Key clinical point: Administration of ceftaroline alone or in combination resulted in lower in-hospital mortality rates in patients with community-acquired pneumonia (CAP) vs. standard therapy.

Main finding: After adjustment for confounding factors, patients receiving ceftaroline had a lower in-hospital mortality rate (13% vs. 21%; adjusted hazard ratio 0.41; P = .031) and longer median hospital stay (13 days vs. 10 days; P = .007) than those receiving standard therapy.

Study details: This retrospective observational study matched 78 patients with CAP who received ceftaroline (as monotherapy or in combination with azithromycin, levofloxacin, etc.) with 78 control patients who received standard therapy.

Disclosures: The study received financial support from Pfizer, CIBER de Enfermedades Respiratorias, and 2009 Support to Research Groups of Catalonia 911, IDIBAPS. Pfizer, in addition to a couple of other sources, provided research grants/fellowships to Dr. Cilloniz and other authors.

Source: Cilloniz C et al. Eur J Clin Microbiol Infect Dis. 2021 (Nov 12). Doi: 10.1007/s10096-021-04378-0.

Key clinical point: Administration of ceftaroline alone or in combination resulted in lower in-hospital mortality rates in patients with community-acquired pneumonia (CAP) vs. standard therapy.

Main finding: After adjustment for confounding factors, patients receiving ceftaroline had a lower in-hospital mortality rate (13% vs. 21%; adjusted hazard ratio 0.41; P = .031) and longer median hospital stay (13 days vs. 10 days; P = .007) than those receiving standard therapy.

Study details: This retrospective observational study matched 78 patients with CAP who received ceftaroline (as monotherapy or in combination with azithromycin, levofloxacin, etc.) with 78 control patients who received standard therapy.

Disclosures: The study received financial support from Pfizer, CIBER de Enfermedades Respiratorias, and 2009 Support to Research Groups of Catalonia 911, IDIBAPS. Pfizer, in addition to a couple of other sources, provided research grants/fellowships to Dr. Cilloniz and other authors.

Source: Cilloniz C et al. Eur J Clin Microbiol Infect Dis. 2021 (Nov 12). Doi: 10.1007/s10096-021-04378-0.

Key clinical point: Administration of ceftaroline alone or in combination resulted in lower in-hospital mortality rates in patients with community-acquired pneumonia (CAP) vs. standard therapy.

Main finding: After adjustment for confounding factors, patients receiving ceftaroline had a lower in-hospital mortality rate (13% vs. 21%; adjusted hazard ratio 0.41; P = .031) and longer median hospital stay (13 days vs. 10 days; P = .007) than those receiving standard therapy.

Study details: This retrospective observational study matched 78 patients with CAP who received ceftaroline (as monotherapy or in combination with azithromycin, levofloxacin, etc.) with 78 control patients who received standard therapy.

Disclosures: The study received financial support from Pfizer, CIBER de Enfermedades Respiratorias, and 2009 Support to Research Groups of Catalonia 911, IDIBAPS. Pfizer, in addition to a couple of other sources, provided research grants/fellowships to Dr. Cilloniz and other authors.

Source: Cilloniz C et al. Eur J Clin Microbiol Infect Dis. 2021 (Nov 12). Doi: 10.1007/s10096-021-04378-0.

Key clinical point: On comparing regimes recommended by the 2019 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines, those containing doxycycline were associated with decreased mortality in elderly patients with community-acquired pneumonia (CAP).

Main finding: After propensity-matching, patients receiving beta-lactam + doxycycline showed significantly reduced 30-day (odds ratio [OR] 0.72; 95% CI 0.63-0.84) and 90-day (OR 0.83; 95% CI 0.74-0.92) mortality vs. those on nondoxycycline-containing regimes.

Study details: This retrospective observational cohort study included 70,533 patients aged ≥65 years who were admitted to a non-ICU hospital ward for CAP and received at least 1 dose of the 2019 ATS/IDSA guideline-recommended antimicrobial therapy within 48 hours after admission. Of these, 5,282 patients received doxycycline-containing combinations.

Disclosures: The study was supported by the US National Institute of Nursing Research. CA Alvarez declared serving as an advisory board member for a pharmaceutical organization.

Source: Uddin M et al. Clin Infect Dis. 2021;ciab863 (Nov 9). Doi: 10.1093/cid/ciab863.

Key clinical point: On comparing regimes recommended by the 2019 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines, those containing doxycycline were associated with decreased mortality in elderly patients with community-acquired pneumonia (CAP).

Main finding: After propensity-matching, patients receiving beta-lactam + doxycycline showed significantly reduced 30-day (odds ratio [OR] 0.72; 95% CI 0.63-0.84) and 90-day (OR 0.83; 95% CI 0.74-0.92) mortality vs. those on nondoxycycline-containing regimes.

Study details: This retrospective observational cohort study included 70,533 patients aged ≥65 years who were admitted to a non-ICU hospital ward for CAP and received at least 1 dose of the 2019 ATS/IDSA guideline-recommended antimicrobial therapy within 48 hours after admission. Of these, 5,282 patients received doxycycline-containing combinations.

Disclosures: The study was supported by the US National Institute of Nursing Research. CA Alvarez declared serving as an advisory board member for a pharmaceutical organization.

Source: Uddin M et al. Clin Infect Dis. 2021;ciab863 (Nov 9). Doi: 10.1093/cid/ciab863.

Key clinical point: On comparing regimes recommended by the 2019 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines, those containing doxycycline were associated with decreased mortality in elderly patients with community-acquired pneumonia (CAP).

Main finding: After propensity-matching, patients receiving beta-lactam + doxycycline showed significantly reduced 30-day (odds ratio [OR] 0.72; 95% CI 0.63-0.84) and 90-day (OR 0.83; 95% CI 0.74-0.92) mortality vs. those on nondoxycycline-containing regimes.

Study details: This retrospective observational cohort study included 70,533 patients aged ≥65 years who were admitted to a non-ICU hospital ward for CAP and received at least 1 dose of the 2019 ATS/IDSA guideline-recommended antimicrobial therapy within 48 hours after admission. Of these, 5,282 patients received doxycycline-containing combinations.

Disclosures: The study was supported by the US National Institute of Nursing Research. CA Alvarez declared serving as an advisory board member for a pharmaceutical organization.

Source: Uddin M et al. Clin Infect Dis. 2021;ciab863 (Nov 9). Doi: 10.1093/cid/ciab863.

Key clinical point: Occurrence of community-acquired pneumonia (CAP) in infants aged below 2 years increases their risk for subsequent respiratory disease when between 2 and 5 years of age.

Main finding: The rate of chronic respiratory disorder from 2-5 years of age, reactive airway disease, and CAP hospitalization after 2 years of age was 2.4-fold (95% CI 2.1-2.6), 3.2-fold (95% CI 2.6-3.8), and 6.3-fold (95% CI 3.6-10.9) higher in patients with CAP vs. comparison patients.

Study details: The data come from a retrospective study including 1,343 infants less than 2 years of age who were hospitalized once or more for CAP and matched with 6,715 comparator infants with no evidence of pneumonia.

Disclosures: The study was sponsored by Pfizer Inc. Some of the authors declared being directly employed by Pfizer or another organization that received financial support from Pfizer.

Source: Lapidot R et al. Repir Med. 2021:106671 (Oct 27). Doi: 10.1016/j.rmed.2021.106671.

Key clinical point: Occurrence of community-acquired pneumonia (CAP) in infants aged below 2 years increases their risk for subsequent respiratory disease when between 2 and 5 years of age.

Main finding: The rate of chronic respiratory disorder from 2-5 years of age, reactive airway disease, and CAP hospitalization after 2 years of age was 2.4-fold (95% CI 2.1-2.6), 3.2-fold (95% CI 2.6-3.8), and 6.3-fold (95% CI 3.6-10.9) higher in patients with CAP vs. comparison patients.

Study details: The data come from a retrospective study including 1,343 infants less than 2 years of age who were hospitalized once or more for CAP and matched with 6,715 comparator infants with no evidence of pneumonia.

Disclosures: The study was sponsored by Pfizer Inc. Some of the authors declared being directly employed by Pfizer or another organization that received financial support from Pfizer.

Source: Lapidot R et al. Repir Med. 2021:106671 (Oct 27). Doi: 10.1016/j.rmed.2021.106671.

Key clinical point: Occurrence of community-acquired pneumonia (CAP) in infants aged below 2 years increases their risk for subsequent respiratory disease when between 2 and 5 years of age.

Main finding: The rate of chronic respiratory disorder from 2-5 years of age, reactive airway disease, and CAP hospitalization after 2 years of age was 2.4-fold (95% CI 2.1-2.6), 3.2-fold (95% CI 2.6-3.8), and 6.3-fold (95% CI 3.6-10.9) higher in patients with CAP vs. comparison patients.

Study details: The data come from a retrospective study including 1,343 infants less than 2 years of age who were hospitalized once or more for CAP and matched with 6,715 comparator infants with no evidence of pneumonia.

Disclosures: The study was sponsored by Pfizer Inc. Some of the authors declared being directly employed by Pfizer or another organization that received financial support from Pfizer.

Source: Lapidot R et al. Repir Med. 2021:106671 (Oct 27). Doi: 10.1016/j.rmed.2021.106671.

Key clinical point: Pneumonia Severity Index (PSI) and the confusion, urea, respiratory rate, and blood pressure (CURB)-65 score are as effective at predicting in-hospital mortality in patients with SARS-CoV-2 community-acquired pneumonia (CAP) as they are in those with non-SARS-CoV-2 CAP.

Main finding: The area under the receiver operating characteristic curve in patients with SARS-CoV-2 CAP and non-SARS-CoV-2 CAP for PSI was 0.82 (95% Bayesian credible interval [bCI] 0.78-0.86) and 0.79 (95% bCI 0.77-0.80) and that for CURB-65 was 0.79 (95% bCI 0.75-0.84) and 0.75 (95% bCI 0.73-0.77), respectively.

Study details: This was a secondary analysis of 8,081 patients from 2 population-based cohort studies, each of which included adults hospitalized for either SARS-CoV-2 CAP or non-SARS-CoV-2 CAP.

Disclosures: The study was supported by the Center for Excellence for Research in Infectious Diseases at the University of Louisville. None of the authors declared any potential conflict of interests.

Source: Bradley J et al. Chest. 2021 (Nov 2). Doi: 10.1016/j.chest.2021.10.031.

Key clinical point: Pneumonia Severity Index (PSI) and the confusion, urea, respiratory rate, and blood pressure (CURB)-65 score are as effective at predicting in-hospital mortality in patients with SARS-CoV-2 community-acquired pneumonia (CAP) as they are in those with non-SARS-CoV-2 CAP.

Main finding: The area under the receiver operating characteristic curve in patients with SARS-CoV-2 CAP and non-SARS-CoV-2 CAP for PSI was 0.82 (95% Bayesian credible interval [bCI] 0.78-0.86) and 0.79 (95% bCI 0.77-0.80) and that for CURB-65 was 0.79 (95% bCI 0.75-0.84) and 0.75 (95% bCI 0.73-0.77), respectively.

Study details: This was a secondary analysis of 8,081 patients from 2 population-based cohort studies, each of which included adults hospitalized for either SARS-CoV-2 CAP or non-SARS-CoV-2 CAP.

Disclosures: The study was supported by the Center for Excellence for Research in Infectious Diseases at the University of Louisville. None of the authors declared any potential conflict of interests.

Source: Bradley J et al. Chest. 2021 (Nov 2). Doi: 10.1016/j.chest.2021.10.031.

Key clinical point: Pneumonia Severity Index (PSI) and the confusion, urea, respiratory rate, and blood pressure (CURB)-65 score are as effective at predicting in-hospital mortality in patients with SARS-CoV-2 community-acquired pneumonia (CAP) as they are in those with non-SARS-CoV-2 CAP.

Main finding: The area under the receiver operating characteristic curve in patients with SARS-CoV-2 CAP and non-SARS-CoV-2 CAP for PSI was 0.82 (95% Bayesian credible interval [bCI] 0.78-0.86) and 0.79 (95% bCI 0.77-0.80) and that for CURB-65 was 0.79 (95% bCI 0.75-0.84) and 0.75 (95% bCI 0.73-0.77), respectively.

Study details: This was a secondary analysis of 8,081 patients from 2 population-based cohort studies, each of which included adults hospitalized for either SARS-CoV-2 CAP or non-SARS-CoV-2 CAP.

Disclosures: The study was supported by the Center for Excellence for Research in Infectious Diseases at the University of Louisville. None of the authors declared any potential conflict of interests.

Source: Bradley J et al. Chest. 2021 (Nov 2). Doi: 10.1016/j.chest.2021.10.031.

Key clinical point: In patients with moderately severe community-acquired pneumonia (CAP) who reached clinical stability after 3 days of antibiotic treatment, male sex and age were the main risk factors for treatment failure.

Main finding: After excluding the Pneumonia Severity Index score and urea level at day 0, male sex (odds ratio [OR] 1.92; 95% CI 1.08-3.49) and age per year (OR 1.02; 95% CI 1.00-1.05) showed a significant association with treatment failure at day 15.

Study details: This was a secondary analysis including 291 of the 310 patients from the Pneumonia Short Treatment trial who were hospitalized for moderately severe CAP and were clinically stable after 3 days of receiving β-lactams, which is when they were randomly assigned to receive oral amoxicillin-clavulanate or placebo for 5 further days.

Disclosures: The study was supported by the French Ministry of Health and DRCI of Versailles. Dr. Crémieux reported receiving grants from an additional source outside the study.

Source: Dinh A et al. JAMA Netw Open. 2021;4(10):e2129566 (Oct 15). Doi: 10.1001/jamanetworkopen.2021.29566.

Key clinical point: In patients with moderately severe community-acquired pneumonia (CAP) who reached clinical stability after 3 days of antibiotic treatment, male sex and age were the main risk factors for treatment failure.

Main finding: After excluding the Pneumonia Severity Index score and urea level at day 0, male sex (odds ratio [OR] 1.92; 95% CI 1.08-3.49) and age per year (OR 1.02; 95% CI 1.00-1.05) showed a significant association with treatment failure at day 15.

Study details: This was a secondary analysis including 291 of the 310 patients from the Pneumonia Short Treatment trial who were hospitalized for moderately severe CAP and were clinically stable after 3 days of receiving β-lactams, which is when they were randomly assigned to receive oral amoxicillin-clavulanate or placebo for 5 further days.

Disclosures: The study was supported by the French Ministry of Health and DRCI of Versailles. Dr. Crémieux reported receiving grants from an additional source outside the study.

Source: Dinh A et al. JAMA Netw Open. 2021;4(10):e2129566 (Oct 15). Doi: 10.1001/jamanetworkopen.2021.29566.

Key clinical point: In patients with moderately severe community-acquired pneumonia (CAP) who reached clinical stability after 3 days of antibiotic treatment, male sex and age were the main risk factors for treatment failure.

Main finding: After excluding the Pneumonia Severity Index score and urea level at day 0, male sex (odds ratio [OR] 1.92; 95% CI 1.08-3.49) and age per year (OR 1.02; 95% CI 1.00-1.05) showed a significant association with treatment failure at day 15.

Study details: This was a secondary analysis including 291 of the 310 patients from the Pneumonia Short Treatment trial who were hospitalized for moderately severe CAP and were clinically stable after 3 days of receiving β-lactams, which is when they were randomly assigned to receive oral amoxicillin-clavulanate or placebo for 5 further days.

Disclosures: The study was supported by the French Ministry of Health and DRCI of Versailles. Dr. Crémieux reported receiving grants from an additional source outside the study.

Source: Dinh A et al. JAMA Netw Open. 2021;4(10):e2129566 (Oct 15). Doi: 10.1001/jamanetworkopen.2021.29566.

Key clinical point: In children with community-acquired pneumonia (CAP) discharged from emergency departments or inpatient wards, further outpatient treatment with amoxicillin at a lower dose was not inferior to a higher dose, and a 3-day treatment course was not inferior to a 7-day treatment course.

Main finding: Antibiotic retreatment rates in the 4-week period after hospital discharge in the lower dose vs. the higher dose group were 12.6% vs. 12.4% (difference 0.2%; 95% CI –∞ to 4.0%) and those in the shorter duration vs. the longer duration group were 12.5% vs. 12.5% (difference 0.1%; 95% CI –∞ to 3.9%).

Study details: Findings are from the CAP-IT trial including 814 children > 6 months old with CAP who were randomly assigned 1:1 after hospital discharge to receive the 4 possible combinations of amoxicillin dose (35-50 or 70-90 mg/kg) and duration (3 or 7 days).

Disclosures: The trial was funded by the National Institute of Health Research (NIHR) Health Technology Assessment (HTA) Program and Antimicrobial Resistance Themed Call. Some of the authors including the lead author reported receiving research grants from the NIHR/HTA.

Source: Bielicki JA et al. JAMA. 2021;326(17):1713-1724 (Nov 2). Doi: 10.1001/jama.2021.17843.

Key clinical point: In children with community-acquired pneumonia (CAP) discharged from emergency departments or inpatient wards, further outpatient treatment with amoxicillin at a lower dose was not inferior to a higher dose, and a 3-day treatment course was not inferior to a 7-day treatment course.

Main finding: Antibiotic retreatment rates in the 4-week period after hospital discharge in the lower dose vs. the higher dose group were 12.6% vs. 12.4% (difference 0.2%; 95% CI –∞ to 4.0%) and those in the shorter duration vs. the longer duration group were 12.5% vs. 12.5% (difference 0.1%; 95% CI –∞ to 3.9%).

Study details: Findings are from the CAP-IT trial including 814 children > 6 months old with CAP who were randomly assigned 1:1 after hospital discharge to receive the 4 possible combinations of amoxicillin dose (35-50 or 70-90 mg/kg) and duration (3 or 7 days).

Disclosures: The trial was funded by the National Institute of Health Research (NIHR) Health Technology Assessment (HTA) Program and Antimicrobial Resistance Themed Call. Some of the authors including the lead author reported receiving research grants from the NIHR/HTA.

Source: Bielicki JA et al. JAMA. 2021;326(17):1713-1724 (Nov 2). Doi: 10.1001/jama.2021.17843.

Key clinical point: In children with community-acquired pneumonia (CAP) discharged from emergency departments or inpatient wards, further outpatient treatment with amoxicillin at a lower dose was not inferior to a higher dose, and a 3-day treatment course was not inferior to a 7-day treatment course.

Main finding: Antibiotic retreatment rates in the 4-week period after hospital discharge in the lower dose vs. the higher dose group were 12.6% vs. 12.4% (difference 0.2%; 95% CI –∞ to 4.0%) and those in the shorter duration vs. the longer duration group were 12.5% vs. 12.5% (difference 0.1%; 95% CI –∞ to 3.9%).

Study details: Findings are from the CAP-IT trial including 814 children > 6 months old with CAP who were randomly assigned 1:1 after hospital discharge to receive the 4 possible combinations of amoxicillin dose (35-50 or 70-90 mg/kg) and duration (3 or 7 days).

Disclosures: The trial was funded by the National Institute of Health Research (NIHR) Health Technology Assessment (HTA) Program and Antimicrobial Resistance Themed Call. Some of the authors including the lead author reported receiving research grants from the NIHR/HTA.

Source: Bielicki JA et al. JAMA. 2021;326(17):1713-1724 (Nov 2). Doi: 10.1001/jama.2021.17843.

Key clinical point: Antimicrobial stewardship intervention emerged successful in advocating a shift from broad-spectrum to narrow-spectrum antibiotics for treating moderately severe community-acquired pneumonia (CAP) while averting any safety concerns.

Main finding: Antimicrobial stewardship intervention effectuated a decrease in the adjusted mean broad-spectrum days of therapy per patient from 6.5 days to 4.8 days, with an adjusted relative reduction of 26.6% (95% CI 18.0%-35.3%). The adjusted risk difference of 0.4% (90% CI –2.7% to 2.4%) indicated noninferiority.

Study details: The data come from the investigator-initiated, noninferiority, CAP-PACT trial including 4,084 adult patients receiving antibiotics for moderately severe CAP post admission to a non-ICU hospital ward, of whom 2,235 patients were admitted during the control period and 1,849 during the intervention period.

Disclosures: The authors received no financial support for the study. CH van Werkhoven reported receiving grants, personal fees, and nonfinancial support from a few sources outside the study, in addition to obtaining a patent for the prediction of clinical manifestations of gut microbiota.

Source: Schweitzer VA et al. Lancet Infect Dis. 2021(Oct 7). Doi: 10.1016/S1473-3099(21)00255-3.

Key clinical point: Antimicrobial stewardship intervention emerged successful in advocating a shift from broad-spectrum to narrow-spectrum antibiotics for treating moderately severe community-acquired pneumonia (CAP) while averting any safety concerns.

Main finding: Antimicrobial stewardship intervention effectuated a decrease in the adjusted mean broad-spectrum days of therapy per patient from 6.5 days to 4.8 days, with an adjusted relative reduction of 26.6% (95% CI 18.0%-35.3%). The adjusted risk difference of 0.4% (90% CI –2.7% to 2.4%) indicated noninferiority.

Study details: The data come from the investigator-initiated, noninferiority, CAP-PACT trial including 4,084 adult patients receiving antibiotics for moderately severe CAP post admission to a non-ICU hospital ward, of whom 2,235 patients were admitted during the control period and 1,849 during the intervention period.

Disclosures: The authors received no financial support for the study. CH van Werkhoven reported receiving grants, personal fees, and nonfinancial support from a few sources outside the study, in addition to obtaining a patent for the prediction of clinical manifestations of gut microbiota.

Source: Schweitzer VA et al. Lancet Infect Dis. 2021(Oct 7). Doi: 10.1016/S1473-3099(21)00255-3.

Key clinical point: Antimicrobial stewardship intervention emerged successful in advocating a shift from broad-spectrum to narrow-spectrum antibiotics for treating moderately severe community-acquired pneumonia (CAP) while averting any safety concerns.

Main finding: Antimicrobial stewardship intervention effectuated a decrease in the adjusted mean broad-spectrum days of therapy per patient from 6.5 days to 4.8 days, with an adjusted relative reduction of 26.6% (95% CI 18.0%-35.3%). The adjusted risk difference of 0.4% (90% CI –2.7% to 2.4%) indicated noninferiority.

Study details: The data come from the investigator-initiated, noninferiority, CAP-PACT trial including 4,084 adult patients receiving antibiotics for moderately severe CAP post admission to a non-ICU hospital ward, of whom 2,235 patients were admitted during the control period and 1,849 during the intervention period.

Disclosures: The authors received no financial support for the study. CH van Werkhoven reported receiving grants, personal fees, and nonfinancial support from a few sources outside the study, in addition to obtaining a patent for the prediction of clinical manifestations of gut microbiota.

Source: Schweitzer VA et al. Lancet Infect Dis. 2021(Oct 7). Doi: 10.1016/S1473-3099(21)00255-3.

A French population-based study provides further evidence that the BNT162b2 Pfizer-BioNTech mRNA COVID-19 vaccine does not increase the short-term risk for serious cardiovascular adverse events in older people.

The study showed no increased risk of myocardial infarction (MI), stroke, or pulmonary embolism (PE) following vaccination in adults aged 75 years or older in the 14 days following vaccination.

“These findings regarding the BNT162b2 vaccine’s short-term cardiovascular safety profile in older people are reassuring. They should be taken into account by doctors when considering implementing a third dose of the vaccine in older people,” Marie Joelle Jabagi, PharmD, PhD, with the French National Agency for Medicines and Health Products Safety, Saint-Denis, France, said in an interview.

Ridofranz/Getty Images

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

A French population-based study provides further evidence that the BNT162b2 Pfizer-BioNTech mRNA COVID-19 vaccine does not increase the short-term risk for serious cardiovascular adverse events in older people.

The study showed no increased risk of myocardial infarction (MI), stroke, or pulmonary embolism (PE) following vaccination in adults aged 75 years or older in the 14 days following vaccination.

“These findings regarding the BNT162b2 vaccine’s short-term cardiovascular safety profile in older people are reassuring. They should be taken into account by doctors when considering implementing a third dose of the vaccine in older people,” Marie Joelle Jabagi, PharmD, PhD, with the French National Agency for Medicines and Health Products Safety, Saint-Denis, France, said in an interview.

Ridofranz/Getty Images

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

A French population-based study provides further evidence that the BNT162b2 Pfizer-BioNTech mRNA COVID-19 vaccine does not increase the short-term risk for serious cardiovascular adverse events in older people.

The study showed no increased risk of myocardial infarction (MI), stroke, or pulmonary embolism (PE) following vaccination in adults aged 75 years or older in the 14 days following vaccination.

“These findings regarding the BNT162b2 vaccine’s short-term cardiovascular safety profile in older people are reassuring. They should be taken into account by doctors when considering implementing a third dose of the vaccine in older people,” Marie Joelle Jabagi, PharmD, PhD, with the French National Agency for Medicines and Health Products Safety, Saint-Denis, France, said in an interview.

Ridofranz/Getty Images

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

According to an analysis by the Pew Research Center and a report by the National Women’s Law Center, women were earning approximately $0.83-$0.84 for every $1.00 earned by their male counterparts in 2020. Accordingly, women would need to work an additional 42 days to receive compensation for earnings by men during that year. Moreover, these gaps exist with respect to race inequalities. For example, Black and Latinx women who are working full-time were reported to earn approximately $0.64 and $0.57, respectively, for every $1.00 compared with their white, non-Hispanic male counterparts. Striking, isn’t it?

The gender pay gap also affects physicians. A 2021 Medscape survey found that male physicians earn 35% more than female physicians. The biggest gap seems to be between male and female specialists, with men earning $376,000 and women $283,000.
 

Gender inequality and COVID-19

In addition to workplace responsibilities, women are more likely to take on unpaid positions in the informal care economy – examples of these tasks include cleaning, grocery shopping, and child care. In fact, the COVID-19 pandemic has increased the burden of unpaid care work among women, which often incurs a significant impact on their participation in the paid economy.

A study in the United States evaluating the impact of gender inequality during COVID-19 suggested that the rise in unemployment among women during this time may be related to decreased occupational flexibility. Accordingly, the closure of schools and caregiving facilities has translated into increased responsibilities as the informal caregiver, and a decreased ability to fulfill work obligations. Consequently, women may be overwhelmed and unable to maintain their employment status, are limited in their work opportunities, and/or are furloughed or passed over for promotions.
 

Gendered pay gaps affect mental health

A study by Platt and colleagues investigated the relationship between gendered wage gaps and gendered disparities in depression and anxiety disorders. Researchers found that females with a lower income compared with their matched male counterparts were more likely to experience depression and generalized anxiety disorders (i.e., they were 2.4 times more likely to experience depression and 4 times more likely to experience anxiety), while women who earned more than men did not report a significant difference in depression there were reduced gaps in the prevalence of anxiety disorders. As such, it has been suggested that wage gap inequalities are a contributing factor to gendered mental health disparities.

Reduced pay is not only a signifier of reduced returns on human capital. It may also have implications for one’s role in the care economy (e.g., greater time allocation as a result of reduced return), and may result in a higher likelihood for relocation as it relates to a partner’s work, overqualification for a position, inflexible work schedules, and reduced work autonomy.

Wage inequalities may act as a proxy for workplace inequalities such as promotions, prestigious projects, limited upward mobility, and internalized negative workplace experiences, all of which may contribute to increased sleep loss, stress, and related mental health stressors.

One might say, “A few cents, so what?” In addition to income itself, there’s a broader theme at play, which is gender discrimination and inequality. We should encourage conversations around the gender pay gap and develop strategies to combat this economic and social disparity.
 

Ms. Lui completed an HBSc global health specialist degree at the University of Toronto, where she is now an MSc candidate. She has received income from Braxia Scientific Corp. A version of this article first appeared on Medscape.com.

According to an analysis by the Pew Research Center and a report by the National Women’s Law Center, women were earning approximately $0.83-$0.84 for every $1.00 earned by their male counterparts in 2020. Accordingly, women would need to work an additional 42 days to receive compensation for earnings by men during that year. Moreover, these gaps exist with respect to race inequalities. For example, Black and Latinx women who are working full-time were reported to earn approximately $0.64 and $0.57, respectively, for every $1.00 compared with their white, non-Hispanic male counterparts. Striking, isn’t it?

The gender pay gap also affects physicians. A 2021 Medscape survey found that male physicians earn 35% more than female physicians. The biggest gap seems to be between male and female specialists, with men earning $376,000 and women $283,000.
 

Gender inequality and COVID-19

In addition to workplace responsibilities, women are more likely to take on unpaid positions in the informal care economy – examples of these tasks include cleaning, grocery shopping, and child care. In fact, the COVID-19 pandemic has increased the burden of unpaid care work among women, which often incurs a significant impact on their participation in the paid economy.

A study in the United States evaluating the impact of gender inequality during COVID-19 suggested that the rise in unemployment among women during this time may be related to decreased occupational flexibility. Accordingly, the closure of schools and caregiving facilities has translated into increased responsibilities as the informal caregiver, and a decreased ability to fulfill work obligations. Consequently, women may be overwhelmed and unable to maintain their employment status, are limited in their work opportunities, and/or are furloughed or passed over for promotions.
 

Gendered pay gaps affect mental health

A study by Platt and colleagues investigated the relationship between gendered wage gaps and gendered disparities in depression and anxiety disorders. Researchers found that females with a lower income compared with their matched male counterparts were more likely to experience depression and generalized anxiety disorders (i.e., they were 2.4 times more likely to experience depression and 4 times more likely to experience anxiety), while women who earned more than men did not report a significant difference in depression there were reduced gaps in the prevalence of anxiety disorders. As such, it has been suggested that wage gap inequalities are a contributing factor to gendered mental health disparities.

Reduced pay is not only a signifier of reduced returns on human capital. It may also have implications for one’s role in the care economy (e.g., greater time allocation as a result of reduced return), and may result in a higher likelihood for relocation as it relates to a partner’s work, overqualification for a position, inflexible work schedules, and reduced work autonomy.

Wage inequalities may act as a proxy for workplace inequalities such as promotions, prestigious projects, limited upward mobility, and internalized negative workplace experiences, all of which may contribute to increased sleep loss, stress, and related mental health stressors.

One might say, “A few cents, so what?” In addition to income itself, there’s a broader theme at play, which is gender discrimination and inequality. We should encourage conversations around the gender pay gap and develop strategies to combat this economic and social disparity.
 

Ms. Lui completed an HBSc global health specialist degree at the University of Toronto, where she is now an MSc candidate. She has received income from Braxia Scientific Corp. A version of this article first appeared on Medscape.com.

According to an analysis by the Pew Research Center and a report by the National Women’s Law Center, women were earning approximately $0.83-$0.84 for every $1.00 earned by their male counterparts in 2020. Accordingly, women would need to work an additional 42 days to receive compensation for earnings by men during that year. Moreover, these gaps exist with respect to race inequalities. For example, Black and Latinx women who are working full-time were reported to earn approximately $0.64 and $0.57, respectively, for every $1.00 compared with their white, non-Hispanic male counterparts. Striking, isn’t it?

The gender pay gap also affects physicians. A 2021 Medscape survey found that male physicians earn 35% more than female physicians. The biggest gap seems to be between male and female specialists, with men earning $376,000 and women $283,000.
 

Gender inequality and COVID-19

In addition to workplace responsibilities, women are more likely to take on unpaid positions in the informal care economy – examples of these tasks include cleaning, grocery shopping, and child care. In fact, the COVID-19 pandemic has increased the burden of unpaid care work among women, which often incurs a significant impact on their participation in the paid economy.

A study in the United States evaluating the impact of gender inequality during COVID-19 suggested that the rise in unemployment among women during this time may be related to decreased occupational flexibility. Accordingly, the closure of schools and caregiving facilities has translated into increased responsibilities as the informal caregiver, and a decreased ability to fulfill work obligations. Consequently, women may be overwhelmed and unable to maintain their employment status, are limited in their work opportunities, and/or are furloughed or passed over for promotions.
 

Gendered pay gaps affect mental health

A study by Platt and colleagues investigated the relationship between gendered wage gaps and gendered disparities in depression and anxiety disorders. Researchers found that females with a lower income compared with their matched male counterparts were more likely to experience depression and generalized anxiety disorders (i.e., they were 2.4 times more likely to experience depression and 4 times more likely to experience anxiety), while women who earned more than men did not report a significant difference in depression there were reduced gaps in the prevalence of anxiety disorders. As such, it has been suggested that wage gap inequalities are a contributing factor to gendered mental health disparities.

Reduced pay is not only a signifier of reduced returns on human capital. It may also have implications for one’s role in the care economy (e.g., greater time allocation as a result of reduced return), and may result in a higher likelihood for relocation as it relates to a partner’s work, overqualification for a position, inflexible work schedules, and reduced work autonomy.

Wage inequalities may act as a proxy for workplace inequalities such as promotions, prestigious projects, limited upward mobility, and internalized negative workplace experiences, all of which may contribute to increased sleep loss, stress, and related mental health stressors.

One might say, “A few cents, so what?” In addition to income itself, there’s a broader theme at play, which is gender discrimination and inequality. We should encourage conversations around the gender pay gap and develop strategies to combat this economic and social disparity.
 

Ms. Lui completed an HBSc global health specialist degree at the University of Toronto, where she is now an MSc candidate. She has received income from Braxia Scientific Corp. A version of this article first appeared on Medscape.com.

A new lipid-lowering agent in a class that had been written off by many is being developed by a group of academic experts, with new data showing large LDL reductions on top of high-intensity statins.

Obicetrapib is a member of the cholesteryl ester transfer protein (CETP) inhibitor class, which had fallen out of favor after several disappointments with previous drugs in this class.

These agents were initially developed for their ability to raise HDL cholesterol, which was thought to be beneficial. But that approach has now been virtually abandoned after several studies failed to show a link between raising HDL and a reduction in subsequent cardiovascular events.

However, obicetrapib, which is said to be the most potent CETP inhibitor to date, has been shown to produce impressive LDL reductions, and it’s this important data that has caused several lipid experts to want to continue its development.

New data, presented at the recent American Heart Association scientific sessions, show that obicetrapib reduces LDL by 50% when given in addition to high-intensity statins, which could place it as competition for PCSK9 inhibitors or the new agent, inclisiran, but with the advantage of oral dosing.

The drug was in development by Amgen, but the company decided to discontinue its development in 2017 after disappointing results had been seen with several other CETP inhibitors and interest in this class of agent was waning.

But academic experts in the lipid field, led by John Kastelein, MD, PhD, professor of medicine at the Academic Medical Center, University of Amsterdam, and Michael Davidson, MD, clinical professor of medicine at University of Chicago, believed the drug had potential and have acquired obicetrapib from Amgen.

Dr. Kastelein and Dr. Davidson have set up a new company – New Amsterdam Pharma – to further develop obicetrapib, and have raised $200 million from venture capital funding to complete phase 2 and phase 3 studies.

The company has a heavyweight academic advisory board including Stephen Nicholls, MD, Monash University, Clayton, Australia; Kausik Ray, MD, Imperial College London; and Christie Ballantyne, MD, Baylor College of Medicine, Houston.

“We wanted to develop obicetrapib further because of its amazing LDL-lowering properties,” Dr. Kastelein said in an interview.

“No one has paid much attention to CETP inhibitors after the HDL hypothesis was disregarded, as everyone thought these drugs were just about raising HDL. But actually, they can also lower LDL, and this particular agent reduces LDL very effectively,” Dr. Kastelein said.
 

ROSE study

Dr. Nicholls presented the latest data on obicetrapib at the AHA meeting.

“Despite the use of high-intensity statins, two-thirds of patients do not reach their target LDL level, so we have a need for new therapies that lower LDL and can be used in combination with high-intensity statins,” he explained.

He noted that earlier studies with obicetrapib showed a 45% lowering of LDL with monotherapy.

Dr. Nicholls reported that recent evidence has emerged that increases interest in inhibiting CETP to be potentially cardioprotective.

To begin, genetic studies have shown that genetic polymorphisms associated with lower levels of CETP appear to be cardioprotective, and this is associated with lower levels of LDL rather than higher levels of HDL. 

Furthermore, the REVEAL cardiovascular outcomes trial with anacetrapib (also a CETP inhibitor) in 2017 showed a significant 9% reduction in major adverse cardiac events (MACE) after 4 years of follow-up. “This was exactly predicted by the 11 mg/dL drop in absolute LDL cholesterol level. It was not predicted or associated with the increase in HDL level observed with that agent,” Dr. Nicholls said.

The objective of the current ROSE study was to evaluate the lipid-lowering ability, safety, and tolerability of obicetrapib in patients on high-intensity statins.

The study included 120 patients who had been treated on a stable dose of high-intensity statins (atorvastatin at a dose of at least 40 mg daily or rosuvastatin at a dose of 20 mg daily) for at least 8 weeks. All patients were required to have a fasting LDL of at least 70 mg/dL and the median baseline LDL was 90 mg/dL. They were randomly assigned to obicetrapib (5 mg or 10 mg daily) or placebo.

The primary endpoint was the difference between groups in percentage change in LDL from baseline to week 8, with LDL levels measured by two different techniques.

Results showed a “robust” 51% reduction in LDL with the 10-mg dose of obicetrapib, and a 42% reduction with the 5-mg dose, Dr. Nicholls reported.

These effects were comparable regardless of baseline LDL and were similar with both methods of LDL measurement. 

Almost all patients demonstrated some degree of LDL cholesterol lowering, with only three patients on the 5-mg dose and one patient on the 10-mg dose not showing any reduction in LDL.

Other results showed a dose-dependent lowering of Apo B of up to 30%, and a reduction of non-HDL cholesterol of up to 44%.

“Predictably, there were also increases of HDL cholesterol,” Dr. Nicholls said. “At the 10-mg dose, we see a 165% increase in HDL levels. That is associated with a 48% increase in Apo A1 levels. This is very consistent with findings from the previous monotherapy study.”  

There was a 56% reduction in Lp(a) levels, and a modest 11% reduction in triglycerides.

Both doses of obicetrapib were well tolerated, with no increase in the rate of adverse events. Only one patient discontinued the study drug because of an adverse event and that patient was in the placebo group, Dr. Nicholls noted.  

“Blood pressure is an important adverse event to look at in the CETP class given the challenges seen with the first CETP evaluated – torcetrapib,” Dr. Nicholls said. “But in the three clinical trials with obicetrapib conducted to date, reassuringly, we see no increase in either systolic or diastolic blood pressure with either the 5-mg or 10-mg dose.”

He concluded that obicetrapib “could be a valuable addition to high-risk patients with atherosclerotic cardiovascular disease who do not achieve their target LDL level despite use of high-intensity statin therapy.”
 

Differences from other CETP inhibitors

Asked how obicetrapib differs from other agents in the CETP inhibitor class, Dr. Nicholls replied that obicetrapib is much more potent, as shown by the large lipid changes seen with very small quantities of this drug, 5 mg or 10 mg, whereas prior CETP inhibitors showed smaller changes with much higher doses.

“We are giving very small amounts of obicetrapib and seeing very robust effects on both atherogenic and lipid parameters,” he said.  

“The other major point with this class of agent is that the first drug, torcetrapib, had toxicity, which resulted in increased cardiovascular events. But it has now been established that torcetrapib had a number of off-target effects that have not been seen with subsequent agents in this class,” he said.

Studies so far show that obicetrapib does not have torcetrapib-like effects. “That is encouraging. This, and the impressive LDL lowering effects, certainly lay the foundation for larger studies moving forward,” he added.

“This has been an intriguing field to many of us involved from the start. We started with a very disappointing result with torcetrapib. Then a couple of studies looked to be clinically futile, but we were encouraged by the REVEAL study which suggested that there might be benefit,” Dr. Nicholls said.

“If we combined the REVEAL results with the genetic data, it has actually flipped the whole CETP story upside down. We started thinking that inhibiting CETP was all about raising HDL, but it turns out that it is about LDL lowering,” he said. “And that is not only important in terms of the lipid effects but also the trials and the way they are designed.

“I think you’ll find that the future trials in this class and with this agent will have LDL very much in mind and that will very much influence the study design,” he said, adding that a larger cardiovascular outcome trial is now being planned. 

“The regulatory perspective is that LDL is a pretty trusted surrogate ... but I think an outcomes trial will be important to reinforce and reassure on safety and outline cost-effectiveness, which will help us understand where the sweet spot for using this agent in the clinic will be,” Dr. Nicholls noted.  

Dr. Kastelein explained that it has taken some time to realize that CETP inhibitors may be valuable for reducing LDL.   

“The first agent, torcetrapib, had an off-target toxicity that led to increased blood pressure but a specific part of the torcetrapib molecule was subsequently identified that was responsible for that, and subsequent agents in the CETP inhibitor class did not have such adverse effects,” he said.  

“The next agent, dalcetrapib (Roche), raised HDL but didn’t move LDL, and an outcomes trial with evacetrapib (Lilly) was stopped after 2 years because of futility, but we now believe that lipid lowering trials need longer term follow-up – up to 5 years – to see a benefit,” he noted.  

Dr. Kastelein reports that anacetrapib (Merck) has been the most powerful CETP inhibitor until now, giving an LDL reduction of about 20%, which was associated with a 10% reduction in cardiovascular events in first 4 years of follow-up. 

“Oxford academic researchers decided to continue follow-up in this trial without Merck and showed a 20% reduction in cardiovascular events by 6 years. This has been the strongest rationale for our investors,” Dr. Kastelein said.   

He pointed out that obicetrapib is much more potent than anacetrapib. “Obicetrapib reduces LDL by 50% at just a 10-mg dose, whereas anacetrapib was used at a dose of 100 mg to give a 17%-20% LDL reduction.”
 

Could HDL increase be beneficial after all?

Although increasing HDL is currently not thought to bring about a direct reduction in cardiovascular events, there is new evidence emerging that increasing HDL may confer some benefit in protecting against the development of type 2 diabetes, Dr. Kastelein noted.

“We know that statins can increase risk of developing type 2 diabetes, and post hoc analyses of previous trials with CETP inhibitors suggest that these drugs have the opposite effect,” he said. “We will investigate this protectively in our phase 3 outcomes trial. If this is a true effect, it should eventually translate into a reduction in cardiovascular outcomes, but this could take a longer time to see than the benefits of lowering LDL.”

Commenting on the current data, Steven Nissen, MD, of Cleveland Clinic, said: “The results are truly impressive – a nearly 50% LDL reduction on a background of statins with a once-daily oral agent. While PCSK9 inhibitors can achieve similar results, they are injectable and costly.

“Since anacetrapib, a much weaker CETP inhibitor, was successful at reducing major adverse cardiac events, the likelihood that obicetrapib would reduce MACE even more substantially is very high,” he added.

Dr. Nissen said he has been aware of this drug for some time and has advised the company about development options and regulatory strategy. “I have encouraged this company to develop this very promising drug,” he said.

The current study was funded by New Amsterdam Pharma. Dr. Nicholls reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, Infraredx, Roche, Sanofi-Regeneron and LipoScience, and honoraria from New Amsterdam Pharma, AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr. Kastelein is chief scientific officer of New Amsterdam Pharma.  

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

A new lipid-lowering agent in a class that had been written off by many is being developed by a group of academic experts, with new data showing large LDL reductions on top of high-intensity statins.

Obicetrapib is a member of the cholesteryl ester transfer protein (CETP) inhibitor class, which had fallen out of favor after several disappointments with previous drugs in this class.

These agents were initially developed for their ability to raise HDL cholesterol, which was thought to be beneficial. But that approach has now been virtually abandoned after several studies failed to show a link between raising HDL and a reduction in subsequent cardiovascular events.

However, obicetrapib, which is said to be the most potent CETP inhibitor to date, has been shown to produce impressive LDL reductions, and it’s this important data that has caused several lipid experts to want to continue its development.

New data, presented at the recent American Heart Association scientific sessions, show that obicetrapib reduces LDL by 50% when given in addition to high-intensity statins, which could place it as competition for PCSK9 inhibitors or the new agent, inclisiran, but with the advantage of oral dosing.

The drug was in development by Amgen, but the company decided to discontinue its development in 2017 after disappointing results had been seen with several other CETP inhibitors and interest in this class of agent was waning.

But academic experts in the lipid field, led by John Kastelein, MD, PhD, professor of medicine at the Academic Medical Center, University of Amsterdam, and Michael Davidson, MD, clinical professor of medicine at University of Chicago, believed the drug had potential and have acquired obicetrapib from Amgen.

Dr. Kastelein and Dr. Davidson have set up a new company – New Amsterdam Pharma – to further develop obicetrapib, and have raised $200 million from venture capital funding to complete phase 2 and phase 3 studies.

The company has a heavyweight academic advisory board including Stephen Nicholls, MD, Monash University, Clayton, Australia; Kausik Ray, MD, Imperial College London; and Christie Ballantyne, MD, Baylor College of Medicine, Houston.

“We wanted to develop obicetrapib further because of its amazing LDL-lowering properties,” Dr. Kastelein said in an interview.

“No one has paid much attention to CETP inhibitors after the HDL hypothesis was disregarded, as everyone thought these drugs were just about raising HDL. But actually, they can also lower LDL, and this particular agent reduces LDL very effectively,” Dr. Kastelein said.
 

ROSE study

Dr. Nicholls presented the latest data on obicetrapib at the AHA meeting.

“Despite the use of high-intensity statins, two-thirds of patients do not reach their target LDL level, so we have a need for new therapies that lower LDL and can be used in combination with high-intensity statins,” he explained.

He noted that earlier studies with obicetrapib showed a 45% lowering of LDL with monotherapy.

Dr. Nicholls reported that recent evidence has emerged that increases interest in inhibiting CETP to be potentially cardioprotective.

To begin, genetic studies have shown that genetic polymorphisms associated with lower levels of CETP appear to be cardioprotective, and this is associated with lower levels of LDL rather than higher levels of HDL. 

Furthermore, the REVEAL cardiovascular outcomes trial with anacetrapib (also a CETP inhibitor) in 2017 showed a significant 9% reduction in major adverse cardiac events (MACE) after 4 years of follow-up. “This was exactly predicted by the 11 mg/dL drop in absolute LDL cholesterol level. It was not predicted or associated with the increase in HDL level observed with that agent,” Dr. Nicholls said.

The objective of the current ROSE study was to evaluate the lipid-lowering ability, safety, and tolerability of obicetrapib in patients on high-intensity statins.

The study included 120 patients who had been treated on a stable dose of high-intensity statins (atorvastatin at a dose of at least 40 mg daily or rosuvastatin at a dose of 20 mg daily) for at least 8 weeks. All patients were required to have a fasting LDL of at least 70 mg/dL and the median baseline LDL was 90 mg/dL. They were randomly assigned to obicetrapib (5 mg or 10 mg daily) or placebo.

The primary endpoint was the difference between groups in percentage change in LDL from baseline to week 8, with LDL levels measured by two different techniques.

Results showed a “robust” 51% reduction in LDL with the 10-mg dose of obicetrapib, and a 42% reduction with the 5-mg dose, Dr. Nicholls reported.

These effects were comparable regardless of baseline LDL and were similar with both methods of LDL measurement. 

Almost all patients demonstrated some degree of LDL cholesterol lowering, with only three patients on the 5-mg dose and one patient on the 10-mg dose not showing any reduction in LDL.

Other results showed a dose-dependent lowering of Apo B of up to 30%, and a reduction of non-HDL cholesterol of up to 44%.

“Predictably, there were also increases of HDL cholesterol,” Dr. Nicholls said. “At the 10-mg dose, we see a 165% increase in HDL levels. That is associated with a 48% increase in Apo A1 levels. This is very consistent with findings from the previous monotherapy study.”  

There was a 56% reduction in Lp(a) levels, and a modest 11% reduction in triglycerides.

Both doses of obicetrapib were well tolerated, with no increase in the rate of adverse events. Only one patient discontinued the study drug because of an adverse event and that patient was in the placebo group, Dr. Nicholls noted.  

“Blood pressure is an important adverse event to look at in the CETP class given the challenges seen with the first CETP evaluated – torcetrapib,” Dr. Nicholls said. “But in the three clinical trials with obicetrapib conducted to date, reassuringly, we see no increase in either systolic or diastolic blood pressure with either the 5-mg or 10-mg dose.”

He concluded that obicetrapib “could be a valuable addition to high-risk patients with atherosclerotic cardiovascular disease who do not achieve their target LDL level despite use of high-intensity statin therapy.”
 

Differences from other CETP inhibitors

Asked how obicetrapib differs from other agents in the CETP inhibitor class, Dr. Nicholls replied that obicetrapib is much more potent, as shown by the large lipid changes seen with very small quantities of this drug, 5 mg or 10 mg, whereas prior CETP inhibitors showed smaller changes with much higher doses.

“We are giving very small amounts of obicetrapib and seeing very robust effects on both atherogenic and lipid parameters,” he said.  

“The other major point with this class of agent is that the first drug, torcetrapib, had toxicity, which resulted in increased cardiovascular events. But it has now been established that torcetrapib had a number of off-target effects that have not been seen with subsequent agents in this class,” he said.

Studies so far show that obicetrapib does not have torcetrapib-like effects. “That is encouraging. This, and the impressive LDL lowering effects, certainly lay the foundation for larger studies moving forward,” he added.

“This has been an intriguing field to many of us involved from the start. We started with a very disappointing result with torcetrapib. Then a couple of studies looked to be clinically futile, but we were encouraged by the REVEAL study which suggested that there might be benefit,” Dr. Nicholls said.

“If we combined the REVEAL results with the genetic data, it has actually flipped the whole CETP story upside down. We started thinking that inhibiting CETP was all about raising HDL, but it turns out that it is about LDL lowering,” he said. “And that is not only important in terms of the lipid effects but also the trials and the way they are designed.

“I think you’ll find that the future trials in this class and with this agent will have LDL very much in mind and that will very much influence the study design,” he said, adding that a larger cardiovascular outcome trial is now being planned. 

“The regulatory perspective is that LDL is a pretty trusted surrogate ... but I think an outcomes trial will be important to reinforce and reassure on safety and outline cost-effectiveness, which will help us understand where the sweet spot for using this agent in the clinic will be,” Dr. Nicholls noted.  

Dr. Kastelein explained that it has taken some time to realize that CETP inhibitors may be valuable for reducing LDL.   

“The first agent, torcetrapib, had an off-target toxicity that led to increased blood pressure but a specific part of the torcetrapib molecule was subsequently identified that was responsible for that, and subsequent agents in the CETP inhibitor class did not have such adverse effects,” he said.  

“The next agent, dalcetrapib (Roche), raised HDL but didn’t move LDL, and an outcomes trial with evacetrapib (Lilly) was stopped after 2 years because of futility, but we now believe that lipid lowering trials need longer term follow-up – up to 5 years – to see a benefit,” he noted.  

Dr. Kastelein reports that anacetrapib (Merck) has been the most powerful CETP inhibitor until now, giving an LDL reduction of about 20%, which was associated with a 10% reduction in cardiovascular events in first 4 years of follow-up. 

“Oxford academic researchers decided to continue follow-up in this trial without Merck and showed a 20% reduction in cardiovascular events by 6 years. This has been the strongest rationale for our investors,” Dr. Kastelein said.   

He pointed out that obicetrapib is much more potent than anacetrapib. “Obicetrapib reduces LDL by 50% at just a 10-mg dose, whereas anacetrapib was used at a dose of 100 mg to give a 17%-20% LDL reduction.”
 

Could HDL increase be beneficial after all?

Although increasing HDL is currently not thought to bring about a direct reduction in cardiovascular events, there is new evidence emerging that increasing HDL may confer some benefit in protecting against the development of type 2 diabetes, Dr. Kastelein noted.

“We know that statins can increase risk of developing type 2 diabetes, and post hoc analyses of previous trials with CETP inhibitors suggest that these drugs have the opposite effect,” he said. “We will investigate this protectively in our phase 3 outcomes trial. If this is a true effect, it should eventually translate into a reduction in cardiovascular outcomes, but this could take a longer time to see than the benefits of lowering LDL.”

Commenting on the current data, Steven Nissen, MD, of Cleveland Clinic, said: “The results are truly impressive – a nearly 50% LDL reduction on a background of statins with a once-daily oral agent. While PCSK9 inhibitors can achieve similar results, they are injectable and costly.

“Since anacetrapib, a much weaker CETP inhibitor, was successful at reducing major adverse cardiac events, the likelihood that obicetrapib would reduce MACE even more substantially is very high,” he added.

Dr. Nissen said he has been aware of this drug for some time and has advised the company about development options and regulatory strategy. “I have encouraged this company to develop this very promising drug,” he said.

The current study was funded by New Amsterdam Pharma. Dr. Nicholls reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, Infraredx, Roche, Sanofi-Regeneron and LipoScience, and honoraria from New Amsterdam Pharma, AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr. Kastelein is chief scientific officer of New Amsterdam Pharma.  

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

A new lipid-lowering agent in a class that had been written off by many is being developed by a group of academic experts, with new data showing large LDL reductions on top of high-intensity statins.

Obicetrapib is a member of the cholesteryl ester transfer protein (CETP) inhibitor class, which had fallen out of favor after several disappointments with previous drugs in this class.

These agents were initially developed for their ability to raise HDL cholesterol, which was thought to be beneficial. But that approach has now been virtually abandoned after several studies failed to show a link between raising HDL and a reduction in subsequent cardiovascular events.

However, obicetrapib, which is said to be the most potent CETP inhibitor to date, has been shown to produce impressive LDL reductions, and it’s this important data that has caused several lipid experts to want to continue its development.

New data, presented at the recent American Heart Association scientific sessions, show that obicetrapib reduces LDL by 50% when given in addition to high-intensity statins, which could place it as competition for PCSK9 inhibitors or the new agent, inclisiran, but with the advantage of oral dosing.

The drug was in development by Amgen, but the company decided to discontinue its development in 2017 after disappointing results had been seen with several other CETP inhibitors and interest in this class of agent was waning.

But academic experts in the lipid field, led by John Kastelein, MD, PhD, professor of medicine at the Academic Medical Center, University of Amsterdam, and Michael Davidson, MD, clinical professor of medicine at University of Chicago, believed the drug had potential and have acquired obicetrapib from Amgen.

Dr. Kastelein and Dr. Davidson have set up a new company – New Amsterdam Pharma – to further develop obicetrapib, and have raised $200 million from venture capital funding to complete phase 2 and phase 3 studies.

The company has a heavyweight academic advisory board including Stephen Nicholls, MD, Monash University, Clayton, Australia; Kausik Ray, MD, Imperial College London; and Christie Ballantyne, MD, Baylor College of Medicine, Houston.

“We wanted to develop obicetrapib further because of its amazing LDL-lowering properties,” Dr. Kastelein said in an interview.

“No one has paid much attention to CETP inhibitors after the HDL hypothesis was disregarded, as everyone thought these drugs were just about raising HDL. But actually, they can also lower LDL, and this particular agent reduces LDL very effectively,” Dr. Kastelein said.
 

ROSE study

Dr. Nicholls presented the latest data on obicetrapib at the AHA meeting.

“Despite the use of high-intensity statins, two-thirds of patients do not reach their target LDL level, so we have a need for new therapies that lower LDL and can be used in combination with high-intensity statins,” he explained.

He noted that earlier studies with obicetrapib showed a 45% lowering of LDL with monotherapy.

Dr. Nicholls reported that recent evidence has emerged that increases interest in inhibiting CETP to be potentially cardioprotective.

To begin, genetic studies have shown that genetic polymorphisms associated with lower levels of CETP appear to be cardioprotective, and this is associated with lower levels of LDL rather than higher levels of HDL. 

Furthermore, the REVEAL cardiovascular outcomes trial with anacetrapib (also a CETP inhibitor) in 2017 showed a significant 9% reduction in major adverse cardiac events (MACE) after 4 years of follow-up. “This was exactly predicted by the 11 mg/dL drop in absolute LDL cholesterol level. It was not predicted or associated with the increase in HDL level observed with that agent,” Dr. Nicholls said.

The objective of the current ROSE study was to evaluate the lipid-lowering ability, safety, and tolerability of obicetrapib in patients on high-intensity statins.

The study included 120 patients who had been treated on a stable dose of high-intensity statins (atorvastatin at a dose of at least 40 mg daily or rosuvastatin at a dose of 20 mg daily) for at least 8 weeks. All patients were required to have a fasting LDL of at least 70 mg/dL and the median baseline LDL was 90 mg/dL. They were randomly assigned to obicetrapib (5 mg or 10 mg daily) or placebo.

The primary endpoint was the difference between groups in percentage change in LDL from baseline to week 8, with LDL levels measured by two different techniques.

Results showed a “robust” 51% reduction in LDL with the 10-mg dose of obicetrapib, and a 42% reduction with the 5-mg dose, Dr. Nicholls reported.

These effects were comparable regardless of baseline LDL and were similar with both methods of LDL measurement. 

Almost all patients demonstrated some degree of LDL cholesterol lowering, with only three patients on the 5-mg dose and one patient on the 10-mg dose not showing any reduction in LDL.

Other results showed a dose-dependent lowering of Apo B of up to 30%, and a reduction of non-HDL cholesterol of up to 44%.

“Predictably, there were also increases of HDL cholesterol,” Dr. Nicholls said. “At the 10-mg dose, we see a 165% increase in HDL levels. That is associated with a 48% increase in Apo A1 levels. This is very consistent with findings from the previous monotherapy study.”  

There was a 56% reduction in Lp(a) levels, and a modest 11% reduction in triglycerides.

Both doses of obicetrapib were well tolerated, with no increase in the rate of adverse events. Only one patient discontinued the study drug because of an adverse event and that patient was in the placebo group, Dr. Nicholls noted.  

“Blood pressure is an important adverse event to look at in the CETP class given the challenges seen with the first CETP evaluated – torcetrapib,” Dr. Nicholls said. “But in the three clinical trials with obicetrapib conducted to date, reassuringly, we see no increase in either systolic or diastolic blood pressure with either the 5-mg or 10-mg dose.”

He concluded that obicetrapib “could be a valuable addition to high-risk patients with atherosclerotic cardiovascular disease who do not achieve their target LDL level despite use of high-intensity statin therapy.”
 

Differences from other CETP inhibitors

Asked how obicetrapib differs from other agents in the CETP inhibitor class, Dr. Nicholls replied that obicetrapib is much more potent, as shown by the large lipid changes seen with very small quantities of this drug, 5 mg or 10 mg, whereas prior CETP inhibitors showed smaller changes with much higher doses.

“We are giving very small amounts of obicetrapib and seeing very robust effects on both atherogenic and lipid parameters,” he said.  

“The other major point with this class of agent is that the first drug, torcetrapib, had toxicity, which resulted in increased cardiovascular events. But it has now been established that torcetrapib had a number of off-target effects that have not been seen with subsequent agents in this class,” he said.

Studies so far show that obicetrapib does not have torcetrapib-like effects. “That is encouraging. This, and the impressive LDL lowering effects, certainly lay the foundation for larger studies moving forward,” he added.

“This has been an intriguing field to many of us involved from the start. We started with a very disappointing result with torcetrapib. Then a couple of studies looked to be clinically futile, but we were encouraged by the REVEAL study which suggested that there might be benefit,” Dr. Nicholls said.

“If we combined the REVEAL results with the genetic data, it has actually flipped the whole CETP story upside down. We started thinking that inhibiting CETP was all about raising HDL, but it turns out that it is about LDL lowering,” he said. “And that is not only important in terms of the lipid effects but also the trials and the way they are designed.

“I think you’ll find that the future trials in this class and with this agent will have LDL very much in mind and that will very much influence the study design,” he said, adding that a larger cardiovascular outcome trial is now being planned. 

“The regulatory perspective is that LDL is a pretty trusted surrogate ... but I think an outcomes trial will be important to reinforce and reassure on safety and outline cost-effectiveness, which will help us understand where the sweet spot for using this agent in the clinic will be,” Dr. Nicholls noted.  

Dr. Kastelein explained that it has taken some time to realize that CETP inhibitors may be valuable for reducing LDL.   

“The first agent, torcetrapib, had an off-target toxicity that led to increased blood pressure but a specific part of the torcetrapib molecule was subsequently identified that was responsible for that, and subsequent agents in the CETP inhibitor class did not have such adverse effects,” he said.  

“The next agent, dalcetrapib (Roche), raised HDL but didn’t move LDL, and an outcomes trial with evacetrapib (Lilly) was stopped after 2 years because of futility, but we now believe that lipid lowering trials need longer term follow-up – up to 5 years – to see a benefit,” he noted.  

Dr. Kastelein reports that anacetrapib (Merck) has been the most powerful CETP inhibitor until now, giving an LDL reduction of about 20%, which was associated with a 10% reduction in cardiovascular events in first 4 years of follow-up. 

“Oxford academic researchers decided to continue follow-up in this trial without Merck and showed a 20% reduction in cardiovascular events by 6 years. This has been the strongest rationale for our investors,” Dr. Kastelein said.   

He pointed out that obicetrapib is much more potent than anacetrapib. “Obicetrapib reduces LDL by 50% at just a 10-mg dose, whereas anacetrapib was used at a dose of 100 mg to give a 17%-20% LDL reduction.”
 

Could HDL increase be beneficial after all?

Although increasing HDL is currently not thought to bring about a direct reduction in cardiovascular events, there is new evidence emerging that increasing HDL may confer some benefit in protecting against the development of type 2 diabetes, Dr. Kastelein noted.

“We know that statins can increase risk of developing type 2 diabetes, and post hoc analyses of previous trials with CETP inhibitors suggest that these drugs have the opposite effect,” he said. “We will investigate this protectively in our phase 3 outcomes trial. If this is a true effect, it should eventually translate into a reduction in cardiovascular outcomes, but this could take a longer time to see than the benefits of lowering LDL.”

Commenting on the current data, Steven Nissen, MD, of Cleveland Clinic, said: “The results are truly impressive – a nearly 50% LDL reduction on a background of statins with a once-daily oral agent. While PCSK9 inhibitors can achieve similar results, they are injectable and costly.

“Since anacetrapib, a much weaker CETP inhibitor, was successful at reducing major adverse cardiac events, the likelihood that obicetrapib would reduce MACE even more substantially is very high,” he added.

Dr. Nissen said he has been aware of this drug for some time and has advised the company about development options and regulatory strategy. “I have encouraged this company to develop this very promising drug,” he said.

The current study was funded by New Amsterdam Pharma. Dr. Nicholls reports grants from AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, Infraredx, Roche, Sanofi-Regeneron and LipoScience, and honoraria from New Amsterdam Pharma, AstraZeneca, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, and Boehringer Ingelheim. Dr. Kastelein is chief scientific officer of New Amsterdam Pharma.  

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