Pharmacology

The effectiveness of the human papillomavirus (HPV) vaccine against HPV types 16 and 18 is highly dependent on the age at which it is given. Prevalence rates have been shown to be significantly lower among girls who are vaccinated at the recommended ages of 9-12 years, compared with those who are vaccinated after their sexual debut, data from the National Health and Nutrition Examination Survey (NHANES) indicate.

“HPV vaccination does not have any therapeutic effect on HPV infections already acquired, which is more likely to explain the difference in prevalence between predebut versus postdebut recipients than a lower immune response [among older recipients],” lead study author Didem Egemen, PhD, National Cancer Institute, Rockville, Md., told this news organization in an email.

“Still, among older females, the immune response of the vaccine is likely to still be quite strong, and we would encourage vaccination [of female patients] if unvaccinated, as our paper showed that vaccination post debut will still reduce HPV 16/18 prevalence by half,” she added.

The research letter was published online in JAMA Network Open.
 

National sample evaluated

Using data from NHANES, a biennial, cross-sectional sample (cycles 2011 through 2018), the researchers identified female persons who were aged 26 years or younger in 2006, when HPV vaccination was introduced, and who were eligible for routine vaccination or “catch-up” vaccination (given between the ages of 13 and 26 years), as per recommendations from the Advisory Committee on Immunization Practices. The investigators then compared the prevalence of HPV types 16 and 18 among unvaccinated female patients, female patients who had been vaccinated prior to their sexual debut (predebut group), and those who had been vaccinated after their sexual debut (postdebut group).

They also estimated vaccine uptake among those who were eligible for routine vaccination, as well as the proportion of vaccinated female patients with respect to racial and ethnic subgroups.

In the overall cohort, the prevalence of HPV types 16 and 18 decreased by 6% (95% confidence interval, 4%-7%) in the unvaccinated group to 3% (95% CI, 1%-6%) in the postdebut group and to less than 1% (95% CI, <1%-1%) in the predebut group, Dr. Egemen and colleagues report.

In real percentages, the prevalence of HPV 16 and 18 was 89% lower in the predebut group (P < .001) but only 41% lower in the postdebut group (P = .29) compared with unvaccinated female patients. And compared with female patients who were vaccinated after their sexual debut, the prevalence of HPV 16 and 18 was reduced by 82% among those who had received the vaccine at the recommended ages of 9-12 years (P = .08).

In the current study, Dr. Egeman acknowledged that only 38% of ever-eligible female patients received the vaccine, although the prevalence increased to 56% when only female patients who were eligible for routine vaccination were taken into account. On the other hand, only 21% (95% CI, 14%-28%) of female patients eligible for routine vaccination received their first dose by age 12 years.

Indeed, the mean age on receipt of the first vaccination dose was 14.5 years (95% CI, 14.1-14.8 years), the authors note, and only 59% of girls received their first dose prior to their sexual debut. Additionally, among routine vaccination–eligible girls aged 12 years or younger in 2006, 33% were vaccinated before and 23% after their sexual debut, and the rest were not vaccinated.

Interestingly, differences in the age at which the HPV vaccine was received by race and ethnicity were negligible, the investigators point out.
 

Vaccination rates increasing

Asked to comment on the findings, Rebecca Perkins, MD, professor of obstetrics and gynecology at Boston University, Boston Medical Center, pointed out that the investigators evaluated data from 2011 to 2018. “We know that HPV vaccination rates have increased over that period and continue to increase,” she emphasized in an email to this news organization.

Physicians also know that more persons are being vaccinated between the ages of 9 and 12 than was the case at the beginning of this study. “This is good news,” she said, “as it means that more adolescents now in 2022 are benefiting fully from vaccination than they were in 2011,” she added.

At the same time, Dr. Perkins acknowledged that many persons are still missing out on the chance to receive the vaccine on time – which means they are missing out on the chance to prevent cancer.

“Making sure that all adolescents receive vaccination between the ages of 9 to 12 has the potential to prevent up to 40,000 cancers every year in the U.S., [including] the most common HPV-related cancers, such as cervical cancer in women and tongue and tonsillar cancer in men,” Dr. Perkins noted.

“Thus, it’s critical that doctors and parents get the message that you can’t vaccinate too early, only too late,” she emphasized.

Dr. Edgman and Dr. Perkins report no relevant financial relationships.

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

The effectiveness of the human papillomavirus (HPV) vaccine against HPV types 16 and 18 is highly dependent on the age at which it is given. Prevalence rates have been shown to be significantly lower among girls who are vaccinated at the recommended ages of 9-12 years, compared with those who are vaccinated after their sexual debut, data from the National Health and Nutrition Examination Survey (NHANES) indicate.

“HPV vaccination does not have any therapeutic effect on HPV infections already acquired, which is more likely to explain the difference in prevalence between predebut versus postdebut recipients than a lower immune response [among older recipients],” lead study author Didem Egemen, PhD, National Cancer Institute, Rockville, Md., told this news organization in an email.

“Still, among older females, the immune response of the vaccine is likely to still be quite strong, and we would encourage vaccination [of female patients] if unvaccinated, as our paper showed that vaccination post debut will still reduce HPV 16/18 prevalence by half,” she added.

The research letter was published online in JAMA Network Open.
 

National sample evaluated

Using data from NHANES, a biennial, cross-sectional sample (cycles 2011 through 2018), the researchers identified female persons who were aged 26 years or younger in 2006, when HPV vaccination was introduced, and who were eligible for routine vaccination or “catch-up” vaccination (given between the ages of 13 and 26 years), as per recommendations from the Advisory Committee on Immunization Practices. The investigators then compared the prevalence of HPV types 16 and 18 among unvaccinated female patients, female patients who had been vaccinated prior to their sexual debut (predebut group), and those who had been vaccinated after their sexual debut (postdebut group).

They also estimated vaccine uptake among those who were eligible for routine vaccination, as well as the proportion of vaccinated female patients with respect to racial and ethnic subgroups.

In the overall cohort, the prevalence of HPV types 16 and 18 decreased by 6% (95% confidence interval, 4%-7%) in the unvaccinated group to 3% (95% CI, 1%-6%) in the postdebut group and to less than 1% (95% CI, <1%-1%) in the predebut group, Dr. Egemen and colleagues report.

In real percentages, the prevalence of HPV 16 and 18 was 89% lower in the predebut group (P < .001) but only 41% lower in the postdebut group (P = .29) compared with unvaccinated female patients. And compared with female patients who were vaccinated after their sexual debut, the prevalence of HPV 16 and 18 was reduced by 82% among those who had received the vaccine at the recommended ages of 9-12 years (P = .08).

In the current study, Dr. Egeman acknowledged that only 38% of ever-eligible female patients received the vaccine, although the prevalence increased to 56% when only female patients who were eligible for routine vaccination were taken into account. On the other hand, only 21% (95% CI, 14%-28%) of female patients eligible for routine vaccination received their first dose by age 12 years.

Indeed, the mean age on receipt of the first vaccination dose was 14.5 years (95% CI, 14.1-14.8 years), the authors note, and only 59% of girls received their first dose prior to their sexual debut. Additionally, among routine vaccination–eligible girls aged 12 years or younger in 2006, 33% were vaccinated before and 23% after their sexual debut, and the rest were not vaccinated.

Interestingly, differences in the age at which the HPV vaccine was received by race and ethnicity were negligible, the investigators point out.
 

Vaccination rates increasing

Asked to comment on the findings, Rebecca Perkins, MD, professor of obstetrics and gynecology at Boston University, Boston Medical Center, pointed out that the investigators evaluated data from 2011 to 2018. “We know that HPV vaccination rates have increased over that period and continue to increase,” she emphasized in an email to this news organization.

Physicians also know that more persons are being vaccinated between the ages of 9 and 12 than was the case at the beginning of this study. “This is good news,” she said, “as it means that more adolescents now in 2022 are benefiting fully from vaccination than they were in 2011,” she added.

At the same time, Dr. Perkins acknowledged that many persons are still missing out on the chance to receive the vaccine on time – which means they are missing out on the chance to prevent cancer.

“Making sure that all adolescents receive vaccination between the ages of 9 to 12 has the potential to prevent up to 40,000 cancers every year in the U.S., [including] the most common HPV-related cancers, such as cervical cancer in women and tongue and tonsillar cancer in men,” Dr. Perkins noted.

“Thus, it’s critical that doctors and parents get the message that you can’t vaccinate too early, only too late,” she emphasized.

Dr. Edgman and Dr. Perkins report no relevant financial relationships.

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

The effectiveness of the human papillomavirus (HPV) vaccine against HPV types 16 and 18 is highly dependent on the age at which it is given. Prevalence rates have been shown to be significantly lower among girls who are vaccinated at the recommended ages of 9-12 years, compared with those who are vaccinated after their sexual debut, data from the National Health and Nutrition Examination Survey (NHANES) indicate.

“HPV vaccination does not have any therapeutic effect on HPV infections already acquired, which is more likely to explain the difference in prevalence between predebut versus postdebut recipients than a lower immune response [among older recipients],” lead study author Didem Egemen, PhD, National Cancer Institute, Rockville, Md., told this news organization in an email.

“Still, among older females, the immune response of the vaccine is likely to still be quite strong, and we would encourage vaccination [of female patients] if unvaccinated, as our paper showed that vaccination post debut will still reduce HPV 16/18 prevalence by half,” she added.

The research letter was published online in JAMA Network Open.
 

National sample evaluated

Using data from NHANES, a biennial, cross-sectional sample (cycles 2011 through 2018), the researchers identified female persons who were aged 26 years or younger in 2006, when HPV vaccination was introduced, and who were eligible for routine vaccination or “catch-up” vaccination (given between the ages of 13 and 26 years), as per recommendations from the Advisory Committee on Immunization Practices. The investigators then compared the prevalence of HPV types 16 and 18 among unvaccinated female patients, female patients who had been vaccinated prior to their sexual debut (predebut group), and those who had been vaccinated after their sexual debut (postdebut group).

They also estimated vaccine uptake among those who were eligible for routine vaccination, as well as the proportion of vaccinated female patients with respect to racial and ethnic subgroups.

In the overall cohort, the prevalence of HPV types 16 and 18 decreased by 6% (95% confidence interval, 4%-7%) in the unvaccinated group to 3% (95% CI, 1%-6%) in the postdebut group and to less than 1% (95% CI, <1%-1%) in the predebut group, Dr. Egemen and colleagues report.

In real percentages, the prevalence of HPV 16 and 18 was 89% lower in the predebut group (P < .001) but only 41% lower in the postdebut group (P = .29) compared with unvaccinated female patients. And compared with female patients who were vaccinated after their sexual debut, the prevalence of HPV 16 and 18 was reduced by 82% among those who had received the vaccine at the recommended ages of 9-12 years (P = .08).

In the current study, Dr. Egeman acknowledged that only 38% of ever-eligible female patients received the vaccine, although the prevalence increased to 56% when only female patients who were eligible for routine vaccination were taken into account. On the other hand, only 21% (95% CI, 14%-28%) of female patients eligible for routine vaccination received their first dose by age 12 years.

Indeed, the mean age on receipt of the first vaccination dose was 14.5 years (95% CI, 14.1-14.8 years), the authors note, and only 59% of girls received their first dose prior to their sexual debut. Additionally, among routine vaccination–eligible girls aged 12 years or younger in 2006, 33% were vaccinated before and 23% after their sexual debut, and the rest were not vaccinated.

Interestingly, differences in the age at which the HPV vaccine was received by race and ethnicity were negligible, the investigators point out.
 

Vaccination rates increasing

Asked to comment on the findings, Rebecca Perkins, MD, professor of obstetrics and gynecology at Boston University, Boston Medical Center, pointed out that the investigators evaluated data from 2011 to 2018. “We know that HPV vaccination rates have increased over that period and continue to increase,” she emphasized in an email to this news organization.

Physicians also know that more persons are being vaccinated between the ages of 9 and 12 than was the case at the beginning of this study. “This is good news,” she said, “as it means that more adolescents now in 2022 are benefiting fully from vaccination than they were in 2011,” she added.

At the same time, Dr. Perkins acknowledged that many persons are still missing out on the chance to receive the vaccine on time – which means they are missing out on the chance to prevent cancer.

“Making sure that all adolescents receive vaccination between the ages of 9 to 12 has the potential to prevent up to 40,000 cancers every year in the U.S., [including] the most common HPV-related cancers, such as cervical cancer in women and tongue and tonsillar cancer in men,” Dr. Perkins noted.

“Thus, it’s critical that doctors and parents get the message that you can’t vaccinate too early, only too late,” she emphasized.

Dr. Edgman and Dr. Perkins report no relevant financial relationships.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

ORLANDO – Treatment with a renin-angiotensin system (RAS) inhibitor is widely accepted as standard practice for slowing progression of chronic kidney disease (CKD), but data have been inconsistent as to whether there is benefit to continuing RAS inhibition when patients develop advanced CKD, defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min per 1.73 m².

Now, in STOP ACEi, a new multicenter, randomized trial of 411 patients, maintaining treatment with a RAS inhibitor in adults with advanced and progressive CKD did not cause a clinically relevant change in kidney function, or in the long-term rate of decline in kidney function, compared with stopping treatment, for 3 years.

People who continued RAS inhibitor treatment did not develop a significant or clinically relevant decrease in eGFR, the study’s primary outcome, both overall as well as in several prespecified subgroups compared with those who discontinued treatment, said Sunil Bhandari, MBChB, PhD, and associates, who presented the research in a poster at the annual meeting of the American Society of Nephrology.

“I hope these results will reassure clinicians to continue ACE inhibitors or ARBs” in patients with advanced CKD, “with their known beneficial cardiovascular effects,” Dr. Bhandari said in an interview.

The results were simultaneously published in the New England Journal of Medicine.
 

Similar eGFR levels after 3 years

While it’s clear that in patients with mild or moderate CKD, treatment with a RAS inhibitor, which includes angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), reduces blood pressure, slows decline in eGFR, reduces proteinuria, and delays progression to advanced CKD, there has been little evidence that the use of RAS inhibitors benefits patients with advanced CKD.

Data from previous trials have been inconsistent regarding whether the use of RAS inhibitors is nephroprotective in patients with advanced CKD, say Dr. Bhandari, a nephrologist and professor at Hull York Medical School, Hull, England, and colleagues.

“Current guidelines do not provide specific advice on whether to continue or stop ACE inhibitors or ARBs for advanced chronic kidney disease,” they also note.

And so they decided to assess whether discontinuation of ACE inhibitors/ARBs could slow progression of CKD in patients with advanced CKD.

Three years after 206 study participants stopped RAS inhibitor treatment, the least-squares mean eGFR was 12.6 mL/min per 1.73m² in the discontinuation group and 13.3 mL/min per 1.73 m² in the 205 patients in the continuation group, a difference that was not significant.

In addition to the primary outcome, 62% of patients who stopped RAS inhibitor treatment and 56% of those who continued developed end-stage kidney disease or required renal-replacement therapy, which translated into an adjusted hazard ratio of 1.28 for this outcome among those who discontinued compared with those who continued, which was just short of significance (95% CI, 0.99-1.65).

The two study groups also showed no significant differences in the 3-year incidence of hospitalization for any reason, cardiovascular events, or deaths. The two groups also showed no meaningful differences in various domains of quality of life and no differences in serious adverse effects.
 

Participants had an eGFR less than 30 mL/min per 1.73 m²

The study ran at 39 United Kingdom centers in 2014-2019. Investigators enrolled adults with an eGFR of less than 30 mL/min per 1.73 m² who were not on dialysis and had not received a kidney transplant. In addition, all enrolled patients had to have an annual drop in eGFR of more than 2 mL/min per 1.73 m² during the prior 2 years and had to have been on treatment with at least one RAS inhibitor for more than 6 months.

The randomization protocol insured balanced distribution of subjects between the two study arms by age, eGFR, presence of diabetes, and level of proteinuria, among other factors. The study design also mandated that participants maintain a blood pressure of no more than 140/85 mm Hg.

Those who discontinued RAS-inhibitor treatment could receive any guideline-recommended antihypertensive agent that was not a RAS inhibitor, although adding a RAS inhibitor was permitted as a last treatment resort.

People in the maintenance group could receive whichever additional antihypertensive agents their treating clinicians deemed necessary for maintaining the target blood pressure.

The enrolled population was a median age of 63 years old and 68% were men. Their average eGFR at baseline was 18 mL/min per 1.73 m², and 118 (29%) had an eGFR of less than 15 mL/min per 1.73 m². Their median level of proteinuria was 115 mg/mmol (about 1,018 mg/g). Diabetes was prevalent in 37%, and 58% of participants were taking at least three antihypertensive medications at entry.

Among the study’s limitations, the researchers cited the open-label design, which may have affected clinical care and the tally of subjective endpoints, including quality of life and exercise capacity. Also, because the study enrolled people who were on a RAS inhibitor at the time of randomization, it did not include anyone who had already discontinued these agents.
 

Continue RAS inhibitors in advanced CKD for best outcomes

Dr. Bhandari and colleagues note that in a large observational trial published in January 2021, Swedish researchers found an increase in the incidence of major cardiovascular events and death among patients with advanced CKD who had discontinued RAS inhibitors.

But they observe, “Our trial did not have sufficient power to investigate the effect of the discontinuation of RAS inhibitors on cardiovascular events or mortality. However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety.”

“Our findings do not support the hypothesis that the discontinuation of RAS inhibitors in patients with advanced and progressive chronic kidney disease would improve kidney function, quality of life, or exercise capacity.”

“The results of this trial will inform future clinical practice worldwide and guideline recommendations,” they conclude.

STOP ACEi received no commercial funding. Dr. Bhandari has reported no relevant financial relationships.

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

The U.S. Centers for Disease Control and Prevention has released updated and expanded recommendations for prescribing opioids for adults with acute and chronic pain not related to cancer, sickle cell disease, or palliative/end-of-life care.

The 2022 Clinical Practice Guideline provides guidance on determining whether to initiate opioids for pain; selecting opioids and determining opioid dosages; deciding duration of initial opioid prescription and conducting follow-up; and assessing risk and addressing potential harms of opioid use.

“Patients with pain should receive compassionate, safe, and effective pain care. We want clinicians and patients to have the information they need to weigh the benefits of different approaches to pain care, with the goal of helping people reduce their pain and improve their quality of life,” Christopher M. Jones, PharmD, DrPH, acting director for the CDC’s National Center for Injury Prevention and Control, said in a news release.
 

How to taper safely

The last guideline on the topic was released by CDC in 2016. Since then, new evidence has emerged regarding the benefits and risks of prescription opioids for acute and chronic pain, comparisons with nonopioid pain treatments, dosing strategies, opioid dose-dependent effects, risk mitigation strategies, and opioid tapering and discontinuation, the CDC says.

A “critical” addition to the 2022 guideline is advice on tapering opioids, Dr. Jones said during a press briefing.

“Practical tips on how to taper in an individualized patient-centered manner have been added to help clinicians if the decision is made to taper opioids, and the guideline explicitly advises against abrupt discontinuation or rapid dose reductions of opioids,” Dr. Jones said.

“That is based on lessons learned over the last several years as well as new science about how we approach tapering and the real harms that can result when patients are abruptly discontinued or rapidly tapered,” he added.

The updated guideline was published online Nov. 3 in the Morbidity and Mortality Weekly Report.

Key recommendations in the 100-page document include the following:

• In determining whether or not to initiate opioids, nonopioid therapies are at least as effective as opioids for many common types of acute pain. Use of nondrug and nonopioid drug therapies should be maximized as appropriate, and opioid therapy should only be considered for acute pain if it is anticipated that benefits outweigh risks to the patient.
• Before starting opioid therapy, providers should discuss with patients the realistic benefits and known risks of opioid therapy.
• Before starting ongoing opioid therapy for patients with subacute pain lasting 1 to 3 months or chronic pain lasting more than 3 months, providers should work with patients to establish treatment goals for pain and function, and consideration should be given as to how opioid therapy will be discontinued if benefits do not outweigh risks.
• Once opioids are started, the lowest effective dose of immediate-release opioids should be prescribed for no longer than needed for the expected duration of pain severe enough to require opioids.
• Within 1 to 4 weeks of starting opioid therapy for subacute or chronic pain, providers should work with patients to evaluate and carefully weigh benefits and risks of continuing opioid therapy; care should be exercised when increasing, continuing, or reducing opioid dosage.
• Before starting and periodically during ongoing opioid therapy, providers should evaluate risk for opioid-related harms and should work with patients to incorporate relevant strategies to mitigate risk, including offering naloxone and reviewing potential interactions with any other prescribed medications or substance used.
• Abrupt discontinuation of opioids should be avoided, especially for patients receiving high doses.
• For treating patients with opioid use disorder, treatment with evidence-based medications should be provided, or arrangements for such treatment should be made.

Dr. Jones emphasized that the guideline is “voluntary and meant to guide shared decision-making between a clinician and patient. It’s not meant to be implemented as absolute limits of policy or practice by clinicians, health systems, insurance companies, governmental entities.”

He also noted that the “current state of the overdose crisis, which is very much driven by illicit synthetic opioids, is not the aim of this guideline.

“The release of this guideline is really about advancing pain care and improving the lives of patients living with pain,” he said.

“We know that at least 1 in 5 people in the country have chronic pain. It’s one of the most common reasons why people present to their health care provider, and the goal here is to advance pain care, function, and quality of life for that patient population, while also reducing misuse, diversion, and consequences of prescription opioid misuse,” Dr. Jones added.

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

The U.S. Centers for Disease Control and Prevention has released updated and expanded recommendations for prescribing opioids for adults with acute and chronic pain not related to cancer, sickle cell disease, or palliative/end-of-life care.

The 2022 Clinical Practice Guideline provides guidance on determining whether to initiate opioids for pain; selecting opioids and determining opioid dosages; deciding duration of initial opioid prescription and conducting follow-up; and assessing risk and addressing potential harms of opioid use.

“Patients with pain should receive compassionate, safe, and effective pain care. We want clinicians and patients to have the information they need to weigh the benefits of different approaches to pain care, with the goal of helping people reduce their pain and improve their quality of life,” Christopher M. Jones, PharmD, DrPH, acting director for the CDC’s National Center for Injury Prevention and Control, said in a news release.
 

How to taper safely

The last guideline on the topic was released by CDC in 2016. Since then, new evidence has emerged regarding the benefits and risks of prescription opioids for acute and chronic pain, comparisons with nonopioid pain treatments, dosing strategies, opioid dose-dependent effects, risk mitigation strategies, and opioid tapering and discontinuation, the CDC says.

A “critical” addition to the 2022 guideline is advice on tapering opioids, Dr. Jones said during a press briefing.

“Practical tips on how to taper in an individualized patient-centered manner have been added to help clinicians if the decision is made to taper opioids, and the guideline explicitly advises against abrupt discontinuation or rapid dose reductions of opioids,” Dr. Jones said.

“That is based on lessons learned over the last several years as well as new science about how we approach tapering and the real harms that can result when patients are abruptly discontinued or rapidly tapered,” he added.

The updated guideline was published online Nov. 3 in the Morbidity and Mortality Weekly Report.

Key recommendations in the 100-page document include the following:

• In determining whether or not to initiate opioids, nonopioid therapies are at least as effective as opioids for many common types of acute pain. Use of nondrug and nonopioid drug therapies should be maximized as appropriate, and opioid therapy should only be considered for acute pain if it is anticipated that benefits outweigh risks to the patient.
• Before starting opioid therapy, providers should discuss with patients the realistic benefits and known risks of opioid therapy.
• Before starting ongoing opioid therapy for patients with subacute pain lasting 1 to 3 months or chronic pain lasting more than 3 months, providers should work with patients to establish treatment goals for pain and function, and consideration should be given as to how opioid therapy will be discontinued if benefits do not outweigh risks.
• Once opioids are started, the lowest effective dose of immediate-release opioids should be prescribed for no longer than needed for the expected duration of pain severe enough to require opioids.
• Within 1 to 4 weeks of starting opioid therapy for subacute or chronic pain, providers should work with patients to evaluate and carefully weigh benefits and risks of continuing opioid therapy; care should be exercised when increasing, continuing, or reducing opioid dosage.
• Before starting and periodically during ongoing opioid therapy, providers should evaluate risk for opioid-related harms and should work with patients to incorporate relevant strategies to mitigate risk, including offering naloxone and reviewing potential interactions with any other prescribed medications or substance used.
• Abrupt discontinuation of opioids should be avoided, especially for patients receiving high doses.
• For treating patients with opioid use disorder, treatment with evidence-based medications should be provided, or arrangements for such treatment should be made.

Dr. Jones emphasized that the guideline is “voluntary and meant to guide shared decision-making between a clinician and patient. It’s not meant to be implemented as absolute limits of policy or practice by clinicians, health systems, insurance companies, governmental entities.”

He also noted that the “current state of the overdose crisis, which is very much driven by illicit synthetic opioids, is not the aim of this guideline.

“The release of this guideline is really about advancing pain care and improving the lives of patients living with pain,” he said.

“We know that at least 1 in 5 people in the country have chronic pain. It’s one of the most common reasons why people present to their health care provider, and the goal here is to advance pain care, function, and quality of life for that patient population, while also reducing misuse, diversion, and consequences of prescription opioid misuse,” Dr. Jones added.

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

The U.S. Centers for Disease Control and Prevention has released updated and expanded recommendations for prescribing opioids for adults with acute and chronic pain not related to cancer, sickle cell disease, or palliative/end-of-life care.

The 2022 Clinical Practice Guideline provides guidance on determining whether to initiate opioids for pain; selecting opioids and determining opioid dosages; deciding duration of initial opioid prescription and conducting follow-up; and assessing risk and addressing potential harms of opioid use.

“Patients with pain should receive compassionate, safe, and effective pain care. We want clinicians and patients to have the information they need to weigh the benefits of different approaches to pain care, with the goal of helping people reduce their pain and improve their quality of life,” Christopher M. Jones, PharmD, DrPH, acting director for the CDC’s National Center for Injury Prevention and Control, said in a news release.
 

How to taper safely

The last guideline on the topic was released by CDC in 2016. Since then, new evidence has emerged regarding the benefits and risks of prescription opioids for acute and chronic pain, comparisons with nonopioid pain treatments, dosing strategies, opioid dose-dependent effects, risk mitigation strategies, and opioid tapering and discontinuation, the CDC says.

A “critical” addition to the 2022 guideline is advice on tapering opioids, Dr. Jones said during a press briefing.

“Practical tips on how to taper in an individualized patient-centered manner have been added to help clinicians if the decision is made to taper opioids, and the guideline explicitly advises against abrupt discontinuation or rapid dose reductions of opioids,” Dr. Jones said.

“That is based on lessons learned over the last several years as well as new science about how we approach tapering and the real harms that can result when patients are abruptly discontinued or rapidly tapered,” he added.

The updated guideline was published online Nov. 3 in the Morbidity and Mortality Weekly Report.

Key recommendations in the 100-page document include the following:

• In determining whether or not to initiate opioids, nonopioid therapies are at least as effective as opioids for many common types of acute pain. Use of nondrug and nonopioid drug therapies should be maximized as appropriate, and opioid therapy should only be considered for acute pain if it is anticipated that benefits outweigh risks to the patient.
• Before starting opioid therapy, providers should discuss with patients the realistic benefits and known risks of opioid therapy.
• Before starting ongoing opioid therapy for patients with subacute pain lasting 1 to 3 months or chronic pain lasting more than 3 months, providers should work with patients to establish treatment goals for pain and function, and consideration should be given as to how opioid therapy will be discontinued if benefits do not outweigh risks.
• Once opioids are started, the lowest effective dose of immediate-release opioids should be prescribed for no longer than needed for the expected duration of pain severe enough to require opioids.
• Within 1 to 4 weeks of starting opioid therapy for subacute or chronic pain, providers should work with patients to evaluate and carefully weigh benefits and risks of continuing opioid therapy; care should be exercised when increasing, continuing, or reducing opioid dosage.
• Before starting and periodically during ongoing opioid therapy, providers should evaluate risk for opioid-related harms and should work with patients to incorporate relevant strategies to mitigate risk, including offering naloxone and reviewing potential interactions with any other prescribed medications or substance used.
• Abrupt discontinuation of opioids should be avoided, especially for patients receiving high doses.
• For treating patients with opioid use disorder, treatment with evidence-based medications should be provided, or arrangements for such treatment should be made.

Dr. Jones emphasized that the guideline is “voluntary and meant to guide shared decision-making between a clinician and patient. It’s not meant to be implemented as absolute limits of policy or practice by clinicians, health systems, insurance companies, governmental entities.”

He also noted that the “current state of the overdose crisis, which is very much driven by illicit synthetic opioids, is not the aim of this guideline.

“The release of this guideline is really about advancing pain care and improving the lives of patients living with pain,” he said.

“We know that at least 1 in 5 people in the country have chronic pain. It’s one of the most common reasons why people present to their health care provider, and the goal here is to advance pain care, function, and quality of life for that patient population, while also reducing misuse, diversion, and consequences of prescription opioid misuse,” Dr. Jones added.

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

A single 25-mg dose of synthetic psilocybin in combination with psychotherapy appears to effectively ease symptoms of treatment-resistant depression (TRD) – at least in the short term, new research shows.

In the largest study of psilocybin for TRD to date, results of the phase 2b randomized, double-blind trial show participants in the 25-mg dose group experienced a significant reduction in depressive symptoms for at least 3 weeks vs. patients in the 10-mg or 1-mg group, which served as the control group.

Investigators found that 29% of participants who received the 25-mg dose were in remission 3 weeks after the treatment and 37% had at least a 50% drop in depression scores. However, at the 3-month mark, only 20% of those on the 25-mg dose experienced significant improvement.

The change from baseline to week 3 in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score was significantly better with a 25-mg dose than with a 1-mg dose; there was no significant difference between the 10-mg dose and the 1-mg dose, the investigators reported.

The response rate was high for those receiving the 25-mg dose, lead  investigator Guy Goodwin, MD, DPhil, told reporters attending a press briefing.

“It’s important to understand that response rates in these patients are usually somewhere between 10% and 20%, and we are seeing remission rates at three weeks of 30%,” he said.

Dr. Goodwin is chief medical officer of COMPASS Pathways, the company that funded the trial and created COMP360, the synthetic formulation of psilocybin used in the trial, and professor emeritus of psychiatry at the University of Oxford, England.

Based on the results of the trial it was announced that a phase 3 trial will launch in December.

The study was published online in the New England Journal of Medicine.
 

Further research planned

Psilocybin has been under investigation for TRD for some time, including one study that compared it with the antidepressant escitalopram (Lexapro) with promising results.

In the current study the researchers sought to find an acceptable, efficacious dose and the safety of a synthetic formulation of the drug administered in combination with psychological support.

The multicenter study was conducted at 22 sites in 10 countries and included 233 participants with TRD and evaluated the safety and efficacy of one of three doses. The study’s primary endpoint was change from baseline to 3 weeks in MADRS scores in patients with TRD. The scale runs from 0 to 60 with higher scores indicating more severe depression.

Participants were randomly assigned to receive 25 mg of psilocybin (n = 79), 10 mg (n = 75) or 1 mg (n = 79). Those taking medications discontinued them at least 2 weeks before the baseline visit. The mean MADRS score was 32 or 33 in each study group.

There was a 3- to 6-week run-up period to the study in which each participant met with a study therapist about three times to build trust and prepare for the psychedelic experience.

On the day of psilocybin administration, each participant listened to a tailored music playlist and wore eye shades while reclining in a comfortable chair to direct attention inwardly.

The psychotherapy sessions lasted 6-8 hours, and two therapists were always present. The following day, participants returned for an “integration” session with the therapists that was designed to help the participants explore insights from their session.

MADRS scores were measured at baseline, the day following psilocybin administration, and at weeks 1, 3, 6, 9, and 12.

Participants were asked to stay off standard antidepressant treatment during the first 3 weeks of the trial but could be restarted at any time if deemed necessary by a trial investigator.

Mean changes from baseline to week 3 in MADRS scores were −12.0 for 25-mg, −7.9 for 10-mg, and −5.4 for 1-mg groups. The difference between the 25-mg group and 1-mg group was −6.6 (95% confidence interval [CI], −10.2 to −2.9; P < .001 and between the 10-mg group and 1-mg group was −2.5 (95% CI, −6.2 to 1.2; P = .18).

The investigators reported that in the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results.

Up to 84% of those who received the 25-mg dosage reported adverse events, with the occurrence dropping slightly with each dosage group. The most frequent adverse events included headache, nausea, dizziness, and fatigue, and occurred only on administration day.

Among those who received the 25-mg dose of psilocybin, two participants reported suicidal thoughts during the 3 weeks following treatment, and 3 months post treatment, three patients exhibited suicidal behavior.

Dr. Goodwin noted that these participants had a prior history of suicidal behavior. Two participants in the 10-mg group also had suicidal thoughts. However, the investigators also noted that suicidal ideation, behavior, or self-injury occurred in all dose groups.

The researchers noted that longer and larger trials, including comparisons with existing depression treatments, are needed to determine the safety and efficacy of psilocybin for TRD.
 

Intriguing, sobering

In an accompanying editorial, Bertha Madras, PhD, McLean Hospital, Belmont, Mass., and Harvard Medical School, Boston, noted “the findings are both intriguing and sobering. The highest dose (25 mg), but not the intermediate dose (10 mg), resulted in significantly lower levels of depressive symptoms after 3 weeks than the lowest dose (1 mg, which served as a control), but the 37% incidence of response with the 25-mg dose was numerically lower than that in large trials of conventional antidepressants and less robust than in a trial showing similar efficacies of psilocybin and a selective serotonin reuptake inhibitor.”

Also sobering, she noted, were the high percentages of adverse events in the 25-mg group and suicidal ideation and behavior. Dr. Madras also wondered if “legalization and commercialization [of psychedelics] are allied with the medical movement, psychedelic shops and ‘clinics’ could proliferate even for vulnerable populations, and rigorously designed medical protocols will be compromised.

“Nevertheless,” she concluded, “it is provocative that these agents show some short-term benefit for depression in selected populations.”

Dr. Goodwin is CMO of Compass Pathways, which funded the study. He and several coauthors disclosed relationships with industry. Dr. Madras reports no relevant financial relationships.

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

A single 25-mg dose of synthetic psilocybin in combination with psychotherapy appears to effectively ease symptoms of treatment-resistant depression (TRD) – at least in the short term, new research shows.

In the largest study of psilocybin for TRD to date, results of the phase 2b randomized, double-blind trial show participants in the 25-mg dose group experienced a significant reduction in depressive symptoms for at least 3 weeks vs. patients in the 10-mg or 1-mg group, which served as the control group.

Investigators found that 29% of participants who received the 25-mg dose were in remission 3 weeks after the treatment and 37% had at least a 50% drop in depression scores. However, at the 3-month mark, only 20% of those on the 25-mg dose experienced significant improvement.

The change from baseline to week 3 in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score was significantly better with a 25-mg dose than with a 1-mg dose; there was no significant difference between the 10-mg dose and the 1-mg dose, the investigators reported.

The response rate was high for those receiving the 25-mg dose, lead  investigator Guy Goodwin, MD, DPhil, told reporters attending a press briefing.

“It’s important to understand that response rates in these patients are usually somewhere between 10% and 20%, and we are seeing remission rates at three weeks of 30%,” he said.

Dr. Goodwin is chief medical officer of COMPASS Pathways, the company that funded the trial and created COMP360, the synthetic formulation of psilocybin used in the trial, and professor emeritus of psychiatry at the University of Oxford, England.

Based on the results of the trial it was announced that a phase 3 trial will launch in December.

The study was published online in the New England Journal of Medicine.
 

Further research planned

Psilocybin has been under investigation for TRD for some time, including one study that compared it with the antidepressant escitalopram (Lexapro) with promising results.

In the current study the researchers sought to find an acceptable, efficacious dose and the safety of a synthetic formulation of the drug administered in combination with psychological support.

The multicenter study was conducted at 22 sites in 10 countries and included 233 participants with TRD and evaluated the safety and efficacy of one of three doses. The study’s primary endpoint was change from baseline to 3 weeks in MADRS scores in patients with TRD. The scale runs from 0 to 60 with higher scores indicating more severe depression.

Participants were randomly assigned to receive 25 mg of psilocybin (n = 79), 10 mg (n = 75) or 1 mg (n = 79). Those taking medications discontinued them at least 2 weeks before the baseline visit. The mean MADRS score was 32 or 33 in each study group.

There was a 3- to 6-week run-up period to the study in which each participant met with a study therapist about three times to build trust and prepare for the psychedelic experience.

On the day of psilocybin administration, each participant listened to a tailored music playlist and wore eye shades while reclining in a comfortable chair to direct attention inwardly.

The psychotherapy sessions lasted 6-8 hours, and two therapists were always present. The following day, participants returned for an “integration” session with the therapists that was designed to help the participants explore insights from their session.

MADRS scores were measured at baseline, the day following psilocybin administration, and at weeks 1, 3, 6, 9, and 12.

Participants were asked to stay off standard antidepressant treatment during the first 3 weeks of the trial but could be restarted at any time if deemed necessary by a trial investigator.

Mean changes from baseline to week 3 in MADRS scores were −12.0 for 25-mg, −7.9 for 10-mg, and −5.4 for 1-mg groups. The difference between the 25-mg group and 1-mg group was −6.6 (95% confidence interval [CI], −10.2 to −2.9; P < .001 and between the 10-mg group and 1-mg group was −2.5 (95% CI, −6.2 to 1.2; P = .18).

The investigators reported that in the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results.

Up to 84% of those who received the 25-mg dosage reported adverse events, with the occurrence dropping slightly with each dosage group. The most frequent adverse events included headache, nausea, dizziness, and fatigue, and occurred only on administration day.

Among those who received the 25-mg dose of psilocybin, two participants reported suicidal thoughts during the 3 weeks following treatment, and 3 months post treatment, three patients exhibited suicidal behavior.

Dr. Goodwin noted that these participants had a prior history of suicidal behavior. Two participants in the 10-mg group also had suicidal thoughts. However, the investigators also noted that suicidal ideation, behavior, or self-injury occurred in all dose groups.

The researchers noted that longer and larger trials, including comparisons with existing depression treatments, are needed to determine the safety and efficacy of psilocybin for TRD.
 

Intriguing, sobering

In an accompanying editorial, Bertha Madras, PhD, McLean Hospital, Belmont, Mass., and Harvard Medical School, Boston, noted “the findings are both intriguing and sobering. The highest dose (25 mg), but not the intermediate dose (10 mg), resulted in significantly lower levels of depressive symptoms after 3 weeks than the lowest dose (1 mg, which served as a control), but the 37% incidence of response with the 25-mg dose was numerically lower than that in large trials of conventional antidepressants and less robust than in a trial showing similar efficacies of psilocybin and a selective serotonin reuptake inhibitor.”

Also sobering, she noted, were the high percentages of adverse events in the 25-mg group and suicidal ideation and behavior. Dr. Madras also wondered if “legalization and commercialization [of psychedelics] are allied with the medical movement, psychedelic shops and ‘clinics’ could proliferate even for vulnerable populations, and rigorously designed medical protocols will be compromised.

“Nevertheless,” she concluded, “it is provocative that these agents show some short-term benefit for depression in selected populations.”

Dr. Goodwin is CMO of Compass Pathways, which funded the study. He and several coauthors disclosed relationships with industry. Dr. Madras reports no relevant financial relationships.

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

A single 25-mg dose of synthetic psilocybin in combination with psychotherapy appears to effectively ease symptoms of treatment-resistant depression (TRD) – at least in the short term, new research shows.

In the largest study of psilocybin for TRD to date, results of the phase 2b randomized, double-blind trial show participants in the 25-mg dose group experienced a significant reduction in depressive symptoms for at least 3 weeks vs. patients in the 10-mg or 1-mg group, which served as the control group.

Investigators found that 29% of participants who received the 25-mg dose were in remission 3 weeks after the treatment and 37% had at least a 50% drop in depression scores. However, at the 3-month mark, only 20% of those on the 25-mg dose experienced significant improvement.

The change from baseline to week 3 in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score was significantly better with a 25-mg dose than with a 1-mg dose; there was no significant difference between the 10-mg dose and the 1-mg dose, the investigators reported.

The response rate was high for those receiving the 25-mg dose, lead  investigator Guy Goodwin, MD, DPhil, told reporters attending a press briefing.

“It’s important to understand that response rates in these patients are usually somewhere between 10% and 20%, and we are seeing remission rates at three weeks of 30%,” he said.

Dr. Goodwin is chief medical officer of COMPASS Pathways, the company that funded the trial and created COMP360, the synthetic formulation of psilocybin used in the trial, and professor emeritus of psychiatry at the University of Oxford, England.

Based on the results of the trial it was announced that a phase 3 trial will launch in December.

The study was published online in the New England Journal of Medicine.
 

Further research planned

Psilocybin has been under investigation for TRD for some time, including one study that compared it with the antidepressant escitalopram (Lexapro) with promising results.

In the current study the researchers sought to find an acceptable, efficacious dose and the safety of a synthetic formulation of the drug administered in combination with psychological support.

The multicenter study was conducted at 22 sites in 10 countries and included 233 participants with TRD and evaluated the safety and efficacy of one of three doses. The study’s primary endpoint was change from baseline to 3 weeks in MADRS scores in patients with TRD. The scale runs from 0 to 60 with higher scores indicating more severe depression.

Participants were randomly assigned to receive 25 mg of psilocybin (n = 79), 10 mg (n = 75) or 1 mg (n = 79). Those taking medications discontinued them at least 2 weeks before the baseline visit. The mean MADRS score was 32 or 33 in each study group.

There was a 3- to 6-week run-up period to the study in which each participant met with a study therapist about three times to build trust and prepare for the psychedelic experience.

On the day of psilocybin administration, each participant listened to a tailored music playlist and wore eye shades while reclining in a comfortable chair to direct attention inwardly.

The psychotherapy sessions lasted 6-8 hours, and two therapists were always present. The following day, participants returned for an “integration” session with the therapists that was designed to help the participants explore insights from their session.

MADRS scores were measured at baseline, the day following psilocybin administration, and at weeks 1, 3, 6, 9, and 12.

Participants were asked to stay off standard antidepressant treatment during the first 3 weeks of the trial but could be restarted at any time if deemed necessary by a trial investigator.

Mean changes from baseline to week 3 in MADRS scores were −12.0 for 25-mg, −7.9 for 10-mg, and −5.4 for 1-mg groups. The difference between the 25-mg group and 1-mg group was −6.6 (95% confidence interval [CI], −10.2 to −2.9; P < .001 and between the 10-mg group and 1-mg group was −2.5 (95% CI, −6.2 to 1.2; P = .18).

The investigators reported that in the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results.

Up to 84% of those who received the 25-mg dosage reported adverse events, with the occurrence dropping slightly with each dosage group. The most frequent adverse events included headache, nausea, dizziness, and fatigue, and occurred only on administration day.

Among those who received the 25-mg dose of psilocybin, two participants reported suicidal thoughts during the 3 weeks following treatment, and 3 months post treatment, three patients exhibited suicidal behavior.

Dr. Goodwin noted that these participants had a prior history of suicidal behavior. Two participants in the 10-mg group also had suicidal thoughts. However, the investigators also noted that suicidal ideation, behavior, or self-injury occurred in all dose groups.

The researchers noted that longer and larger trials, including comparisons with existing depression treatments, are needed to determine the safety and efficacy of psilocybin for TRD.
 

Intriguing, sobering

In an accompanying editorial, Bertha Madras, PhD, McLean Hospital, Belmont, Mass., and Harvard Medical School, Boston, noted “the findings are both intriguing and sobering. The highest dose (25 mg), but not the intermediate dose (10 mg), resulted in significantly lower levels of depressive symptoms after 3 weeks than the lowest dose (1 mg, which served as a control), but the 37% incidence of response with the 25-mg dose was numerically lower than that in large trials of conventional antidepressants and less robust than in a trial showing similar efficacies of psilocybin and a selective serotonin reuptake inhibitor.”

Also sobering, she noted, were the high percentages of adverse events in the 25-mg group and suicidal ideation and behavior. Dr. Madras also wondered if “legalization and commercialization [of psychedelics] are allied with the medical movement, psychedelic shops and ‘clinics’ could proliferate even for vulnerable populations, and rigorously designed medical protocols will be compromised.

“Nevertheless,” she concluded, “it is provocative that these agents show some short-term benefit for depression in selected populations.”

Dr. Goodwin is CMO of Compass Pathways, which funded the study. He and several coauthors disclosed relationships with industry. Dr. Madras reports no relevant financial relationships.

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

The U.S. Food and Drug Administration (FDA) has declined to approve bulevirtide, Gilead Sciences’ drug for the treatment of hepatitis delta virus (HDV) infection and compensated liver disease.

In a complete response letter, the FDA voiced concerns over the production and delivery of bulevirtide, an investigational, first-in-class HDV entry-inhibitor that received conditional approved in Europe in 2020.

The FDA did not request new studies to evaluate the safety and efficacy of bulevirtide.

As reported previously by this news organization, data from an ongoing phase 3 trial showed that after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable HDV RNA levels and normalized alanine aminotransferase levels.

Chronic HDV infection is the most severe form of viral hepatitis. It is associated with a poor prognosis and high mortality rates.

There are currently no approved treatments for HDV in the United States. Bulevirtide was granted breakthrough therapy and orphan drug designations by the FDA.

Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, wrote in a news release that the company looks forward to “continuing our active discussions with FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”

This is the second manufacturing-related complete response letter Gilead has received in the past 8 months. In March, the FDA rejected the long-acting HIV drug lenacapavir. The drug was sanctioned in Europe and the United Kingdom in September.

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

The U.S. Food and Drug Administration (FDA) has declined to approve bulevirtide, Gilead Sciences’ drug for the treatment of hepatitis delta virus (HDV) infection and compensated liver disease.

In a complete response letter, the FDA voiced concerns over the production and delivery of bulevirtide, an investigational, first-in-class HDV entry-inhibitor that received conditional approved in Europe in 2020.

The FDA did not request new studies to evaluate the safety and efficacy of bulevirtide.

As reported previously by this news organization, data from an ongoing phase 3 trial showed that after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable HDV RNA levels and normalized alanine aminotransferase levels.

Chronic HDV infection is the most severe form of viral hepatitis. It is associated with a poor prognosis and high mortality rates.

There are currently no approved treatments for HDV in the United States. Bulevirtide was granted breakthrough therapy and orphan drug designations by the FDA.

Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, wrote in a news release that the company looks forward to “continuing our active discussions with FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”

This is the second manufacturing-related complete response letter Gilead has received in the past 8 months. In March, the FDA rejected the long-acting HIV drug lenacapavir. The drug was sanctioned in Europe and the United Kingdom in September.

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

The U.S. Food and Drug Administration (FDA) has declined to approve bulevirtide, Gilead Sciences’ drug for the treatment of hepatitis delta virus (HDV) infection and compensated liver disease.

In a complete response letter, the FDA voiced concerns over the production and delivery of bulevirtide, an investigational, first-in-class HDV entry-inhibitor that received conditional approved in Europe in 2020.

The FDA did not request new studies to evaluate the safety and efficacy of bulevirtide.

As reported previously by this news organization, data from an ongoing phase 3 trial showed that after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable HDV RNA levels and normalized alanine aminotransferase levels.

Chronic HDV infection is the most severe form of viral hepatitis. It is associated with a poor prognosis and high mortality rates.

There are currently no approved treatments for HDV in the United States. Bulevirtide was granted breakthrough therapy and orphan drug designations by the FDA.

Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, wrote in a news release that the company looks forward to “continuing our active discussions with FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”

This is the second manufacturing-related complete response letter Gilead has received in the past 8 months. In March, the FDA rejected the long-acting HIV drug lenacapavir. The drug was sanctioned in Europe and the United Kingdom in September.

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

A commonly prescribed direct oral anticoagulant (DOAC) has the lowest risk of bleeding, say researchers. Used to prevent strokes in those with atrial fibrillation (AFib), DOACs have recently become more common than warfarin, the previous standard treatment, as they do not require as much follow-up monitoring – which was “particularly valuable” during the COVID-19 pandemic – and have “less risk” of side effects, highlighted the authors of a new study, published in Annals of Internal Medicine.

However, the authors explained that, although current guidelines recommend using DOACs over warfarin in patients with AFib, “head-to-head trial data do not exist to guide the choice of DOAC.” So, they set out to try and fill this evidence gap by doing a large-scale comparison between all DOACs – apixaban, dabigatran, edoxaban, and rivaroxaban – in routine clinical practice.

Wallis Lau, PhD, University College London, and co–lead author, said: “Direct oral anticoagulants have been prescribed with increasing frequency worldwide in recent years, but evidence comparing them directly has been limited.”
 

One drug stood out

For the multinational population-based cohort study the researchers compared the efficacy and risk of side effects for the four most common DOACs. They reviewed data – from five standardized electronic health care databases that covered 221 million people in the United Kingdom, France, Germany, and the United States – of 527,226 patients who had been newly diagnosed with AFib between 2010 and 2019, and who had received a new DOAC prescription. The study included 281,320 apixaban users, 61,008 dabigatran users, 12,722 edoxaban users, and 172,176 rivaroxaban users.

Database-specific hazard ratios of ischemic stroke or systemic embolism, intracranial hemorrhage, gastrointestinal bleeding, and all-cause mortality between DOACs were estimated using a Cox regression model stratified by propensity score and pooled using a random-effects model.

In total, 9,530 ischemic stroke or systemic embolism events, 841 intercranial hemorrhage events, 8,319 gastrointestinal bleeding events, and 1,476 deaths were identified over the study follow-up. The researchers found that all four drugs were comparable on outcomes for ischemic stroke, intercranial hemorrhage, and all-cause mortality.

However, they identified a difference in the risk of gastrointestinal bleeding, which they highlighted “is one of the most common and concerning side effects of DOACs.”

“Apixaban stood out as having lower risk of gastrointestinal bleeding,” said the authors, with a 19%-28% lower risk when compared directly with each of the other three DOACs. Specifically, apixaban use was associated with lower risk for gastrointestinal bleeding than use of dabigatran (HR, 0.81; 95% confidence interval, 0.70-0.94), edoxaban (HR, 0.77; 95% CI, 0.66-0.91), or rivaroxaban (HR, 0.72; 95% CI, 0.66-0.79).

The researchers also highlighted that their findings held true when looking at data only from those aged over 80, and those with chronic kidney disease, two groups that are “often underrepresented” in clinical trials.
 

Apixaban may be preferable

The researchers concluded that, among patients with AFib, apixaban use was associated with lower risk for gastrointestinal bleeding and similar rates of ischemic stroke or systemic embolism, intracranial hemorrhage and all-cause mortality, compared with dabigatran, edoxaban, and rivaroxaban.

“Our results indicate that apixaban may be preferable to other blood thinners because of the lower rate of gastrointestinal bleeding and similar rates of stroke, a finding that we hope will be supported by randomized controlled trials,” said Dr. Lau.

However, he emphasized that, “as with all medications, potential risks and benefits can differ between people, so considering the full spectrum of outcomes and side effects will still be necessary for each individual patient.”

The authors all declared no conflicting interests.

A version of this article first appeared on Medscape UK.

A commonly prescribed direct oral anticoagulant (DOAC) has the lowest risk of bleeding, say researchers. Used to prevent strokes in those with atrial fibrillation (AFib), DOACs have recently become more common than warfarin, the previous standard treatment, as they do not require as much follow-up monitoring – which was “particularly valuable” during the COVID-19 pandemic – and have “less risk” of side effects, highlighted the authors of a new study, published in Annals of Internal Medicine.

However, the authors explained that, although current guidelines recommend using DOACs over warfarin in patients with AFib, “head-to-head trial data do not exist to guide the choice of DOAC.” So, they set out to try and fill this evidence gap by doing a large-scale comparison between all DOACs – apixaban, dabigatran, edoxaban, and rivaroxaban – in routine clinical practice.

Wallis Lau, PhD, University College London, and co–lead author, said: “Direct oral anticoagulants have been prescribed with increasing frequency worldwide in recent years, but evidence comparing them directly has been limited.”
 

One drug stood out

For the multinational population-based cohort study the researchers compared the efficacy and risk of side effects for the four most common DOACs. They reviewed data – from five standardized electronic health care databases that covered 221 million people in the United Kingdom, France, Germany, and the United States – of 527,226 patients who had been newly diagnosed with AFib between 2010 and 2019, and who had received a new DOAC prescription. The study included 281,320 apixaban users, 61,008 dabigatran users, 12,722 edoxaban users, and 172,176 rivaroxaban users.

Database-specific hazard ratios of ischemic stroke or systemic embolism, intracranial hemorrhage, gastrointestinal bleeding, and all-cause mortality between DOACs were estimated using a Cox regression model stratified by propensity score and pooled using a random-effects model.

In total, 9,530 ischemic stroke or systemic embolism events, 841 intercranial hemorrhage events, 8,319 gastrointestinal bleeding events, and 1,476 deaths were identified over the study follow-up. The researchers found that all four drugs were comparable on outcomes for ischemic stroke, intercranial hemorrhage, and all-cause mortality.

However, they identified a difference in the risk of gastrointestinal bleeding, which they highlighted “is one of the most common and concerning side effects of DOACs.”

“Apixaban stood out as having lower risk of gastrointestinal bleeding,” said the authors, with a 19%-28% lower risk when compared directly with each of the other three DOACs. Specifically, apixaban use was associated with lower risk for gastrointestinal bleeding than use of dabigatran (HR, 0.81; 95% confidence interval, 0.70-0.94), edoxaban (HR, 0.77; 95% CI, 0.66-0.91), or rivaroxaban (HR, 0.72; 95% CI, 0.66-0.79).

The researchers also highlighted that their findings held true when looking at data only from those aged over 80, and those with chronic kidney disease, two groups that are “often underrepresented” in clinical trials.
 

Apixaban may be preferable

The researchers concluded that, among patients with AFib, apixaban use was associated with lower risk for gastrointestinal bleeding and similar rates of ischemic stroke or systemic embolism, intracranial hemorrhage and all-cause mortality, compared with dabigatran, edoxaban, and rivaroxaban.

“Our results indicate that apixaban may be preferable to other blood thinners because of the lower rate of gastrointestinal bleeding and similar rates of stroke, a finding that we hope will be supported by randomized controlled trials,” said Dr. Lau.

However, he emphasized that, “as with all medications, potential risks and benefits can differ between people, so considering the full spectrum of outcomes and side effects will still be necessary for each individual patient.”

The authors all declared no conflicting interests.

A version of this article first appeared on Medscape UK.

A commonly prescribed direct oral anticoagulant (DOAC) has the lowest risk of bleeding, say researchers. Used to prevent strokes in those with atrial fibrillation (AFib), DOACs have recently become more common than warfarin, the previous standard treatment, as they do not require as much follow-up monitoring – which was “particularly valuable” during the COVID-19 pandemic – and have “less risk” of side effects, highlighted the authors of a new study, published in Annals of Internal Medicine.

However, the authors explained that, although current guidelines recommend using DOACs over warfarin in patients with AFib, “head-to-head trial data do not exist to guide the choice of DOAC.” So, they set out to try and fill this evidence gap by doing a large-scale comparison between all DOACs – apixaban, dabigatran, edoxaban, and rivaroxaban – in routine clinical practice.

Wallis Lau, PhD, University College London, and co–lead author, said: “Direct oral anticoagulants have been prescribed with increasing frequency worldwide in recent years, but evidence comparing them directly has been limited.”
 

One drug stood out

For the multinational population-based cohort study the researchers compared the efficacy and risk of side effects for the four most common DOACs. They reviewed data – from five standardized electronic health care databases that covered 221 million people in the United Kingdom, France, Germany, and the United States – of 527,226 patients who had been newly diagnosed with AFib between 2010 and 2019, and who had received a new DOAC prescription. The study included 281,320 apixaban users, 61,008 dabigatran users, 12,722 edoxaban users, and 172,176 rivaroxaban users.

Database-specific hazard ratios of ischemic stroke or systemic embolism, intracranial hemorrhage, gastrointestinal bleeding, and all-cause mortality between DOACs were estimated using a Cox regression model stratified by propensity score and pooled using a random-effects model.

In total, 9,530 ischemic stroke or systemic embolism events, 841 intercranial hemorrhage events, 8,319 gastrointestinal bleeding events, and 1,476 deaths were identified over the study follow-up. The researchers found that all four drugs were comparable on outcomes for ischemic stroke, intercranial hemorrhage, and all-cause mortality.

However, they identified a difference in the risk of gastrointestinal bleeding, which they highlighted “is one of the most common and concerning side effects of DOACs.”

“Apixaban stood out as having lower risk of gastrointestinal bleeding,” said the authors, with a 19%-28% lower risk when compared directly with each of the other three DOACs. Specifically, apixaban use was associated with lower risk for gastrointestinal bleeding than use of dabigatran (HR, 0.81; 95% confidence interval, 0.70-0.94), edoxaban (HR, 0.77; 95% CI, 0.66-0.91), or rivaroxaban (HR, 0.72; 95% CI, 0.66-0.79).

The researchers also highlighted that their findings held true when looking at data only from those aged over 80, and those with chronic kidney disease, two groups that are “often underrepresented” in clinical trials.
 

Apixaban may be preferable

The researchers concluded that, among patients with AFib, apixaban use was associated with lower risk for gastrointestinal bleeding and similar rates of ischemic stroke or systemic embolism, intracranial hemorrhage and all-cause mortality, compared with dabigatran, edoxaban, and rivaroxaban.

“Our results indicate that apixaban may be preferable to other blood thinners because of the lower rate of gastrointestinal bleeding and similar rates of stroke, a finding that we hope will be supported by randomized controlled trials,” said Dr. Lau.

However, he emphasized that, “as with all medications, potential risks and benefits can differ between people, so considering the full spectrum of outcomes and side effects will still be necessary for each individual patient.”

The authors all declared no conflicting interests.

A version of this article first appeared on Medscape UK.

Dupilumab appears to improve clinical, symptomatic, histologic, and endoscopic aspects of eosinophilic esophagitis (EoE) up to 24 weeks, according to findings presented at the annual meeting of the American College of Gastroenterology.

The drug was also well tolerated, demonstrating consistency with the known dupilumab safety profile, said Evan S. Dellon, MD, a gastroenterologist at the University of North Carolina at Chapel Hill.

In May, the Food and Drug Administration approved dupilumab (Dupixent) for the treatment of EoE in adults and adolescents who are 12 years and older and weigh at least 40 kg (about 88 pounds), based on safety and efficacy data previously presented by Dr. Dellon and colleagues as part of the phase 3 LIBERTY-EoE-TREET study (NCT03633617).

“Dupilumab is now the only medication FDA approved to treat EoE in the U.S.,” Dr. Dellon said. “The findings here are that the pooled efficacy and safety data for parts A and B of the phase 3 trial are consistent with the results of the individual parts of the study that were previously reported, and which led to the drug being approved for EoE.”

EoE is a chronic, progressive, type 2 inflammatory disease of the esophagus, which can lead to symptoms of esophageal dysfunction that affect quality of life. Current treatment options often lack specificity, present adherence challenges, and provide suboptimal long-term disease control, Dr. Dellon said.

Dupilumab, a fully human monoclonal antibody manufactured by Regeneron Pharmaceuticals, blocks the shared receptor component for interleukin-4 and IL-13, which are central drivers of type 2 inflammation in EoE.
 

Study population difficult to treat

In the three-part, double-blind, placebo-controlled, phase 3 study, dupilumab was administered to 122 patients as 300-mg weekly doses through subcutaneous injection. In parts A and B, dupilumab demonstrated statistically significant and clinically meaningful improvement in adults and adolescents up to 24 weeks. In patients from part A who continued to an extended active treatment period called part C, efficacy was sustained to week 52.

Participants were included if they had EoE that hadn’t responded to high-dose proton pump inhibitors, had baseline esophageal biopsies with a peak intraepithelial eosinophilic count of 15 eosinophils per high-power field (eos/HPF) or higher in two or more esophageal regions, had a history of an average of two or more episodes of dysphagia per week in the 4 weeks prior to screening, had four or more episodes of dysphagia in the 2 weeks prior to randomization with two or more episodes that required liquids or medical attention, and had a baseline Dysphagia Symptom Questionnaire (DSQ) score of 10 or higher.

On the other hand, participants were excluded if they initiated or changed a food-elimination diet regimen or reintroduced a previously eliminated food group in the 6 weeks before screening, had other causes of esophageal eosinophilia, had a history of other inflammatory diseases such as Crohn’s disease or ulcerative colitis, or were treated with swallowed topical corticosteroids within 8 weeks prior to baseline.

Dr. Dellon and colleagues focused on co–primary endpoints: The proportion of patients who achieved peak esophageal intraepithelial eosinophil count of 6 eos/HPF or less, and the absolute change in DSQ score from baseline to week 24.

Key secondary endpoints included percentage change in eos/HPF, absolute change in EoE-Endoscopic Reference Score (EREFS), absolute change in EoE-Histologic Scoring System (EoE-HSS) grade score, and EoE-HSS stage score. Other secondary endpoints included percentage change in DSQ score and proportion of patients achieving less than 15 eos/HPF.

The baseline demographics and clinical characteristics were similar between the treatment and placebo groups. Importantly, about 70% had been treated with topical corticosteroids, and about 40% had a history of esophageal dilation, Dr. Dellon said. The DSQ scores, peak eosinophil counts, and EREFS scores were high, indicating an inflamed, symptomatic, and difficult-to-treat population.
 

Pooled parts A and B findings

Overall, dupilumab reduced peak esophageal intraepithelial eosinophil counts at week 24. In the dupilumab group, 59% of patients were down to 6 eos/HPF or less, compared with 5.9% in the placebo group. In a secondary endpoint, 77% of dupilumab patients were down to 15 eos/HPF, compared with 7.6% in the placebo group. The dupilumab group saw an 80% drop in baseline change, compared with 1.5% in the placebo group.

Dupilumab also reduced dysphagia symptoms and improved endoscopic features of EoE at week 24. The absolute change in DSQ score was –23.21 in the dupilumab group, compared with –12.69 in the placebo group. The percent change in DSQ score was –65.5% in the dupilumab group, compared with –38.2% in the placebo group. The absolute change in EREFS score was –3.95 in the dupilumab group, compared with –0.41 in the placebo group.

In addition, dupilumab reduced histologic scores at week 24. The absolute change in EoE-HSS grade score was –0.82 in the dupilumab group, compared with –0.1 in the placebo group. The absolute change in EoE-HSS stage score was –0.79 in the dupilumab group, compared with –0.09 in the placebo group.

Dupilumab demonstrated an acceptable safety profile, and no new safety signals were noted, Dr. Dellon said. The most common adverse events was injection-site reaction at 37.5% in the dupilumab group and 33.3% in the placebo group. The severe adverse events were not related to the medication.

“If patients have EoE, dupilumab might be an option for treatment. However, it’s important to realize that, in the phase 3 study, all patients were PPI nonresponders, most had been treated with topical steroids [and many were not responsive], and many had prior esophageal dilation,” Dr. Dellon said. “We don’t have a lot of data in more mild EoE patients, and insurances are currently requiring a series of authorization before patients might be able to get this medication. It’s best to talk to their doctor about whether the medication is a good fit for not.”

The study was sponsored by Sanofi and Regeneron Pharmaceuticals. Three of the authors are employees for and have stock options with Regeneron or Sanofi. The other authors reported consultant roles, advisory roles, and research support from numerous pharmaceutical companies, including Regeneron and Sanofi.

Dupilumab appears to improve clinical, symptomatic, histologic, and endoscopic aspects of eosinophilic esophagitis (EoE) up to 24 weeks, according to findings presented at the annual meeting of the American College of Gastroenterology.

The drug was also well tolerated, demonstrating consistency with the known dupilumab safety profile, said Evan S. Dellon, MD, a gastroenterologist at the University of North Carolina at Chapel Hill.

In May, the Food and Drug Administration approved dupilumab (Dupixent) for the treatment of EoE in adults and adolescents who are 12 years and older and weigh at least 40 kg (about 88 pounds), based on safety and efficacy data previously presented by Dr. Dellon and colleagues as part of the phase 3 LIBERTY-EoE-TREET study (NCT03633617).

“Dupilumab is now the only medication FDA approved to treat EoE in the U.S.,” Dr. Dellon said. “The findings here are that the pooled efficacy and safety data for parts A and B of the phase 3 trial are consistent with the results of the individual parts of the study that were previously reported, and which led to the drug being approved for EoE.”

EoE is a chronic, progressive, type 2 inflammatory disease of the esophagus, which can lead to symptoms of esophageal dysfunction that affect quality of life. Current treatment options often lack specificity, present adherence challenges, and provide suboptimal long-term disease control, Dr. Dellon said.

Dupilumab, a fully human monoclonal antibody manufactured by Regeneron Pharmaceuticals, blocks the shared receptor component for interleukin-4 and IL-13, which are central drivers of type 2 inflammation in EoE.
 

Study population difficult to treat

In the three-part, double-blind, placebo-controlled, phase 3 study, dupilumab was administered to 122 patients as 300-mg weekly doses through subcutaneous injection. In parts A and B, dupilumab demonstrated statistically significant and clinically meaningful improvement in adults and adolescents up to 24 weeks. In patients from part A who continued to an extended active treatment period called part C, efficacy was sustained to week 52.

Participants were included if they had EoE that hadn’t responded to high-dose proton pump inhibitors, had baseline esophageal biopsies with a peak intraepithelial eosinophilic count of 15 eosinophils per high-power field (eos/HPF) or higher in two or more esophageal regions, had a history of an average of two or more episodes of dysphagia per week in the 4 weeks prior to screening, had four or more episodes of dysphagia in the 2 weeks prior to randomization with two or more episodes that required liquids or medical attention, and had a baseline Dysphagia Symptom Questionnaire (DSQ) score of 10 or higher.

On the other hand, participants were excluded if they initiated or changed a food-elimination diet regimen or reintroduced a previously eliminated food group in the 6 weeks before screening, had other causes of esophageal eosinophilia, had a history of other inflammatory diseases such as Crohn’s disease or ulcerative colitis, or were treated with swallowed topical corticosteroids within 8 weeks prior to baseline.

Dr. Dellon and colleagues focused on co–primary endpoints: The proportion of patients who achieved peak esophageal intraepithelial eosinophil count of 6 eos/HPF or less, and the absolute change in DSQ score from baseline to week 24.

Key secondary endpoints included percentage change in eos/HPF, absolute change in EoE-Endoscopic Reference Score (EREFS), absolute change in EoE-Histologic Scoring System (EoE-HSS) grade score, and EoE-HSS stage score. Other secondary endpoints included percentage change in DSQ score and proportion of patients achieving less than 15 eos/HPF.

The baseline demographics and clinical characteristics were similar between the treatment and placebo groups. Importantly, about 70% had been treated with topical corticosteroids, and about 40% had a history of esophageal dilation, Dr. Dellon said. The DSQ scores, peak eosinophil counts, and EREFS scores were high, indicating an inflamed, symptomatic, and difficult-to-treat population.
 

Pooled parts A and B findings

Overall, dupilumab reduced peak esophageal intraepithelial eosinophil counts at week 24. In the dupilumab group, 59% of patients were down to 6 eos/HPF or less, compared with 5.9% in the placebo group. In a secondary endpoint, 77% of dupilumab patients were down to 15 eos/HPF, compared with 7.6% in the placebo group. The dupilumab group saw an 80% drop in baseline change, compared with 1.5% in the placebo group.

Dupilumab also reduced dysphagia symptoms and improved endoscopic features of EoE at week 24. The absolute change in DSQ score was –23.21 in the dupilumab group, compared with –12.69 in the placebo group. The percent change in DSQ score was –65.5% in the dupilumab group, compared with –38.2% in the placebo group. The absolute change in EREFS score was –3.95 in the dupilumab group, compared with –0.41 in the placebo group.

In addition, dupilumab reduced histologic scores at week 24. The absolute change in EoE-HSS grade score was –0.82 in the dupilumab group, compared with –0.1 in the placebo group. The absolute change in EoE-HSS stage score was –0.79 in the dupilumab group, compared with –0.09 in the placebo group.

Dupilumab demonstrated an acceptable safety profile, and no new safety signals were noted, Dr. Dellon said. The most common adverse events was injection-site reaction at 37.5% in the dupilumab group and 33.3% in the placebo group. The severe adverse events were not related to the medication.

“If patients have EoE, dupilumab might be an option for treatment. However, it’s important to realize that, in the phase 3 study, all patients were PPI nonresponders, most had been treated with topical steroids [and many were not responsive], and many had prior esophageal dilation,” Dr. Dellon said. “We don’t have a lot of data in more mild EoE patients, and insurances are currently requiring a series of authorization before patients might be able to get this medication. It’s best to talk to their doctor about whether the medication is a good fit for not.”

The study was sponsored by Sanofi and Regeneron Pharmaceuticals. Three of the authors are employees for and have stock options with Regeneron or Sanofi. The other authors reported consultant roles, advisory roles, and research support from numerous pharmaceutical companies, including Regeneron and Sanofi.

Dupilumab appears to improve clinical, symptomatic, histologic, and endoscopic aspects of eosinophilic esophagitis (EoE) up to 24 weeks, according to findings presented at the annual meeting of the American College of Gastroenterology.

The drug was also well tolerated, demonstrating consistency with the known dupilumab safety profile, said Evan S. Dellon, MD, a gastroenterologist at the University of North Carolina at Chapel Hill.

In May, the Food and Drug Administration approved dupilumab (Dupixent) for the treatment of EoE in adults and adolescents who are 12 years and older and weigh at least 40 kg (about 88 pounds), based on safety and efficacy data previously presented by Dr. Dellon and colleagues as part of the phase 3 LIBERTY-EoE-TREET study (NCT03633617).

“Dupilumab is now the only medication FDA approved to treat EoE in the U.S.,” Dr. Dellon said. “The findings here are that the pooled efficacy and safety data for parts A and B of the phase 3 trial are consistent with the results of the individual parts of the study that were previously reported, and which led to the drug being approved for EoE.”

EoE is a chronic, progressive, type 2 inflammatory disease of the esophagus, which can lead to symptoms of esophageal dysfunction that affect quality of life. Current treatment options often lack specificity, present adherence challenges, and provide suboptimal long-term disease control, Dr. Dellon said.

Dupilumab, a fully human monoclonal antibody manufactured by Regeneron Pharmaceuticals, blocks the shared receptor component for interleukin-4 and IL-13, which are central drivers of type 2 inflammation in EoE.
 

Study population difficult to treat

In the three-part, double-blind, placebo-controlled, phase 3 study, dupilumab was administered to 122 patients as 300-mg weekly doses through subcutaneous injection. In parts A and B, dupilumab demonstrated statistically significant and clinically meaningful improvement in adults and adolescents up to 24 weeks. In patients from part A who continued to an extended active treatment period called part C, efficacy was sustained to week 52.

Participants were included if they had EoE that hadn’t responded to high-dose proton pump inhibitors, had baseline esophageal biopsies with a peak intraepithelial eosinophilic count of 15 eosinophils per high-power field (eos/HPF) or higher in two or more esophageal regions, had a history of an average of two or more episodes of dysphagia per week in the 4 weeks prior to screening, had four or more episodes of dysphagia in the 2 weeks prior to randomization with two or more episodes that required liquids or medical attention, and had a baseline Dysphagia Symptom Questionnaire (DSQ) score of 10 or higher.

On the other hand, participants were excluded if they initiated or changed a food-elimination diet regimen or reintroduced a previously eliminated food group in the 6 weeks before screening, had other causes of esophageal eosinophilia, had a history of other inflammatory diseases such as Crohn’s disease or ulcerative colitis, or were treated with swallowed topical corticosteroids within 8 weeks prior to baseline.

Dr. Dellon and colleagues focused on co–primary endpoints: The proportion of patients who achieved peak esophageal intraepithelial eosinophil count of 6 eos/HPF or less, and the absolute change in DSQ score from baseline to week 24.

Key secondary endpoints included percentage change in eos/HPF, absolute change in EoE-Endoscopic Reference Score (EREFS), absolute change in EoE-Histologic Scoring System (EoE-HSS) grade score, and EoE-HSS stage score. Other secondary endpoints included percentage change in DSQ score and proportion of patients achieving less than 15 eos/HPF.

The baseline demographics and clinical characteristics were similar between the treatment and placebo groups. Importantly, about 70% had been treated with topical corticosteroids, and about 40% had a history of esophageal dilation, Dr. Dellon said. The DSQ scores, peak eosinophil counts, and EREFS scores were high, indicating an inflamed, symptomatic, and difficult-to-treat population.
 

Pooled parts A and B findings

Overall, dupilumab reduced peak esophageal intraepithelial eosinophil counts at week 24. In the dupilumab group, 59% of patients were down to 6 eos/HPF or less, compared with 5.9% in the placebo group. In a secondary endpoint, 77% of dupilumab patients were down to 15 eos/HPF, compared with 7.6% in the placebo group. The dupilumab group saw an 80% drop in baseline change, compared with 1.5% in the placebo group.

Dupilumab also reduced dysphagia symptoms and improved endoscopic features of EoE at week 24. The absolute change in DSQ score was –23.21 in the dupilumab group, compared with –12.69 in the placebo group. The percent change in DSQ score was –65.5% in the dupilumab group, compared with –38.2% in the placebo group. The absolute change in EREFS score was –3.95 in the dupilumab group, compared with –0.41 in the placebo group.

In addition, dupilumab reduced histologic scores at week 24. The absolute change in EoE-HSS grade score was –0.82 in the dupilumab group, compared with –0.1 in the placebo group. The absolute change in EoE-HSS stage score was –0.79 in the dupilumab group, compared with –0.09 in the placebo group.

Dupilumab demonstrated an acceptable safety profile, and no new safety signals were noted, Dr. Dellon said. The most common adverse events was injection-site reaction at 37.5% in the dupilumab group and 33.3% in the placebo group. The severe adverse events were not related to the medication.

“If patients have EoE, dupilumab might be an option for treatment. However, it’s important to realize that, in the phase 3 study, all patients were PPI nonresponders, most had been treated with topical steroids [and many were not responsive], and many had prior esophageal dilation,” Dr. Dellon said. “We don’t have a lot of data in more mild EoE patients, and insurances are currently requiring a series of authorization before patients might be able to get this medication. It’s best to talk to their doctor about whether the medication is a good fit for not.”

The study was sponsored by Sanofi and Regeneron Pharmaceuticals. Three of the authors are employees for and have stock options with Regeneron or Sanofi. The other authors reported consultant roles, advisory roles, and research support from numerous pharmaceutical companies, including Regeneron and Sanofi.

CHARLOTTE, N.C. – RBX2660 could be a new option for people who experience recurrent, debilitating Clostridioides difficile infections.

Following a standard course of antibiotics, a one-time treatment with RBX2660 was successful for three quarters of participants at 8 weeks, according to a new study. It also prevented additional bouts, with 84% of these initial responders remaining free of C. difficile infection at 6 months.

The ongoing phase 3, open-label PUNCH CD3-OLS study expands on clinical trial experience by treating more “real-world” patients. People who might have been excluded from previous research because of comorbidities, such as irritable bowel syndrome, inflammatory bowel disease, and immunosuppression, were included.

The study also placed no limit on the number of previous rounds of C. difficile infections.

“Even when you expand the patient population to make it more generalizable, we’re still seeing both a high cure rate and a high success rate,” Sahil Khanna, MBBS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minn., said in an interview.

“We also are not seeing any kind of safety signals that can be attributed to this particular product,” he said.

Dr. Khanna presented the findings during the annual meeting of the American College of Gastroenterology, which were also published simultaneously in the journal Drugs. The research by Dr. Khanna and associates received an ACG Outstanding Research Award in the colon category.
 

Study design and results

RBX2660 (Rebyota) is a microbiota-based live biotherapeutic in development from Ferring Pharmaceuticals. The treatment contains human stool collected from prescreened, qualified donors and is prepared according to good manufacturing standards.

After standard-of-care antibiotics and a 72-hour washout period, participants received a single 150-mL dose rectally by enema. RBX2660 is administered by a health care professional.

The median age of study participants was 63 years, with 45% aged 65 years or older, and 70% were women. Overall, 37% of participants had Crohn’s disease and 4% had ulcerative colitis.

At the time of screening, about half of participants had a history of one or two infections with C. difficile, and the remaining half reported three or more episodes.

Of the 402 participants whose outcomes could be analyzed, 75% reported treatment success, meaning no further C. difficile infections at 8 weeks. This was consistent with the 75% of 60 participants free of C. difficile in the interim analysis reported in 2021. Efficacy results were based on a modified intent-to-treat analysis.

Of the 300 participants who responded to RBX2660 at 8 weeks, 262 were followed up to 6 months, with 84% of these reporting no C. difficile recurrence.

“If you succeeded to 8 weeks, there was a high likelihood that you would succeed up to 6 months,” Dr. Khanna said.

For the subset of participants with inflammatory bowel disease, Dr. Khanna noted that the success rates were in the 80% range, which is higher than what is seen in clinic fecal microbiota transplantation programs.
 

Adverse events

Of the participants, 63% reported treatment-emergent adverse events. Most events were mild to moderate in severity, the researchers reported, with diarrhea and abdominal pain being the most common.

“When you look at the treatment-emergent adverse events, it’s important to put them into context in terms of this patient population,” Dr. Khanna said. “This recurrent population has developed underlying gastrointestinal symptoms like abdominal pain, diarrhea, nausea, vomiting, and weight loss.”

Some of these adverse events persist beyond resolution of the C. difficile infection, and the adverse-event profile with RBX2660 is consistent with what is seen following fecal microbiota transplantation, he added.

The serious adverse events “were very, very few,” Dr. Khanna said.

Overall, 11% of participants reported a serious adverse event. The majority were related to the C. difficile infection or an underlying comorbidity, he noted.
 

“Excruciating for patients to deal with”

Traditionally, there could be “some hesitation on the patient’s part [to undergo therapy] just because it’s delivered rectally,” session comoderator Lisa Malter, MD, said in an interview.

However, C. difficile can be “excruciating for patients to deal with,” said Dr. Malter, a gastroenterologist and professor of medicine at New York University Langone Health. They “may be more than willing to take [this agent] because it gets them feeling better.”

“This is a positive adjunct to our current therapies for C. diff in terms of trying to knock it out once a standard course of antibiotics has been administered,” she added.

Currently, people with recurrent C. difficile seek fecal microbiota material from a biobank or from a close friend or loved one.

But Dr. Malter noted that asking someone you know to donate fecal matter for transplantation requires several steps. Donors are screened to make sure they are free of gastrointestinal illness, are not taking any contraindicated medications, and do not have active infection.

Fecal microbiota samples from a biobank are more standardized, but there have been intermittent shutdowns and availability has been limited during the pandemic, she said.

Dr. Malter added that one unanswered question is how much of the colon is covered by therapy delivery via enema compared with colonoscope delivery during fecal microbiota transplantation.

“If it’s delivered colonoscopically, you get the entire colon. In contrast with an enema, you really only hit the left side of the colon,” she said.
 

FDA advisory committee nod

On Sept. 26, the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee reviewed evidence for RBX2660. The committee voted 13 to 4 that data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults following antibiotic treatment for recurrent infections.

Members also voted 12 to 4, with one abstention, that the data were adequate to support the product’s safety.

The FDA often follows its advisory committee recommendations but is not required to do so.

“The hope would be that this would get through the usual FDA pipeline of an approval in the near future,” Dr. Khanna said.

The study was funded by Ferring Pharmaceuticals. Dr. Khanna reported receiving grant and research funding from Ferring. Dr. Malter reported no relevant financial relationships.

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

CHARLOTTE, N.C. – RBX2660 could be a new option for people who experience recurrent, debilitating Clostridioides difficile infections.

Following a standard course of antibiotics, a one-time treatment with RBX2660 was successful for three quarters of participants at 8 weeks, according to a new study. It also prevented additional bouts, with 84% of these initial responders remaining free of C. difficile infection at 6 months.

The ongoing phase 3, open-label PUNCH CD3-OLS study expands on clinical trial experience by treating more “real-world” patients. People who might have been excluded from previous research because of comorbidities, such as irritable bowel syndrome, inflammatory bowel disease, and immunosuppression, were included.

The study also placed no limit on the number of previous rounds of C. difficile infections.

“Even when you expand the patient population to make it more generalizable, we’re still seeing both a high cure rate and a high success rate,” Sahil Khanna, MBBS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minn., said in an interview.

“We also are not seeing any kind of safety signals that can be attributed to this particular product,” he said.

Dr. Khanna presented the findings during the annual meeting of the American College of Gastroenterology, which were also published simultaneously in the journal Drugs. The research by Dr. Khanna and associates received an ACG Outstanding Research Award in the colon category.
 

Study design and results

RBX2660 (Rebyota) is a microbiota-based live biotherapeutic in development from Ferring Pharmaceuticals. The treatment contains human stool collected from prescreened, qualified donors and is prepared according to good manufacturing standards.

After standard-of-care antibiotics and a 72-hour washout period, participants received a single 150-mL dose rectally by enema. RBX2660 is administered by a health care professional.

The median age of study participants was 63 years, with 45% aged 65 years or older, and 70% were women. Overall, 37% of participants had Crohn’s disease and 4% had ulcerative colitis.

At the time of screening, about half of participants had a history of one or two infections with C. difficile, and the remaining half reported three or more episodes.

Of the 402 participants whose outcomes could be analyzed, 75% reported treatment success, meaning no further C. difficile infections at 8 weeks. This was consistent with the 75% of 60 participants free of C. difficile in the interim analysis reported in 2021. Efficacy results were based on a modified intent-to-treat analysis.

Of the 300 participants who responded to RBX2660 at 8 weeks, 262 were followed up to 6 months, with 84% of these reporting no C. difficile recurrence.

“If you succeeded to 8 weeks, there was a high likelihood that you would succeed up to 6 months,” Dr. Khanna said.

For the subset of participants with inflammatory bowel disease, Dr. Khanna noted that the success rates were in the 80% range, which is higher than what is seen in clinic fecal microbiota transplantation programs.
 

Adverse events

Of the participants, 63% reported treatment-emergent adverse events. Most events were mild to moderate in severity, the researchers reported, with diarrhea and abdominal pain being the most common.

“When you look at the treatment-emergent adverse events, it’s important to put them into context in terms of this patient population,” Dr. Khanna said. “This recurrent population has developed underlying gastrointestinal symptoms like abdominal pain, diarrhea, nausea, vomiting, and weight loss.”

Some of these adverse events persist beyond resolution of the C. difficile infection, and the adverse-event profile with RBX2660 is consistent with what is seen following fecal microbiota transplantation, he added.

The serious adverse events “were very, very few,” Dr. Khanna said.

Overall, 11% of participants reported a serious adverse event. The majority were related to the C. difficile infection or an underlying comorbidity, he noted.
 

“Excruciating for patients to deal with”

Traditionally, there could be “some hesitation on the patient’s part [to undergo therapy] just because it’s delivered rectally,” session comoderator Lisa Malter, MD, said in an interview.

However, C. difficile can be “excruciating for patients to deal with,” said Dr. Malter, a gastroenterologist and professor of medicine at New York University Langone Health. They “may be more than willing to take [this agent] because it gets them feeling better.”

“This is a positive adjunct to our current therapies for C. diff in terms of trying to knock it out once a standard course of antibiotics has been administered,” she added.

Currently, people with recurrent C. difficile seek fecal microbiota material from a biobank or from a close friend or loved one.

But Dr. Malter noted that asking someone you know to donate fecal matter for transplantation requires several steps. Donors are screened to make sure they are free of gastrointestinal illness, are not taking any contraindicated medications, and do not have active infection.

Fecal microbiota samples from a biobank are more standardized, but there have been intermittent shutdowns and availability has been limited during the pandemic, she said.

Dr. Malter added that one unanswered question is how much of the colon is covered by therapy delivery via enema compared with colonoscope delivery during fecal microbiota transplantation.

“If it’s delivered colonoscopically, you get the entire colon. In contrast with an enema, you really only hit the left side of the colon,” she said.
 

FDA advisory committee nod

On Sept. 26, the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee reviewed evidence for RBX2660. The committee voted 13 to 4 that data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults following antibiotic treatment for recurrent infections.

Members also voted 12 to 4, with one abstention, that the data were adequate to support the product’s safety.

The FDA often follows its advisory committee recommendations but is not required to do so.

“The hope would be that this would get through the usual FDA pipeline of an approval in the near future,” Dr. Khanna said.

The study was funded by Ferring Pharmaceuticals. Dr. Khanna reported receiving grant and research funding from Ferring. Dr. Malter reported no relevant financial relationships.

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

CHARLOTTE, N.C. – RBX2660 could be a new option for people who experience recurrent, debilitating Clostridioides difficile infections.

Following a standard course of antibiotics, a one-time treatment with RBX2660 was successful for three quarters of participants at 8 weeks, according to a new study. It also prevented additional bouts, with 84% of these initial responders remaining free of C. difficile infection at 6 months.

The ongoing phase 3, open-label PUNCH CD3-OLS study expands on clinical trial experience by treating more “real-world” patients. People who might have been excluded from previous research because of comorbidities, such as irritable bowel syndrome, inflammatory bowel disease, and immunosuppression, were included.

The study also placed no limit on the number of previous rounds of C. difficile infections.

“Even when you expand the patient population to make it more generalizable, we’re still seeing both a high cure rate and a high success rate,” Sahil Khanna, MBBS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minn., said in an interview.

“We also are not seeing any kind of safety signals that can be attributed to this particular product,” he said.

Dr. Khanna presented the findings during the annual meeting of the American College of Gastroenterology, which were also published simultaneously in the journal Drugs. The research by Dr. Khanna and associates received an ACG Outstanding Research Award in the colon category.
 

Study design and results

RBX2660 (Rebyota) is a microbiota-based live biotherapeutic in development from Ferring Pharmaceuticals. The treatment contains human stool collected from prescreened, qualified donors and is prepared according to good manufacturing standards.

After standard-of-care antibiotics and a 72-hour washout period, participants received a single 150-mL dose rectally by enema. RBX2660 is administered by a health care professional.

The median age of study participants was 63 years, with 45% aged 65 years or older, and 70% were women. Overall, 37% of participants had Crohn’s disease and 4% had ulcerative colitis.

At the time of screening, about half of participants had a history of one or two infections with C. difficile, and the remaining half reported three or more episodes.

Of the 402 participants whose outcomes could be analyzed, 75% reported treatment success, meaning no further C. difficile infections at 8 weeks. This was consistent with the 75% of 60 participants free of C. difficile in the interim analysis reported in 2021. Efficacy results were based on a modified intent-to-treat analysis.

Of the 300 participants who responded to RBX2660 at 8 weeks, 262 were followed up to 6 months, with 84% of these reporting no C. difficile recurrence.

“If you succeeded to 8 weeks, there was a high likelihood that you would succeed up to 6 months,” Dr. Khanna said.

For the subset of participants with inflammatory bowel disease, Dr. Khanna noted that the success rates were in the 80% range, which is higher than what is seen in clinic fecal microbiota transplantation programs.
 

Adverse events

Of the participants, 63% reported treatment-emergent adverse events. Most events were mild to moderate in severity, the researchers reported, with diarrhea and abdominal pain being the most common.

“When you look at the treatment-emergent adverse events, it’s important to put them into context in terms of this patient population,” Dr. Khanna said. “This recurrent population has developed underlying gastrointestinal symptoms like abdominal pain, diarrhea, nausea, vomiting, and weight loss.”

Some of these adverse events persist beyond resolution of the C. difficile infection, and the adverse-event profile with RBX2660 is consistent with what is seen following fecal microbiota transplantation, he added.

The serious adverse events “were very, very few,” Dr. Khanna said.

Overall, 11% of participants reported a serious adverse event. The majority were related to the C. difficile infection or an underlying comorbidity, he noted.
 

“Excruciating for patients to deal with”

Traditionally, there could be “some hesitation on the patient’s part [to undergo therapy] just because it’s delivered rectally,” session comoderator Lisa Malter, MD, said in an interview.

However, C. difficile can be “excruciating for patients to deal with,” said Dr. Malter, a gastroenterologist and professor of medicine at New York University Langone Health. They “may be more than willing to take [this agent] because it gets them feeling better.”

“This is a positive adjunct to our current therapies for C. diff in terms of trying to knock it out once a standard course of antibiotics has been administered,” she added.

Currently, people with recurrent C. difficile seek fecal microbiota material from a biobank or from a close friend or loved one.

But Dr. Malter noted that asking someone you know to donate fecal matter for transplantation requires several steps. Donors are screened to make sure they are free of gastrointestinal illness, are not taking any contraindicated medications, and do not have active infection.

Fecal microbiota samples from a biobank are more standardized, but there have been intermittent shutdowns and availability has been limited during the pandemic, she said.

Dr. Malter added that one unanswered question is how much of the colon is covered by therapy delivery via enema compared with colonoscope delivery during fecal microbiota transplantation.

“If it’s delivered colonoscopically, you get the entire colon. In contrast with an enema, you really only hit the left side of the colon,” she said.
 

FDA advisory committee nod

On Sept. 26, the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee reviewed evidence for RBX2660. The committee voted 13 to 4 that data were adequate to support the effectiveness of RBX2660 to reduce the recurrence of C. difficile infection in adults following antibiotic treatment for recurrent infections.

Members also voted 12 to 4, with one abstention, that the data were adequate to support the product’s safety.

The FDA often follows its advisory committee recommendations but is not required to do so.

“The hope would be that this would get through the usual FDA pipeline of an approval in the near future,” Dr. Khanna said.

The study was funded by Ferring Pharmaceuticals. Dr. Khanna reported receiving grant and research funding from Ferring. Dr. Malter reported no relevant financial relationships.

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

Josie Tenore, MD, and Paul Hinds were introduced by a mutual friend in 2017 and hadn’t been going out long when she laid down the law: He had to get a physical.

“I don’t date people who don’t take care of their health,” said Dr. Tenore, who practices cosmetic dermatology and functional medicine in suburban Chicago.

One of Mr. Hinds’ blood tests that summer came back with an alarming result: His prostate-specific antigen (PSA), level was very high. A biopsy confirmed he had advanced prostate cancer.

There aren’t a lot of comfortable alternatives for treating prostate cancer, which generally progresses as long as testosterone levels remain high. Marijuana appears to lower testosterone levels, so after his diagnosis, he dosed a liquid form of cannabis for several weeks. That cut his PSA in half, but Mr. Hinds, a cybersecurity expert who likes yoga and bicycling, “was stoned out of his mind and couldn’t function,” Dr. Tenore recalled.

With Dr. Tenore guiding his decisions, Mr. Hinds next tried high-frequency ultrasound treatment, but it failed. And in the summer of 2019 doctors removed his prostate gland. Still, the PSA levels climbed again, and doctors assessed that the cancer had metastasized. The only alternative was to drastically lower Mr. Hinds’ testosterone levels – either via surgery or drugs that block all testosterone. In May 2021, he got his first intramuscular shot of Lupron Depot, a brand name for leuprolide, designed to suppress the prostate gland’s release of the hormone for 3 months. That August, he got his second shot.

And then the bills came.

The patient: Paul Hinds, now 60, is covered by United Healthcare through a COBRA plan from his former employer.

Medical service: Two 3-month Lupron Depot injections for metastatic prostate cancer.

Service provider: University of Chicago Medicine, a 900-physician nonprofit system that includes an 811-bed medical center, a suburban hospital, the Pritzker School of Medicine, and outpatient clinics and physician offices throughout the Chicago area.

Total bill: $73,812 for the two shots ($35,414 for the first, $38,398 for the second), including lab work and physician charges. United Healthcare’s negotiated rate for the two shots plus associated fees was $27,568, of which the insurer paid $19,567. After Mr. Hinds haggled with the hospital and insurer for more than a year, his share of the bills was determined to be nearly $7,000.

What gives: The first issue is unrelenting price increases on old drugs that have remained branded as manufacturers find ways to extend patents for decades and maintain sales through marketing.

Though Lupron was invented in 1973, its manufacturer got patent extensions in 1989 by offering a slow-release version. Drugmakers commonly use this tactic to extend their exclusive rights to sell a product.

The development of Lupron Depot as an intramuscular shot that suppressed testosterone for months at a time improved patient compliance and also enabled its maker, Abbott Laboratories, and its Japanese partner, Takeda, to extend their patents on the drug into the 2000s, said Gerald Weisberg, MD, a former Abbott scientist who has been critical of the company’s pricing policies.

In subsequent years, Abbott and Takeda, in a joint venture called TAP Pharmaceuticals, steadily marked up the price of their slow-release product. In 2000, the average wholesale U.S. price for a 3-month shot was $1,245; currently that figure is $5,866. (It is manufactured in the United States by AbbVie now.)

In the United Kingdom, where health care is generally free and Takeda sells the drug under the name Prostap, all physicians can purchase a 3-month dose for about $260.

It’s likely that Chicago Medicine, where Mr. Hinds got his shots, paid something close to the British price. That’s because the health system’s hospital on Chicago’s South Side participates in a federal program called 340B, which allows hospitals that serve low-income populations to purchase drugs at deep discounts.

Lupron Depot is given as a simple injection into the muscle. It takes minutes for a nurse or doctor to administer. Yet hospital systems like Chicago Medicine can and typically do charge lavishly for such services, to enhance revenue, said Morgan Henderson, principal data scientist at the Hilltop Institute at the University of Maryland-Baltimore County. Chicago Medicine declined to say what it paid for the drug.

While U.S. drugmakers can price their drugs however they please, TAP has gotten into trouble for its Lupron sales policies in the past. In 2001, after a Justice Department probe, it paid an $875 million settlement for illegally stimulating sales by giving urologists free and discounted vials of the drug while enabling them to charge Medicare full price.

Since then, many other drugs aimed at lowering testosterone levels have entered the market, including a pill, relugolix (Orgovyx). So why wouldn’t a patient use them?

Lupron Depot is long acting, is easy to prepare and store, and employs a small needle, which some patients prefer, said Brian McNeil, MD, chief of urology at University Hospital of Brooklyn. Orgovyx is convenient, but “a patient has to be very compliant. They have to take it every day around the same time,” he said. “Some people just forget.”

But there is another important factor that may well explain Lupron Depot’s ongoing popularity among medical providers: Doctors and hospitals can earn tens of thousands of dollars each visit by marking up its price and administration fees – as they did with Mr. Hinds. If they merely write a prescription for a drug that can be taken at home, they earn nothing.

Asked about this high patient charge and the possibility of using alternatives, United spokesperson Maria Gordon Shydlo said payment was “appropriately based on the hospital’s contract and the member’s benefit plan,” adding that the insurer encourages customers to shop around for the best quality and price.

Resolution: In addition to leaving Mr. Hinds listless, the Lupron Depot shots were, literally, a pain in the rear end. “Each time he was miserable for 2 weeks,” Dr. Tenore said. After looking over his first bill for the Lupron shot, Dr. Tenore told Mr. Hinds he should ask his doctor whether there was a less expensive drug that was easier to take.

After the second shot, in August 2021, a pharmacist told him he could instead receive the pill. His doctor prescribed Mr. Hinds 3 months’ worth of Orgovyx last November, for which he paid $216 and the insurer paid over $6,000. The drug’s list price is about $2,700 a month. There is evidence that Orgovyx works a little better than leuprolide.

Orgovyx was a “no-brainer,” Mr. Hinds said. “Why would you want a sore ass for two weeks when you can take a pill that kicks in sooner, functions the same way, and clears your body of testosterone faster?”

While Orgovyx is increasingly used for prostate cancer, Lupron and other injections usually remain the standard of care, hospital spokesperson Ashley Heher said. Clinicians “work with patients to determine what treatments are the most medically effective and, when necessary, to find reasonable alternatives that may be less financially burdensome due to insurance coverage limitations.”

Mr. Hinds was baffled by the size of the charges. During months of phone calls and emails, the hospital reversed and then reapplied part of the charge, and then in July agreed to a $666.34 monthly payment plan. After Hinds had made two payments, however, the hospital announced Aug. 29 it was canceling the agreement and sending the remainder of his bill to a collection agency. Two weeks later, the hospital reinstated the payment plan – after KHN asked about the cancellation.

As for Mr. Hinds, he remains active, though his bike rides have been shortened from 50 or 60 miles to about 30, he said.

He’s grateful to have Dr. Tenore as a free consultant and empathizes with those who lack a knowledgeable guide through their disease and health care’s financial maze.

“I’ve got Dr. Josie as an advocate who knows the system,” Mr. Hinds said.

The takeaway: First tip: If you are prescribed an infusion or injection, ask your physician if there are cheaper oral medications to treat your condition. Also, many drugs that are given by injection – ones that are given “subcutaneously,” rather than into a muscle – can be administered by a patient at home, avoiding hefty administration fees. Drugs like Dupixent for eczema fall into this category.

Keep in mind that where you get treatment could make a big difference in your charges: A study found that leading U.S. cancer centers charge enormous markups to private insurers for drug injections or infusions. Another study found that hospital systems charge an average of 86% more than private clinics for cancer drug infusions. And the percentage of cancer infusions done in hospital-operated clinics increased from 6% in 2004 to 43% in 2014, and has grown since.

Under a law that took effect in 2021, hospitals are required to list their charges, though they currently do so in a way that is not user friendly. But it’s worth taking a look at the price list – the hospital chargemaster – to try to decipher the pricing and markup for your medicine. If you’re about to get an injection, infusion, or procedure done in a hospital system, ask ahead of time for an estimate of what you will owe.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Josie Tenore, MD, and Paul Hinds were introduced by a mutual friend in 2017 and hadn’t been going out long when she laid down the law: He had to get a physical.

“I don’t date people who don’t take care of their health,” said Dr. Tenore, who practices cosmetic dermatology and functional medicine in suburban Chicago.

One of Mr. Hinds’ blood tests that summer came back with an alarming result: His prostate-specific antigen (PSA), level was very high. A biopsy confirmed he had advanced prostate cancer.

There aren’t a lot of comfortable alternatives for treating prostate cancer, which generally progresses as long as testosterone levels remain high. Marijuana appears to lower testosterone levels, so after his diagnosis, he dosed a liquid form of cannabis for several weeks. That cut his PSA in half, but Mr. Hinds, a cybersecurity expert who likes yoga and bicycling, “was stoned out of his mind and couldn’t function,” Dr. Tenore recalled.

With Dr. Tenore guiding his decisions, Mr. Hinds next tried high-frequency ultrasound treatment, but it failed. And in the summer of 2019 doctors removed his prostate gland. Still, the PSA levels climbed again, and doctors assessed that the cancer had metastasized. The only alternative was to drastically lower Mr. Hinds’ testosterone levels – either via surgery or drugs that block all testosterone. In May 2021, he got his first intramuscular shot of Lupron Depot, a brand name for leuprolide, designed to suppress the prostate gland’s release of the hormone for 3 months. That August, he got his second shot.

And then the bills came.

The patient: Paul Hinds, now 60, is covered by United Healthcare through a COBRA plan from his former employer.

Medical service: Two 3-month Lupron Depot injections for metastatic prostate cancer.

Service provider: University of Chicago Medicine, a 900-physician nonprofit system that includes an 811-bed medical center, a suburban hospital, the Pritzker School of Medicine, and outpatient clinics and physician offices throughout the Chicago area.

Total bill: $73,812 for the two shots ($35,414 for the first, $38,398 for the second), including lab work and physician charges. United Healthcare’s negotiated rate for the two shots plus associated fees was $27,568, of which the insurer paid $19,567. After Mr. Hinds haggled with the hospital and insurer for more than a year, his share of the bills was determined to be nearly $7,000.

What gives: The first issue is unrelenting price increases on old drugs that have remained branded as manufacturers find ways to extend patents for decades and maintain sales through marketing.

Though Lupron was invented in 1973, its manufacturer got patent extensions in 1989 by offering a slow-release version. Drugmakers commonly use this tactic to extend their exclusive rights to sell a product.

The development of Lupron Depot as an intramuscular shot that suppressed testosterone for months at a time improved patient compliance and also enabled its maker, Abbott Laboratories, and its Japanese partner, Takeda, to extend their patents on the drug into the 2000s, said Gerald Weisberg, MD, a former Abbott scientist who has been critical of the company’s pricing policies.

In subsequent years, Abbott and Takeda, in a joint venture called TAP Pharmaceuticals, steadily marked up the price of their slow-release product. In 2000, the average wholesale U.S. price for a 3-month shot was $1,245; currently that figure is $5,866. (It is manufactured in the United States by AbbVie now.)

In the United Kingdom, where health care is generally free and Takeda sells the drug under the name Prostap, all physicians can purchase a 3-month dose for about $260.

It’s likely that Chicago Medicine, where Mr. Hinds got his shots, paid something close to the British price. That’s because the health system’s hospital on Chicago’s South Side participates in a federal program called 340B, which allows hospitals that serve low-income populations to purchase drugs at deep discounts.

Lupron Depot is given as a simple injection into the muscle. It takes minutes for a nurse or doctor to administer. Yet hospital systems like Chicago Medicine can and typically do charge lavishly for such services, to enhance revenue, said Morgan Henderson, principal data scientist at the Hilltop Institute at the University of Maryland-Baltimore County. Chicago Medicine declined to say what it paid for the drug.

While U.S. drugmakers can price their drugs however they please, TAP has gotten into trouble for its Lupron sales policies in the past. In 2001, after a Justice Department probe, it paid an $875 million settlement for illegally stimulating sales by giving urologists free and discounted vials of the drug while enabling them to charge Medicare full price.

Since then, many other drugs aimed at lowering testosterone levels have entered the market, including a pill, relugolix (Orgovyx). So why wouldn’t a patient use them?

Lupron Depot is long acting, is easy to prepare and store, and employs a small needle, which some patients prefer, said Brian McNeil, MD, chief of urology at University Hospital of Brooklyn. Orgovyx is convenient, but “a patient has to be very compliant. They have to take it every day around the same time,” he said. “Some people just forget.”

But there is another important factor that may well explain Lupron Depot’s ongoing popularity among medical providers: Doctors and hospitals can earn tens of thousands of dollars each visit by marking up its price and administration fees – as they did with Mr. Hinds. If they merely write a prescription for a drug that can be taken at home, they earn nothing.

Asked about this high patient charge and the possibility of using alternatives, United spokesperson Maria Gordon Shydlo said payment was “appropriately based on the hospital’s contract and the member’s benefit plan,” adding that the insurer encourages customers to shop around for the best quality and price.

Resolution: In addition to leaving Mr. Hinds listless, the Lupron Depot shots were, literally, a pain in the rear end. “Each time he was miserable for 2 weeks,” Dr. Tenore said. After looking over his first bill for the Lupron shot, Dr. Tenore told Mr. Hinds he should ask his doctor whether there was a less expensive drug that was easier to take.

After the second shot, in August 2021, a pharmacist told him he could instead receive the pill. His doctor prescribed Mr. Hinds 3 months’ worth of Orgovyx last November, for which he paid $216 and the insurer paid over $6,000. The drug’s list price is about $2,700 a month. There is evidence that Orgovyx works a little better than leuprolide.

Orgovyx was a “no-brainer,” Mr. Hinds said. “Why would you want a sore ass for two weeks when you can take a pill that kicks in sooner, functions the same way, and clears your body of testosterone faster?”

While Orgovyx is increasingly used for prostate cancer, Lupron and other injections usually remain the standard of care, hospital spokesperson Ashley Heher said. Clinicians “work with patients to determine what treatments are the most medically effective and, when necessary, to find reasonable alternatives that may be less financially burdensome due to insurance coverage limitations.”

Mr. Hinds was baffled by the size of the charges. During months of phone calls and emails, the hospital reversed and then reapplied part of the charge, and then in July agreed to a $666.34 monthly payment plan. After Hinds had made two payments, however, the hospital announced Aug. 29 it was canceling the agreement and sending the remainder of his bill to a collection agency. Two weeks later, the hospital reinstated the payment plan – after KHN asked about the cancellation.

As for Mr. Hinds, he remains active, though his bike rides have been shortened from 50 or 60 miles to about 30, he said.

He’s grateful to have Dr. Tenore as a free consultant and empathizes with those who lack a knowledgeable guide through their disease and health care’s financial maze.

“I’ve got Dr. Josie as an advocate who knows the system,” Mr. Hinds said.

The takeaway: First tip: If you are prescribed an infusion or injection, ask your physician if there are cheaper oral medications to treat your condition. Also, many drugs that are given by injection – ones that are given “subcutaneously,” rather than into a muscle – can be administered by a patient at home, avoiding hefty administration fees. Drugs like Dupixent for eczema fall into this category.

Keep in mind that where you get treatment could make a big difference in your charges: A study found that leading U.S. cancer centers charge enormous markups to private insurers for drug injections or infusions. Another study found that hospital systems charge an average of 86% more than private clinics for cancer drug infusions. And the percentage of cancer infusions done in hospital-operated clinics increased from 6% in 2004 to 43% in 2014, and has grown since.

Under a law that took effect in 2021, hospitals are required to list their charges, though they currently do so in a way that is not user friendly. But it’s worth taking a look at the price list – the hospital chargemaster – to try to decipher the pricing and markup for your medicine. If you’re about to get an injection, infusion, or procedure done in a hospital system, ask ahead of time for an estimate of what you will owe.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Josie Tenore, MD, and Paul Hinds were introduced by a mutual friend in 2017 and hadn’t been going out long when she laid down the law: He had to get a physical.

“I don’t date people who don’t take care of their health,” said Dr. Tenore, who practices cosmetic dermatology and functional medicine in suburban Chicago.

One of Mr. Hinds’ blood tests that summer came back with an alarming result: His prostate-specific antigen (PSA), level was very high. A biopsy confirmed he had advanced prostate cancer.

There aren’t a lot of comfortable alternatives for treating prostate cancer, which generally progresses as long as testosterone levels remain high. Marijuana appears to lower testosterone levels, so after his diagnosis, he dosed a liquid form of cannabis for several weeks. That cut his PSA in half, but Mr. Hinds, a cybersecurity expert who likes yoga and bicycling, “was stoned out of his mind and couldn’t function,” Dr. Tenore recalled.

With Dr. Tenore guiding his decisions, Mr. Hinds next tried high-frequency ultrasound treatment, but it failed. And in the summer of 2019 doctors removed his prostate gland. Still, the PSA levels climbed again, and doctors assessed that the cancer had metastasized. The only alternative was to drastically lower Mr. Hinds’ testosterone levels – either via surgery or drugs that block all testosterone. In May 2021, he got his first intramuscular shot of Lupron Depot, a brand name for leuprolide, designed to suppress the prostate gland’s release of the hormone for 3 months. That August, he got his second shot.

And then the bills came.

The patient: Paul Hinds, now 60, is covered by United Healthcare through a COBRA plan from his former employer.

Medical service: Two 3-month Lupron Depot injections for metastatic prostate cancer.

Service provider: University of Chicago Medicine, a 900-physician nonprofit system that includes an 811-bed medical center, a suburban hospital, the Pritzker School of Medicine, and outpatient clinics and physician offices throughout the Chicago area.

Total bill: $73,812 for the two shots ($35,414 for the first, $38,398 for the second), including lab work and physician charges. United Healthcare’s negotiated rate for the two shots plus associated fees was $27,568, of which the insurer paid $19,567. After Mr. Hinds haggled with the hospital and insurer for more than a year, his share of the bills was determined to be nearly $7,000.

What gives: The first issue is unrelenting price increases on old drugs that have remained branded as manufacturers find ways to extend patents for decades and maintain sales through marketing.

Though Lupron was invented in 1973, its manufacturer got patent extensions in 1989 by offering a slow-release version. Drugmakers commonly use this tactic to extend their exclusive rights to sell a product.

The development of Lupron Depot as an intramuscular shot that suppressed testosterone for months at a time improved patient compliance and also enabled its maker, Abbott Laboratories, and its Japanese partner, Takeda, to extend their patents on the drug into the 2000s, said Gerald Weisberg, MD, a former Abbott scientist who has been critical of the company’s pricing policies.

In subsequent years, Abbott and Takeda, in a joint venture called TAP Pharmaceuticals, steadily marked up the price of their slow-release product. In 2000, the average wholesale U.S. price for a 3-month shot was $1,245; currently that figure is $5,866. (It is manufactured in the United States by AbbVie now.)

In the United Kingdom, where health care is generally free and Takeda sells the drug under the name Prostap, all physicians can purchase a 3-month dose for about $260.

It’s likely that Chicago Medicine, where Mr. Hinds got his shots, paid something close to the British price. That’s because the health system’s hospital on Chicago’s South Side participates in a federal program called 340B, which allows hospitals that serve low-income populations to purchase drugs at deep discounts.

Lupron Depot is given as a simple injection into the muscle. It takes minutes for a nurse or doctor to administer. Yet hospital systems like Chicago Medicine can and typically do charge lavishly for such services, to enhance revenue, said Morgan Henderson, principal data scientist at the Hilltop Institute at the University of Maryland-Baltimore County. Chicago Medicine declined to say what it paid for the drug.

While U.S. drugmakers can price their drugs however they please, TAP has gotten into trouble for its Lupron sales policies in the past. In 2001, after a Justice Department probe, it paid an $875 million settlement for illegally stimulating sales by giving urologists free and discounted vials of the drug while enabling them to charge Medicare full price.

Since then, many other drugs aimed at lowering testosterone levels have entered the market, including a pill, relugolix (Orgovyx). So why wouldn’t a patient use them?

Lupron Depot is long acting, is easy to prepare and store, and employs a small needle, which some patients prefer, said Brian McNeil, MD, chief of urology at University Hospital of Brooklyn. Orgovyx is convenient, but “a patient has to be very compliant. They have to take it every day around the same time,” he said. “Some people just forget.”

But there is another important factor that may well explain Lupron Depot’s ongoing popularity among medical providers: Doctors and hospitals can earn tens of thousands of dollars each visit by marking up its price and administration fees – as they did with Mr. Hinds. If they merely write a prescription for a drug that can be taken at home, they earn nothing.

Asked about this high patient charge and the possibility of using alternatives, United spokesperson Maria Gordon Shydlo said payment was “appropriately based on the hospital’s contract and the member’s benefit plan,” adding that the insurer encourages customers to shop around for the best quality and price.

Resolution: In addition to leaving Mr. Hinds listless, the Lupron Depot shots were, literally, a pain in the rear end. “Each time he was miserable for 2 weeks,” Dr. Tenore said. After looking over his first bill for the Lupron shot, Dr. Tenore told Mr. Hinds he should ask his doctor whether there was a less expensive drug that was easier to take.

After the second shot, in August 2021, a pharmacist told him he could instead receive the pill. His doctor prescribed Mr. Hinds 3 months’ worth of Orgovyx last November, for which he paid $216 and the insurer paid over $6,000. The drug’s list price is about $2,700 a month. There is evidence that Orgovyx works a little better than leuprolide.

Orgovyx was a “no-brainer,” Mr. Hinds said. “Why would you want a sore ass for two weeks when you can take a pill that kicks in sooner, functions the same way, and clears your body of testosterone faster?”

While Orgovyx is increasingly used for prostate cancer, Lupron and other injections usually remain the standard of care, hospital spokesperson Ashley Heher said. Clinicians “work with patients to determine what treatments are the most medically effective and, when necessary, to find reasonable alternatives that may be less financially burdensome due to insurance coverage limitations.”

Mr. Hinds was baffled by the size of the charges. During months of phone calls and emails, the hospital reversed and then reapplied part of the charge, and then in July agreed to a $666.34 monthly payment plan. After Hinds had made two payments, however, the hospital announced Aug. 29 it was canceling the agreement and sending the remainder of his bill to a collection agency. Two weeks later, the hospital reinstated the payment plan – after KHN asked about the cancellation.

As for Mr. Hinds, he remains active, though his bike rides have been shortened from 50 or 60 miles to about 30, he said.

He’s grateful to have Dr. Tenore as a free consultant and empathizes with those who lack a knowledgeable guide through their disease and health care’s financial maze.

“I’ve got Dr. Josie as an advocate who knows the system,” Mr. Hinds said.

The takeaway: First tip: If you are prescribed an infusion or injection, ask your physician if there are cheaper oral medications to treat your condition. Also, many drugs that are given by injection – ones that are given “subcutaneously,” rather than into a muscle – can be administered by a patient at home, avoiding hefty administration fees. Drugs like Dupixent for eczema fall into this category.

Keep in mind that where you get treatment could make a big difference in your charges: A study found that leading U.S. cancer centers charge enormous markups to private insurers for drug injections or infusions. Another study found that hospital systems charge an average of 86% more than private clinics for cancer drug infusions. And the percentage of cancer infusions done in hospital-operated clinics increased from 6% in 2004 to 43% in 2014, and has grown since.

Under a law that took effect in 2021, hospitals are required to list their charges, though they currently do so in a way that is not user friendly. But it’s worth taking a look at the price list – the hospital chargemaster – to try to decipher the pricing and markup for your medicine. If you’re about to get an injection, infusion, or procedure done in a hospital system, ask ahead of time for an estimate of what you will owe.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.