia University Heart and Vascular Institute, Morgantown, said the findings “add to the growing body of literature,” but “a head-to-head trial would be necessary to make a definitive change to clinical practice.”
Dr. Bianco, who recently conducted a retrospective analysis of apixaban and rivaroxaban that found no difference in safety and efficacy among a different patient population, said these kinds of studies are helpful in generating hypotheses, but they can’t account for all relevant clinical factors.
“There are just so many things that go into the decision-making process of [prescribing] apixaban and rivaroxaban,” he said. “Even though [Dr. Dawwas and colleagues] used propensity matching, you’re never going to be able to sort that out with a retrospective analysis.”
Specifically, Dr. Bianco noted that the findings did not include dose data. This is a key gap, he said, considering how often real-world datasets have shown that providers underdose DOACs for a number of unaccountable reasons, and how frequently patients exhibit poor adherence.
The study also lacked detail concerning the degree of renal dysfunction, which can determine drug eligibility, Dr. Bianco said. Furthermore, attempts to stratify patients based on thrombosis and bleeding risk were likely “insufficient,” he added.
Dr. Bianco also cautioned that the investigators defined valvular heart disease as any valve-related disease of any severity. In contrast, previous studies have generally restricted valvular heart disease to patients with mitral stenosis or prosthetic valves.
“This is definitely not the traditional definition of valvular heart disease, so the title is a little bit misleading in that sense, although they certainly do disclose that in the methods,” Dr. Bianco said.
On a more positive note, he highlighted the size of the patient population, and the real-world data, which included many patients who would be excluded from clinical trials.
More broadly, the study helps drive research forward, Dr. Bianco concluded; namely, by attracting financial support for a more powerful head-to-head trial that drug makers are unlikely to fund due to inherent market risk.
This study was supported by the National Institutes of Health. The investigators disclosed additional relationships with Takeda, Spark, Sanofi, and others. Dr. Bianco disclosed no conflicts of interest.
FROM ANNALS OF INTERNAL MEDICINE