News

SAN DIEGO — In tough-to-treat chronic inflammatory bowel disease (IBD), a precision-medicine strategy based on patients’ molecular profiles showed efficacy in guiding anti–tumor necrosis factor (TNF) therapy treatment decisions to improve outcomes.

“This is the first study implementing multi-biomarker signatures in informed decisions instead of single biomarker–based trial algorithms [in IBD],” said first author Florian Tran, MD, in presenting the late-breaking study at Digestive Disease Week (DDW) 2025.

“We have now been able to demonstrate for the first time that precision medicine can be successfully applied in the context of chronic inflammatory bowel diseases, leading to improved long-term outcomes,” said Tran, a professor of pathophysiology of chronic inflammation at the Institute of Clinical Molecular Biology and department of internal medicine, Kiel University and University Hospital Schleswig Holstein, Kiel, Germany.

Anti-TNF therapies can be highly effective in a range of immune-mediated inflammatory diseases, including IBD, but not all patients respond. Key singular candidates of biomarkers that could better predict a response show relatively low predictive power or a failure to replicate in independent studies.

In previous research, Tran and colleagues reported identification of early dynamic molecular changes in the blood that are more robustly predictive of responses to anti-TNF therapy.

“We have generated compelling evidence that therapy-induced changes in inflammatory pathways can reliably predict patient outcomes,” he said.

Among them are dynamic transcriptome changes that emerge early during treatment and can predict response to anti-TNF therapy, as well as clinical response trajectories that differ based on subgroups.

To further investigate the benefits of the multi-biomarker signatures collectively, as opposed to single biomarker–based algorithms, Tran and colleagues conducted the phase 3, open-label GUIDE-IBD trial, enrolling 102 adults with a confirmed diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) at three German university hospitals between February 2021 and January 2024.

All patients had been assigned the anti-TNF drug infliximab for the first time.

Study participants were randomized to receive either the molecular-guided care or standard medical care, with stratifications based on diagnosis, recruiting center, and baseline corticosteroid use.

Those in the molecular group received real-time molecular assessments at baseline and weeks 2, 6, 14, and 26, which included peripheral blood samples and biopsies of known messenger ribonucleic acid–based biomarkers.

The assessments also looked at infliximab and anti-drug antibody levels.

Molecular reports were then provided through molecular medicine boards for patients in the molecular-guidance group at weeks 2, 14, 26, and 52, whereas data from the standard-care group was not communicated.

Based on the biomarker data, therapy decisions were made such as adjustments to dosing, intervals, comedication, and switches in therapy.

The primary endpoint was the combined end point of disease control, defined as clinical remission (CD Activity Index < 150, partial Mayo score < 2), endoscopic remission (simplified endoscopic score for CD ≤ 4 [≤ 2 for isolated ileal disease], endoscopic Mayo score ≤ 1), or biochemical remission (C-reactive protein < 5 mg/L, fecal calprotectin < 250 mg/g).

A total of 87 patients completed the study with available primary endpoint data to week 52; there were 38 in the molecular care group and 49 in the standard care group. In each group, approximately half of the patients had CD and half had UC.

For the primary endpoint, comprehensive disease control was significantly more frequent in the molecular care group at week 52 (55.3%) than in the standard-care group (26.5%), with an absolute difference of 29% (P = .0072).

Furthermore, the secondary endpoint of the combined rate of endoscopic and clinical remission at week 52 was also higher in the molecular group (60.5%) than in the standard-care group (32.7%; P = .0163).

An exploratory analysis further showed therapy switches were more common in the molecular group (47%) than in the standard-care group (29%), with an increased rate of drug switching between 14 weeks and 26 weeks.

More patients in the molecular guidance group achieved comprehensive disease control (deep remission) at week 52 (P = .0135).

“The [molecular guidance] group was more likely to switch therapies after the induction period, reducing the number of patients who are suboptimally treated under infliximab,” Tran noted.

The results underscore that “even in the absence of a single ‘magic’ biomarker, precision medicine can materially improve patient outcomes by integrating complex molecular data into everyday clinical decisions, enabling more effective therapy choices and reducing unnecessary drug side effects,” he said.

 

Approach Pioneered in Oncology

Tran noted that the collaboration necessary for the approach was based on strategies pioneered in cancer centers, which have resulted in significant improvements in cancer therapy outcomes.

“For the first time in IBD, we have now integrated multidimensional molecular data and innovative drug-dosing models into these inflammation boards,” he said.

Key components of the intervention include a highly structured patient care process with fixed assessment timepoints, as well as “a multidisciplinary, quality-controlled decision-making process that is meticulously documented,” he explained.

The results underscore that “we must move away from sole physician–driven treatment decisions in IBD toward a structured expert-board model for therapy decision-making.” 

 

Benefits in Other IBD Therapies Unclear

Commenting on the study, Ashwin N. Ananthakrishnan, MBBS, MPH, AGAF, an associate professor of medicine with Massachusetts General Hospital, Boston, noted that “this approach may help optimize existing treatment early and ensure that ineffective treatments don’t get dragged on.”

Importantly, however, a key limitation is that “this does not tell you upfront whether a treatment is likely to work or what the best treatment is,” Ananthakrishnan said in an interview. “That is a critically important unmet need in IBD.”

While doses are escalated, if needed, with infliximab and other biologic drugs, that may not be the case with other therapies, he explained.

“For other agents, such as JAK [Janus kinase] inhibitors, we actually start at a higher dose and then reduce for maintenance,” said Ananthakrishnan.

How this approach would work for these drugs or “for drugs where blood levels are not reflective of efficacy is also not clear,” he said.

Tran’s disclosures included relationships with AbbVie, Bristol-Myers-Squibb, CED Service, Celltrion Healthcare, Eli Lilly, Ferring Pharmaceutical, Janssen, Johnson & Johnson, Takeda, LEK Consulting, and Sanofi/Regeneron. Ananthakrishnan had no disclosures to report.

A version of this article appeared on Medscape.com.

SAN DIEGO — In tough-to-treat chronic inflammatory bowel disease (IBD), a precision-medicine strategy based on patients’ molecular profiles showed efficacy in guiding anti–tumor necrosis factor (TNF) therapy treatment decisions to improve outcomes.

“This is the first study implementing multi-biomarker signatures in informed decisions instead of single biomarker–based trial algorithms [in IBD],” said first author Florian Tran, MD, in presenting the late-breaking study at Digestive Disease Week (DDW) 2025.

“We have now been able to demonstrate for the first time that precision medicine can be successfully applied in the context of chronic inflammatory bowel diseases, leading to improved long-term outcomes,” said Tran, a professor of pathophysiology of chronic inflammation at the Institute of Clinical Molecular Biology and department of internal medicine, Kiel University and University Hospital Schleswig Holstein, Kiel, Germany.

Anti-TNF therapies can be highly effective in a range of immune-mediated inflammatory diseases, including IBD, but not all patients respond. Key singular candidates of biomarkers that could better predict a response show relatively low predictive power or a failure to replicate in independent studies.

In previous research, Tran and colleagues reported identification of early dynamic molecular changes in the blood that are more robustly predictive of responses to anti-TNF therapy.

“We have generated compelling evidence that therapy-induced changes in inflammatory pathways can reliably predict patient outcomes,” he said.

Among them are dynamic transcriptome changes that emerge early during treatment and can predict response to anti-TNF therapy, as well as clinical response trajectories that differ based on subgroups.

To further investigate the benefits of the multi-biomarker signatures collectively, as opposed to single biomarker–based algorithms, Tran and colleagues conducted the phase 3, open-label GUIDE-IBD trial, enrolling 102 adults with a confirmed diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) at three German university hospitals between February 2021 and January 2024.

All patients had been assigned the anti-TNF drug infliximab for the first time.

Study participants were randomized to receive either the molecular-guided care or standard medical care, with stratifications based on diagnosis, recruiting center, and baseline corticosteroid use.

Those in the molecular group received real-time molecular assessments at baseline and weeks 2, 6, 14, and 26, which included peripheral blood samples and biopsies of known messenger ribonucleic acid–based biomarkers.

The assessments also looked at infliximab and anti-drug antibody levels.

Molecular reports were then provided through molecular medicine boards for patients in the molecular-guidance group at weeks 2, 14, 26, and 52, whereas data from the standard-care group was not communicated.

Based on the biomarker data, therapy decisions were made such as adjustments to dosing, intervals, comedication, and switches in therapy.

The primary endpoint was the combined end point of disease control, defined as clinical remission (CD Activity Index < 150, partial Mayo score < 2), endoscopic remission (simplified endoscopic score for CD ≤ 4 [≤ 2 for isolated ileal disease], endoscopic Mayo score ≤ 1), or biochemical remission (C-reactive protein < 5 mg/L, fecal calprotectin < 250 mg/g).

A total of 87 patients completed the study with available primary endpoint data to week 52; there were 38 in the molecular care group and 49 in the standard care group. In each group, approximately half of the patients had CD and half had UC.

For the primary endpoint, comprehensive disease control was significantly more frequent in the molecular care group at week 52 (55.3%) than in the standard-care group (26.5%), with an absolute difference of 29% (P = .0072).

Furthermore, the secondary endpoint of the combined rate of endoscopic and clinical remission at week 52 was also higher in the molecular group (60.5%) than in the standard-care group (32.7%; P = .0163).

An exploratory analysis further showed therapy switches were more common in the molecular group (47%) than in the standard-care group (29%), with an increased rate of drug switching between 14 weeks and 26 weeks.

More patients in the molecular guidance group achieved comprehensive disease control (deep remission) at week 52 (P = .0135).

“The [molecular guidance] group was more likely to switch therapies after the induction period, reducing the number of patients who are suboptimally treated under infliximab,” Tran noted.

The results underscore that “even in the absence of a single ‘magic’ biomarker, precision medicine can materially improve patient outcomes by integrating complex molecular data into everyday clinical decisions, enabling more effective therapy choices and reducing unnecessary drug side effects,” he said.

 

Approach Pioneered in Oncology

Tran noted that the collaboration necessary for the approach was based on strategies pioneered in cancer centers, which have resulted in significant improvements in cancer therapy outcomes.

“For the first time in IBD, we have now integrated multidimensional molecular data and innovative drug-dosing models into these inflammation boards,” he said.

Key components of the intervention include a highly structured patient care process with fixed assessment timepoints, as well as “a multidisciplinary, quality-controlled decision-making process that is meticulously documented,” he explained.

The results underscore that “we must move away from sole physician–driven treatment decisions in IBD toward a structured expert-board model for therapy decision-making.” 

 

Benefits in Other IBD Therapies Unclear

Commenting on the study, Ashwin N. Ananthakrishnan, MBBS, MPH, AGAF, an associate professor of medicine with Massachusetts General Hospital, Boston, noted that “this approach may help optimize existing treatment early and ensure that ineffective treatments don’t get dragged on.”

Importantly, however, a key limitation is that “this does not tell you upfront whether a treatment is likely to work or what the best treatment is,” Ananthakrishnan said in an interview. “That is a critically important unmet need in IBD.”

While doses are escalated, if needed, with infliximab and other biologic drugs, that may not be the case with other therapies, he explained.

“For other agents, such as JAK [Janus kinase] inhibitors, we actually start at a higher dose and then reduce for maintenance,” said Ananthakrishnan.

How this approach would work for these drugs or “for drugs where blood levels are not reflective of efficacy is also not clear,” he said.

Tran’s disclosures included relationships with AbbVie, Bristol-Myers-Squibb, CED Service, Celltrion Healthcare, Eli Lilly, Ferring Pharmaceutical, Janssen, Johnson & Johnson, Takeda, LEK Consulting, and Sanofi/Regeneron. Ananthakrishnan had no disclosures to report.

A version of this article appeared on Medscape.com.

SAN DIEGO — In tough-to-treat chronic inflammatory bowel disease (IBD), a precision-medicine strategy based on patients’ molecular profiles showed efficacy in guiding anti–tumor necrosis factor (TNF) therapy treatment decisions to improve outcomes.

“This is the first study implementing multi-biomarker signatures in informed decisions instead of single biomarker–based trial algorithms [in IBD],” said first author Florian Tran, MD, in presenting the late-breaking study at Digestive Disease Week (DDW) 2025.

“We have now been able to demonstrate for the first time that precision medicine can be successfully applied in the context of chronic inflammatory bowel diseases, leading to improved long-term outcomes,” said Tran, a professor of pathophysiology of chronic inflammation at the Institute of Clinical Molecular Biology and department of internal medicine, Kiel University and University Hospital Schleswig Holstein, Kiel, Germany.

Anti-TNF therapies can be highly effective in a range of immune-mediated inflammatory diseases, including IBD, but not all patients respond. Key singular candidates of biomarkers that could better predict a response show relatively low predictive power or a failure to replicate in independent studies.

In previous research, Tran and colleagues reported identification of early dynamic molecular changes in the blood that are more robustly predictive of responses to anti-TNF therapy.

“We have generated compelling evidence that therapy-induced changes in inflammatory pathways can reliably predict patient outcomes,” he said.

Among them are dynamic transcriptome changes that emerge early during treatment and can predict response to anti-TNF therapy, as well as clinical response trajectories that differ based on subgroups.

To further investigate the benefits of the multi-biomarker signatures collectively, as opposed to single biomarker–based algorithms, Tran and colleagues conducted the phase 3, open-label GUIDE-IBD trial, enrolling 102 adults with a confirmed diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) at three German university hospitals between February 2021 and January 2024.

All patients had been assigned the anti-TNF drug infliximab for the first time.

Study participants were randomized to receive either the molecular-guided care or standard medical care, with stratifications based on diagnosis, recruiting center, and baseline corticosteroid use.

Those in the molecular group received real-time molecular assessments at baseline and weeks 2, 6, 14, and 26, which included peripheral blood samples and biopsies of known messenger ribonucleic acid–based biomarkers.

The assessments also looked at infliximab and anti-drug antibody levels.

Molecular reports were then provided through molecular medicine boards for patients in the molecular-guidance group at weeks 2, 14, 26, and 52, whereas data from the standard-care group was not communicated.

Based on the biomarker data, therapy decisions were made such as adjustments to dosing, intervals, comedication, and switches in therapy.

The primary endpoint was the combined end point of disease control, defined as clinical remission (CD Activity Index < 150, partial Mayo score < 2), endoscopic remission (simplified endoscopic score for CD ≤ 4 [≤ 2 for isolated ileal disease], endoscopic Mayo score ≤ 1), or biochemical remission (C-reactive protein < 5 mg/L, fecal calprotectin < 250 mg/g).

A total of 87 patients completed the study with available primary endpoint data to week 52; there were 38 in the molecular care group and 49 in the standard care group. In each group, approximately half of the patients had CD and half had UC.

For the primary endpoint, comprehensive disease control was significantly more frequent in the molecular care group at week 52 (55.3%) than in the standard-care group (26.5%), with an absolute difference of 29% (P = .0072).

Furthermore, the secondary endpoint of the combined rate of endoscopic and clinical remission at week 52 was also higher in the molecular group (60.5%) than in the standard-care group (32.7%; P = .0163).

An exploratory analysis further showed therapy switches were more common in the molecular group (47%) than in the standard-care group (29%), with an increased rate of drug switching between 14 weeks and 26 weeks.

More patients in the molecular guidance group achieved comprehensive disease control (deep remission) at week 52 (P = .0135).

“The [molecular guidance] group was more likely to switch therapies after the induction period, reducing the number of patients who are suboptimally treated under infliximab,” Tran noted.

The results underscore that “even in the absence of a single ‘magic’ biomarker, precision medicine can materially improve patient outcomes by integrating complex molecular data into everyday clinical decisions, enabling more effective therapy choices and reducing unnecessary drug side effects,” he said.

 

Approach Pioneered in Oncology

Tran noted that the collaboration necessary for the approach was based on strategies pioneered in cancer centers, which have resulted in significant improvements in cancer therapy outcomes.

“For the first time in IBD, we have now integrated multidimensional molecular data and innovative drug-dosing models into these inflammation boards,” he said.

Key components of the intervention include a highly structured patient care process with fixed assessment timepoints, as well as “a multidisciplinary, quality-controlled decision-making process that is meticulously documented,” he explained.

The results underscore that “we must move away from sole physician–driven treatment decisions in IBD toward a structured expert-board model for therapy decision-making.” 

 

Benefits in Other IBD Therapies Unclear

Commenting on the study, Ashwin N. Ananthakrishnan, MBBS, MPH, AGAF, an associate professor of medicine with Massachusetts General Hospital, Boston, noted that “this approach may help optimize existing treatment early and ensure that ineffective treatments don’t get dragged on.”

Importantly, however, a key limitation is that “this does not tell you upfront whether a treatment is likely to work or what the best treatment is,” Ananthakrishnan said in an interview. “That is a critically important unmet need in IBD.”

While doses are escalated, if needed, with infliximab and other biologic drugs, that may not be the case with other therapies, he explained.

“For other agents, such as JAK [Janus kinase] inhibitors, we actually start at a higher dose and then reduce for maintenance,” said Ananthakrishnan.

How this approach would work for these drugs or “for drugs where blood levels are not reflective of efficacy is also not clear,” he said.

Tran’s disclosures included relationships with AbbVie, Bristol-Myers-Squibb, CED Service, Celltrion Healthcare, Eli Lilly, Ferring Pharmaceutical, Janssen, Johnson & Johnson, Takeda, LEK Consulting, and Sanofi/Regeneron. Ananthakrishnan had no disclosures to report.

A version of this article appeared on Medscape.com.

SAN DIEGO — Boston Pharmaceuticals’ once-monthly efimosfermin alfa (formerly BOS-580) prescribed for metabolic dysfunction–associated steatohepatitis (MASH) with F2 and F3 fibrosis significantly improved MASH resolution and fibrosis after 24 weeks, according to results of a phase 2 trial presented at Digestive Disease Week (DDW) 2025.

An analogue of the fibroblast growth factor 21 (FGF21) protein, the agent regulates metabolic processes to reduce liver fat. It has a half-life of about 21 days, said study presenter Margaret J. Koziel, MD, chief medical officer at Boston Pharmaceuticals.

MASH is marked by inflammation and fibrosis and can progress to cirrhosis and liver failure. About 2%-5% of US adults have MASH, according to the American College of Gastroenterology. Up to 20% of adults who are obese may have the condition.

The researchers randomly assigned 84 participants with biopsy-confirmed F2/F3 MASH to receive once-monthly injections of 300 mg efimosfermin alpha (43 patients) or placebo (41 patients) for 24 weeks.

The mean body mass index (BMI) of participants in both groups was about 37. Most study sites were in the southern United States, so that BMI “reflects the demographics,” Koziel said. Mean age was 55 years in the placebo group and 53 years in the treatment group, and about half of patients in both groups were women. Eighteen patients in each group had a fibrosis stage of F3.

Primary endpoints were safety and tolerability.

Exploratory objectives included the proportion of patients achieving fibrosis improvement of one or more stages without MASH worsening, MASH resolution without worsening of fibrosis, or both fibrosis improvement and MASH resolution.

Sixty-seven patients completed the treatment, and 65 post-baseline biopsies were collected — 34 in the placebo group and 31 in the treatment group.

 

Positive Results

“We saw statistically significant changes in fibrosis improvement,” Koziel said. “This has been the hardest barrier to hit.”

After 24 weeks, 45% of patients in the treatment group and 21% in the placebo group showed fibrosis improvement of one or more stages without worsening of MASH (P = .038), and 68% of those in the treatment group and 29% in the placebo group had MASH resolution without fibrosis worsening (P = .002).

The between-group difference in fibrosis improvement and MASH resolution did not reach statistical significance, with 39% of patients in the treatment group and 18% in the placebo group achieving the combined endpoint (P = .066). “It just missed statistical significance,” Koziel said, but she viewed the outcome as meaningful.

Additionally, “a third of the group taking efimosfermin normalized their liver fat, and all but one normalized their liver enzymes,” she said.

Adverse events — most often nausea, vomiting and diarrhea — were mild to moderate in both groups, Koziel said. In the treatment group, one patient withdrew from the study due to a grade 3 serious adverse event, and two others did so due to low-grade adverse events.

“These data support further development of once-monthly efimosfermin for the treatment of MASH-related fibrosis,” the research team concluded.

 

Hopeful Development

“Finally, there’s hope,” said DDW attendee Na Li, MD, associate clinical professor of internal medicine at Ohio State University Wexner Medical Center, Columbus, Ohio, whose clinical focus is on metabolic-associated steatotic liver disease.

The new hope, she said, refers not only to the phase 2 study results but to the Food and Drug Administration approval of resmetirom (Rezdiffra) last year, which reduces liver fat by stimulating thyroid hormone receptor beta. “That was the first medication that got approved with a specific indication to treat MASH,” she said. Before that, lifestyle measures aimed at weight loss were the only approach.

Lifestyle measures are still important, Li said, but it’s helpful to have additional options. “There are quite a few agents in the pipeline now,” she said. One example is another FGF21 analogue efruxifermin, which is in phase 3 trials.

Li had no disclosures. Koziel declared being an employee of Boston Pharmaceuticals.

A version of this article appeared on Medscape.com.

SAN DIEGO — Boston Pharmaceuticals’ once-monthly efimosfermin alfa (formerly BOS-580) prescribed for metabolic dysfunction–associated steatohepatitis (MASH) with F2 and F3 fibrosis significantly improved MASH resolution and fibrosis after 24 weeks, according to results of a phase 2 trial presented at Digestive Disease Week (DDW) 2025.

An analogue of the fibroblast growth factor 21 (FGF21) protein, the agent regulates metabolic processes to reduce liver fat. It has a half-life of about 21 days, said study presenter Margaret J. Koziel, MD, chief medical officer at Boston Pharmaceuticals.

MASH is marked by inflammation and fibrosis and can progress to cirrhosis and liver failure. About 2%-5% of US adults have MASH, according to the American College of Gastroenterology. Up to 20% of adults who are obese may have the condition.

The researchers randomly assigned 84 participants with biopsy-confirmed F2/F3 MASH to receive once-monthly injections of 300 mg efimosfermin alpha (43 patients) or placebo (41 patients) for 24 weeks.

The mean body mass index (BMI) of participants in both groups was about 37. Most study sites were in the southern United States, so that BMI “reflects the demographics,” Koziel said. Mean age was 55 years in the placebo group and 53 years in the treatment group, and about half of patients in both groups were women. Eighteen patients in each group had a fibrosis stage of F3.

Primary endpoints were safety and tolerability.

Exploratory objectives included the proportion of patients achieving fibrosis improvement of one or more stages without MASH worsening, MASH resolution without worsening of fibrosis, or both fibrosis improvement and MASH resolution.

Sixty-seven patients completed the treatment, and 65 post-baseline biopsies were collected — 34 in the placebo group and 31 in the treatment group.

 

Positive Results

“We saw statistically significant changes in fibrosis improvement,” Koziel said. “This has been the hardest barrier to hit.”

After 24 weeks, 45% of patients in the treatment group and 21% in the placebo group showed fibrosis improvement of one or more stages without worsening of MASH (P = .038), and 68% of those in the treatment group and 29% in the placebo group had MASH resolution without fibrosis worsening (P = .002).

The between-group difference in fibrosis improvement and MASH resolution did not reach statistical significance, with 39% of patients in the treatment group and 18% in the placebo group achieving the combined endpoint (P = .066). “It just missed statistical significance,” Koziel said, but she viewed the outcome as meaningful.

Additionally, “a third of the group taking efimosfermin normalized their liver fat, and all but one normalized their liver enzymes,” she said.

Adverse events — most often nausea, vomiting and diarrhea — were mild to moderate in both groups, Koziel said. In the treatment group, one patient withdrew from the study due to a grade 3 serious adverse event, and two others did so due to low-grade adverse events.

“These data support further development of once-monthly efimosfermin for the treatment of MASH-related fibrosis,” the research team concluded.

 

Hopeful Development

“Finally, there’s hope,” said DDW attendee Na Li, MD, associate clinical professor of internal medicine at Ohio State University Wexner Medical Center, Columbus, Ohio, whose clinical focus is on metabolic-associated steatotic liver disease.

The new hope, she said, refers not only to the phase 2 study results but to the Food and Drug Administration approval of resmetirom (Rezdiffra) last year, which reduces liver fat by stimulating thyroid hormone receptor beta. “That was the first medication that got approved with a specific indication to treat MASH,” she said. Before that, lifestyle measures aimed at weight loss were the only approach.

Lifestyle measures are still important, Li said, but it’s helpful to have additional options. “There are quite a few agents in the pipeline now,” she said. One example is another FGF21 analogue efruxifermin, which is in phase 3 trials.

Li had no disclosures. Koziel declared being an employee of Boston Pharmaceuticals.

A version of this article appeared on Medscape.com.

SAN DIEGO — Boston Pharmaceuticals’ once-monthly efimosfermin alfa (formerly BOS-580) prescribed for metabolic dysfunction–associated steatohepatitis (MASH) with F2 and F3 fibrosis significantly improved MASH resolution and fibrosis after 24 weeks, according to results of a phase 2 trial presented at Digestive Disease Week (DDW) 2025.

An analogue of the fibroblast growth factor 21 (FGF21) protein, the agent regulates metabolic processes to reduce liver fat. It has a half-life of about 21 days, said study presenter Margaret J. Koziel, MD, chief medical officer at Boston Pharmaceuticals.

MASH is marked by inflammation and fibrosis and can progress to cirrhosis and liver failure. About 2%-5% of US adults have MASH, according to the American College of Gastroenterology. Up to 20% of adults who are obese may have the condition.

The researchers randomly assigned 84 participants with biopsy-confirmed F2/F3 MASH to receive once-monthly injections of 300 mg efimosfermin alpha (43 patients) or placebo (41 patients) for 24 weeks.

The mean body mass index (BMI) of participants in both groups was about 37. Most study sites were in the southern United States, so that BMI “reflects the demographics,” Koziel said. Mean age was 55 years in the placebo group and 53 years in the treatment group, and about half of patients in both groups were women. Eighteen patients in each group had a fibrosis stage of F3.

Primary endpoints were safety and tolerability.

Exploratory objectives included the proportion of patients achieving fibrosis improvement of one or more stages without MASH worsening, MASH resolution without worsening of fibrosis, or both fibrosis improvement and MASH resolution.

Sixty-seven patients completed the treatment, and 65 post-baseline biopsies were collected — 34 in the placebo group and 31 in the treatment group.

 

Positive Results

“We saw statistically significant changes in fibrosis improvement,” Koziel said. “This has been the hardest barrier to hit.”

After 24 weeks, 45% of patients in the treatment group and 21% in the placebo group showed fibrosis improvement of one or more stages without worsening of MASH (P = .038), and 68% of those in the treatment group and 29% in the placebo group had MASH resolution without fibrosis worsening (P = .002).

The between-group difference in fibrosis improvement and MASH resolution did not reach statistical significance, with 39% of patients in the treatment group and 18% in the placebo group achieving the combined endpoint (P = .066). “It just missed statistical significance,” Koziel said, but she viewed the outcome as meaningful.

Additionally, “a third of the group taking efimosfermin normalized their liver fat, and all but one normalized their liver enzymes,” she said.

Adverse events — most often nausea, vomiting and diarrhea — were mild to moderate in both groups, Koziel said. In the treatment group, one patient withdrew from the study due to a grade 3 serious adverse event, and two others did so due to low-grade adverse events.

“These data support further development of once-monthly efimosfermin for the treatment of MASH-related fibrosis,” the research team concluded.

 

Hopeful Development

“Finally, there’s hope,” said DDW attendee Na Li, MD, associate clinical professor of internal medicine at Ohio State University Wexner Medical Center, Columbus, Ohio, whose clinical focus is on metabolic-associated steatotic liver disease.

The new hope, she said, refers not only to the phase 2 study results but to the Food and Drug Administration approval of resmetirom (Rezdiffra) last year, which reduces liver fat by stimulating thyroid hormone receptor beta. “That was the first medication that got approved with a specific indication to treat MASH,” she said. Before that, lifestyle measures aimed at weight loss were the only approach.

Lifestyle measures are still important, Li said, but it’s helpful to have additional options. “There are quite a few agents in the pipeline now,” she said. One example is another FGF21 analogue efruxifermin, which is in phase 3 trials.

Li had no disclosures. Koziel declared being an employee of Boston Pharmaceuticals.

A version of this article appeared on Medscape.com.

SAN DIEGO – A novel investigational endoscopic procedure targeting the duodenum appears beneficial in improving glycemic parameters in people with type 2 diabetes (T2D).

In a new dose-finding study, the re-cellularization via electroporation therapy (ReCET, Endogenex) improved insulin sensitivity, beta-cell function, and other glycemic parameters at 12 and 48 weeks in 51 individuals with T2D. “The findings suggest that duodenal mucosal and submucosal recellularization are key therapeutic targets in type 2 diabetes management,” said Barham Abu Dayyeh, MD, director of Interventional Gastroenterology at Cedar-Sinai Hospital, Los Angeles, in a presentation at Digestive Disease Week (DDW) 2025.

The outpatient technique is based on pulsed electrical fields, or electroporation, which do not use heat. “It’s nonthermal regeneration, not just ablation. It’s regeneration of the duodenum as a treatment target that could potentially modify type 2 diabetes,” Abu Dayyeh told GI & Hepatology News.

Separately at DDW, Abu Dayyeh presented results from an artificial intelligence–based analysis of duodenal biopsies from 111 individuals with T2D and 120 control individuals without diabetes, demonstrating distinct mucosal features associated with metabolic disease, significant inflammation in the deep mucosa and submucosa with increased fibrosis, and gut-barrier dysfunction. The authors termed this set of abnormalities “diabetic duodenopathy.” 

Abu Dayyeh likened the duodenum to a “conductor” of the “dysfunctional orchestra” of metabolic disease that includes T2D. “It’s tasked with integrating signals from the food that we eat and from our microbiome and communicates that metabolic response to downstream organs like the pancreas, liver, and adipose tissue.”

Currently, he said, “We use treatments that work downstream on components of this dysfunctional orchestra. So we work on the violinist and the flute player, but we do not go upstream to say maybe there’s an opportunity to put the orchestra conductor back in synch…We manage blood glycemia by lowering it, rather than looking at upstream disease-modifying targets that could reverse the course so you require less insulin and less medication.” 

Abu Dayyeh envisions the ReCET procedure as an option for people struggling to control T2D with standard medications, or for early use to avoid or delay medications, particularly insulin. But it won’t replace medications. “On the contrary, I see it as enhancing and complementing medications,” he said.

Asked to comment, Ali Aminian, MD, professor of surgery and director of the Bariatric and Metabolic Institute at the Cleveland Clinic, Cleveland, Ohio, told GI & Hepatology News, “Diabetes is a heterogeneous disease complex with numerous pathophysiological derangements. Although diabetic duodenopathy can be seen in some patients with diabetes, that wouldn’t explain the entire story behind diabetes pathogenesis in all people with diabetes. In a subgroup of people with duodenal involvement in their disease process, endoscopic procedures targeting the duodenum may play a role in the future.”

 

Glycemic Parameters Improve Following ReCET Procedure

The new study, called REGENT-1, was a multicenter, open-label, single-arm dose escalation of three levels of energy delivery in patients who had T2D for 10 years or less with A1c levels 7.5%-11% despite the use of one or more noninsulin glucose-lowering medications. Procedural success, defined as treatment of at least 6 cm of duodenum, was achieved in 100% of participants.

From a baseline A1c of 8.6%, there were dose-response drops at weeks 12 and 48 by energy delivery, with significant reductions at week 48 of 1.00 and 1.70 percentage points, respectively, among the 18 who received the middle dose and the 21 given the highest dose. Body weight also dropped in all three groups in a dose-response way, from 1.2% with the lowest to 6.2% with the highest energy delivery.

In mixed-meal tolerance testing, glucose area under the curve, homeostatic model assessment for insulin resistance, sensitivity index, beta-cell function, and disposition index (a measure of beta-cell response to insulin resistance) were all reduced from baseline at 48 weeks after ReCET, reaching statistical significance with the highest energy dose.

There were no device- or procedure-related serious adverse events.

Based on a literature search, Abu Dayyeh found that modern glucagon like peptide-1 receptor agonist medications have a stronger effect than ReCET or Roux-en-Y gastric bypass (RYGB) on beta-cell function (increases by 239% with semaglutide and 314% with tirzepatide vs 50% with ReCET and 74% for RYGB). However, ReCET procedure produced superior results for both insulin sensitivity (+487% for ReCET and +326% for bypass vs 30% and 62%, respectively for semaglutide and tirzepatide) and disposition index (+1032% for ReCET, +667% with tirzepatide, +642% for RYGB, and +367% for semaglutide).

Aminian commented, “The findings of this single arm clinical trial are promising. The next step is to incorporate a blinded control group who undergoes an endoscopy without any therapeutic intervention.”

In fact, such a study is underway. Results of “a multicenter, randomized, double-blind, sham-controlled study for assessing the safety and effectiveness of endoscopic intestinal re-cellularization therapy in individuals with type 2 diabetes (ReCET)” are expected in late 2026.

In the meantime, Amanian said about the current findings, “I’d argue that the observed improvement in diabetes parameters can be related to more intensive medical therapy during follow-up in this single arm study.”

In the trials, the procedure takes 30 minutes to an hour to perform. However, as the technology improves, “the vision of this is to be a 20-minute outpatient procedure eventually,” Abu Dayyeh said.

He envisions that eventually the procedure will become as accessible as colonoscopy is now, and that primary care physicians and endocrinologists would similarly refer patients to a gastroenterologist or surgeon to have it done. “They do the procedure and send your patient back, hopefully with a less complex management strategy, so you could manage them more efficiently without escalating care.” 

Abu Dayyeh is a co-inventor of the ReCET procedure, with the technology licensed by the Mayo Clinic. He is a consultant for and/or reported receiving research support from Boston Scientific, Olympus, Medtronic, Metamodix, BFKW, Apollo Endosurgery, USGI, Endogastric Solutions, Spatz, and Cairn. Aminian had received grants and personal fees from Medtronic and Ethicon. He serves as a consultant for Medtronic, Ethicon, and Eli Lilly.

A version of this article appeared on Medscape.com.

SAN DIEGO – A novel investigational endoscopic procedure targeting the duodenum appears beneficial in improving glycemic parameters in people with type 2 diabetes (T2D).

In a new dose-finding study, the re-cellularization via electroporation therapy (ReCET, Endogenex) improved insulin sensitivity, beta-cell function, and other glycemic parameters at 12 and 48 weeks in 51 individuals with T2D. “The findings suggest that duodenal mucosal and submucosal recellularization are key therapeutic targets in type 2 diabetes management,” said Barham Abu Dayyeh, MD, director of Interventional Gastroenterology at Cedar-Sinai Hospital, Los Angeles, in a presentation at Digestive Disease Week (DDW) 2025.

The outpatient technique is based on pulsed electrical fields, or electroporation, which do not use heat. “It’s nonthermal regeneration, not just ablation. It’s regeneration of the duodenum as a treatment target that could potentially modify type 2 diabetes,” Abu Dayyeh told GI & Hepatology News.

Separately at DDW, Abu Dayyeh presented results from an artificial intelligence–based analysis of duodenal biopsies from 111 individuals with T2D and 120 control individuals without diabetes, demonstrating distinct mucosal features associated with metabolic disease, significant inflammation in the deep mucosa and submucosa with increased fibrosis, and gut-barrier dysfunction. The authors termed this set of abnormalities “diabetic duodenopathy.” 

Abu Dayyeh likened the duodenum to a “conductor” of the “dysfunctional orchestra” of metabolic disease that includes T2D. “It’s tasked with integrating signals from the food that we eat and from our microbiome and communicates that metabolic response to downstream organs like the pancreas, liver, and adipose tissue.”

Currently, he said, “We use treatments that work downstream on components of this dysfunctional orchestra. So we work on the violinist and the flute player, but we do not go upstream to say maybe there’s an opportunity to put the orchestra conductor back in synch…We manage blood glycemia by lowering it, rather than looking at upstream disease-modifying targets that could reverse the course so you require less insulin and less medication.” 

Abu Dayyeh envisions the ReCET procedure as an option for people struggling to control T2D with standard medications, or for early use to avoid or delay medications, particularly insulin. But it won’t replace medications. “On the contrary, I see it as enhancing and complementing medications,” he said.

Asked to comment, Ali Aminian, MD, professor of surgery and director of the Bariatric and Metabolic Institute at the Cleveland Clinic, Cleveland, Ohio, told GI & Hepatology News, “Diabetes is a heterogeneous disease complex with numerous pathophysiological derangements. Although diabetic duodenopathy can be seen in some patients with diabetes, that wouldn’t explain the entire story behind diabetes pathogenesis in all people with diabetes. In a subgroup of people with duodenal involvement in their disease process, endoscopic procedures targeting the duodenum may play a role in the future.”

 

Glycemic Parameters Improve Following ReCET Procedure

The new study, called REGENT-1, was a multicenter, open-label, single-arm dose escalation of three levels of energy delivery in patients who had T2D for 10 years or less with A1c levels 7.5%-11% despite the use of one or more noninsulin glucose-lowering medications. Procedural success, defined as treatment of at least 6 cm of duodenum, was achieved in 100% of participants.

From a baseline A1c of 8.6%, there were dose-response drops at weeks 12 and 48 by energy delivery, with significant reductions at week 48 of 1.00 and 1.70 percentage points, respectively, among the 18 who received the middle dose and the 21 given the highest dose. Body weight also dropped in all three groups in a dose-response way, from 1.2% with the lowest to 6.2% with the highest energy delivery.

In mixed-meal tolerance testing, glucose area under the curve, homeostatic model assessment for insulin resistance, sensitivity index, beta-cell function, and disposition index (a measure of beta-cell response to insulin resistance) were all reduced from baseline at 48 weeks after ReCET, reaching statistical significance with the highest energy dose.

There were no device- or procedure-related serious adverse events.

Based on a literature search, Abu Dayyeh found that modern glucagon like peptide-1 receptor agonist medications have a stronger effect than ReCET or Roux-en-Y gastric bypass (RYGB) on beta-cell function (increases by 239% with semaglutide and 314% with tirzepatide vs 50% with ReCET and 74% for RYGB). However, ReCET procedure produced superior results for both insulin sensitivity (+487% for ReCET and +326% for bypass vs 30% and 62%, respectively for semaglutide and tirzepatide) and disposition index (+1032% for ReCET, +667% with tirzepatide, +642% for RYGB, and +367% for semaglutide).

Aminian commented, “The findings of this single arm clinical trial are promising. The next step is to incorporate a blinded control group who undergoes an endoscopy without any therapeutic intervention.”

In fact, such a study is underway. Results of “a multicenter, randomized, double-blind, sham-controlled study for assessing the safety and effectiveness of endoscopic intestinal re-cellularization therapy in individuals with type 2 diabetes (ReCET)” are expected in late 2026.

In the meantime, Amanian said about the current findings, “I’d argue that the observed improvement in diabetes parameters can be related to more intensive medical therapy during follow-up in this single arm study.”

In the trials, the procedure takes 30 minutes to an hour to perform. However, as the technology improves, “the vision of this is to be a 20-minute outpatient procedure eventually,” Abu Dayyeh said.

He envisions that eventually the procedure will become as accessible as colonoscopy is now, and that primary care physicians and endocrinologists would similarly refer patients to a gastroenterologist or surgeon to have it done. “They do the procedure and send your patient back, hopefully with a less complex management strategy, so you could manage them more efficiently without escalating care.” 

Abu Dayyeh is a co-inventor of the ReCET procedure, with the technology licensed by the Mayo Clinic. He is a consultant for and/or reported receiving research support from Boston Scientific, Olympus, Medtronic, Metamodix, BFKW, Apollo Endosurgery, USGI, Endogastric Solutions, Spatz, and Cairn. Aminian had received grants and personal fees from Medtronic and Ethicon. He serves as a consultant for Medtronic, Ethicon, and Eli Lilly.

A version of this article appeared on Medscape.com.

SAN DIEGO – A novel investigational endoscopic procedure targeting the duodenum appears beneficial in improving glycemic parameters in people with type 2 diabetes (T2D).

In a new dose-finding study, the re-cellularization via electroporation therapy (ReCET, Endogenex) improved insulin sensitivity, beta-cell function, and other glycemic parameters at 12 and 48 weeks in 51 individuals with T2D. “The findings suggest that duodenal mucosal and submucosal recellularization are key therapeutic targets in type 2 diabetes management,” said Barham Abu Dayyeh, MD, director of Interventional Gastroenterology at Cedar-Sinai Hospital, Los Angeles, in a presentation at Digestive Disease Week (DDW) 2025.

The outpatient technique is based on pulsed electrical fields, or electroporation, which do not use heat. “It’s nonthermal regeneration, not just ablation. It’s regeneration of the duodenum as a treatment target that could potentially modify type 2 diabetes,” Abu Dayyeh told GI & Hepatology News.

Separately at DDW, Abu Dayyeh presented results from an artificial intelligence–based analysis of duodenal biopsies from 111 individuals with T2D and 120 control individuals without diabetes, demonstrating distinct mucosal features associated with metabolic disease, significant inflammation in the deep mucosa and submucosa with increased fibrosis, and gut-barrier dysfunction. The authors termed this set of abnormalities “diabetic duodenopathy.” 

Abu Dayyeh likened the duodenum to a “conductor” of the “dysfunctional orchestra” of metabolic disease that includes T2D. “It’s tasked with integrating signals from the food that we eat and from our microbiome and communicates that metabolic response to downstream organs like the pancreas, liver, and adipose tissue.”

Currently, he said, “We use treatments that work downstream on components of this dysfunctional orchestra. So we work on the violinist and the flute player, but we do not go upstream to say maybe there’s an opportunity to put the orchestra conductor back in synch…We manage blood glycemia by lowering it, rather than looking at upstream disease-modifying targets that could reverse the course so you require less insulin and less medication.” 

Abu Dayyeh envisions the ReCET procedure as an option for people struggling to control T2D with standard medications, or for early use to avoid or delay medications, particularly insulin. But it won’t replace medications. “On the contrary, I see it as enhancing and complementing medications,” he said.

Asked to comment, Ali Aminian, MD, professor of surgery and director of the Bariatric and Metabolic Institute at the Cleveland Clinic, Cleveland, Ohio, told GI & Hepatology News, “Diabetes is a heterogeneous disease complex with numerous pathophysiological derangements. Although diabetic duodenopathy can be seen in some patients with diabetes, that wouldn’t explain the entire story behind diabetes pathogenesis in all people with diabetes. In a subgroup of people with duodenal involvement in their disease process, endoscopic procedures targeting the duodenum may play a role in the future.”

 

Glycemic Parameters Improve Following ReCET Procedure

The new study, called REGENT-1, was a multicenter, open-label, single-arm dose escalation of three levels of energy delivery in patients who had T2D for 10 years or less with A1c levels 7.5%-11% despite the use of one or more noninsulin glucose-lowering medications. Procedural success, defined as treatment of at least 6 cm of duodenum, was achieved in 100% of participants.

From a baseline A1c of 8.6%, there were dose-response drops at weeks 12 and 48 by energy delivery, with significant reductions at week 48 of 1.00 and 1.70 percentage points, respectively, among the 18 who received the middle dose and the 21 given the highest dose. Body weight also dropped in all three groups in a dose-response way, from 1.2% with the lowest to 6.2% with the highest energy delivery.

In mixed-meal tolerance testing, glucose area under the curve, homeostatic model assessment for insulin resistance, sensitivity index, beta-cell function, and disposition index (a measure of beta-cell response to insulin resistance) were all reduced from baseline at 48 weeks after ReCET, reaching statistical significance with the highest energy dose.

There were no device- or procedure-related serious adverse events.

Based on a literature search, Abu Dayyeh found that modern glucagon like peptide-1 receptor agonist medications have a stronger effect than ReCET or Roux-en-Y gastric bypass (RYGB) on beta-cell function (increases by 239% with semaglutide and 314% with tirzepatide vs 50% with ReCET and 74% for RYGB). However, ReCET procedure produced superior results for both insulin sensitivity (+487% for ReCET and +326% for bypass vs 30% and 62%, respectively for semaglutide and tirzepatide) and disposition index (+1032% for ReCET, +667% with tirzepatide, +642% for RYGB, and +367% for semaglutide).

Aminian commented, “The findings of this single arm clinical trial are promising. The next step is to incorporate a blinded control group who undergoes an endoscopy without any therapeutic intervention.”

In fact, such a study is underway. Results of “a multicenter, randomized, double-blind, sham-controlled study for assessing the safety and effectiveness of endoscopic intestinal re-cellularization therapy in individuals with type 2 diabetes (ReCET)” are expected in late 2026.

In the meantime, Amanian said about the current findings, “I’d argue that the observed improvement in diabetes parameters can be related to more intensive medical therapy during follow-up in this single arm study.”

In the trials, the procedure takes 30 minutes to an hour to perform. However, as the technology improves, “the vision of this is to be a 20-minute outpatient procedure eventually,” Abu Dayyeh said.

He envisions that eventually the procedure will become as accessible as colonoscopy is now, and that primary care physicians and endocrinologists would similarly refer patients to a gastroenterologist or surgeon to have it done. “They do the procedure and send your patient back, hopefully with a less complex management strategy, so you could manage them more efficiently without escalating care.” 

Abu Dayyeh is a co-inventor of the ReCET procedure, with the technology licensed by the Mayo Clinic. He is a consultant for and/or reported receiving research support from Boston Scientific, Olympus, Medtronic, Metamodix, BFKW, Apollo Endosurgery, USGI, Endogastric Solutions, Spatz, and Cairn. Aminian had received grants and personal fees from Medtronic and Ethicon. He serves as a consultant for Medtronic, Ethicon, and Eli Lilly.

A version of this article appeared on Medscape.com.

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.

Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.

 

A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. “That study, however, did not show improvement in liver fibrosis, which this study has done,” study co-lead Philip Newsome, PhD, professor in the department of immunology and immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in England, said in an interview.

“The results aligned with expectations in that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.” 

 

Study Details

From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine, Richmond, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.

All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.

Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).

In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).

A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001). 

In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001). 

The mean change in body weight was –10.5% with semaglutide and –2.0% with placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms. 

The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit. 

Gastrointestinal adverse events were more common in the semaglutide group.

 

Commenting on the study from a nonparticipant’s perspective, Naga P. Chalasani, MD, AGAF, professor of gastroenterology and hepatology at Indiana University School of Medicine, Indianapolis, said results from the ESSENCE trial were “long awaited and they certainly advance the field of MASH clinical trials substantially.”

Furthermore, he added, the results are well aligned with those of a phase 2b trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and “they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.” 

“The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,” Chalasani said. “More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.” 

He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. “But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.”

According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. “Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?”

This study was supported by Novo Nordisk, the manufacturer of Wegovy. Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim. Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk. Chalasani declared being involved in several MASH clinical trials conducted by other pharmaceutical companies.

A version of this article appeared on Medscape.com.

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.

Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.

 

A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. “That study, however, did not show improvement in liver fibrosis, which this study has done,” study co-lead Philip Newsome, PhD, professor in the department of immunology and immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in England, said in an interview.

“The results aligned with expectations in that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.” 

 

Study Details

From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine, Richmond, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.

All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.

Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).

In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).

A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001). 

In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001). 

The mean change in body weight was –10.5% with semaglutide and –2.0% with placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms. 

The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit. 

Gastrointestinal adverse events were more common in the semaglutide group.

 

Commenting on the study from a nonparticipant’s perspective, Naga P. Chalasani, MD, AGAF, professor of gastroenterology and hepatology at Indiana University School of Medicine, Indianapolis, said results from the ESSENCE trial were “long awaited and they certainly advance the field of MASH clinical trials substantially.”

Furthermore, he added, the results are well aligned with those of a phase 2b trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and “they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.” 

“The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,” Chalasani said. “More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.” 

He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. “But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.”

According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. “Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?”

This study was supported by Novo Nordisk, the manufacturer of Wegovy. Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim. Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk. Chalasani declared being involved in several MASH clinical trials conducted by other pharmaceutical companies.

A version of this article appeared on Medscape.com.

Adult patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or advanced liver fibrosis showed improved liver histology with a once-weekly dose of semaglutide (Wegovy), an ongoing randomized placebo-controlled trial reported.

The glucagon-like peptide 1 receptor agonist (GLP-1 RA) is currently a candidate for treating MASH.

Preliminary results of the two-part phase 3, double-blind ESSENCE trial, conducted in at 253 clinical sites in 37 countries, were published in The New England Journal of Medicine.

 

A previous phase 2 study by Loomba et al suggested semaglutide was effective in reducing liver injury. “That study, however, did not show improvement in liver fibrosis, which this study has done,” study co-lead Philip Newsome, PhD, professor in the department of immunology and immunotherapy and Honorary Professor of Experimental Hepatology at the University of Birmingham in England, said in an interview.

“The results aligned with expectations in that the impact on liver fibrosis was anticipated — but with some uncertainty, so this study is important in that regard.” 

 

Study Details

From May 2020 to April 2023, researchers led by Newsome and Arun J. Sanyal, MBBS, MD, of Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University School of Medicine, Richmond, randomized 1197 patients with a mean age of 56 years. Of these, 57% were women and 67.5% were White individuals. Mean body mass index was 34.6, and 55.9% had type 2 diabetes.

All had biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network classification and a Nonalcoholic Fatty Liver Disease Activity Score ≥ 4.

Rates of fibrosis were 31.3% for stage 2 fibrosis and 68.8% for stage 3. Diverse geographic site locations included Asia (25.1%), Europe (25.3%), North America (35.0%), and South America (7.9%), and others (6.8%).

In a 2:1 ratio, they were assigned to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. A planned interim analysis of the first 800 patients was done at week 72, with primary endpoints being resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.

Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% CI, 21.1-36.2, P < .001).

A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of semaglutide recipients and 22.4% of placebo recipients (estimated difference, 14.4 percentage points; 95% CI, 7.5-21.3, P < .001). 

In secondary findings, the combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% in the semaglutide group vs 16.1% in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2-22.8; P < .001). 

The mean change in body weight was –10.5% with semaglutide and –2.0% with placebo (estimated difference, –8.5 percentage points; 95% CI, –9.6 to –7.4, P < .001). Mean changes in bodily pain scores did not differ significantly between arms. 

The histologic benefits of semaglutide also emerged in improvements on all prespecified noninvasive tests — including aspartate transaminase and alanine transaminase levels and liver stiffness. Emerging evidence has suggested an association between reductions in liver stiffness and clinical benefit. 

Gastrointestinal adverse events were more common in the semaglutide group.

 

Commenting on the study from a nonparticipant’s perspective, Naga P. Chalasani, MD, AGAF, professor of gastroenterology and hepatology at Indiana University School of Medicine, Indianapolis, said results from the ESSENCE trial were “long awaited and they certainly advance the field of MASH clinical trials substantially.”

Furthermore, he added, the results are well aligned with those of a phase 2b trial of semaglutide by Newsome and colleagues for what was then termed nonalcoholic steatohepatitis, and “they also align with what is known about the positive role of incretins, digestive hormones imitated by GLP-1s to improve liver health in patients with MASLD and MASH.” 

“The results from this study certainly make a case for semaglutide to be the backbone therapy for diabetic or obese patients with MASH and fibrosis,” Chalasani said. “More than 80% of patients with MASH and fibrosis have either diabetes and/or obesity.” 

He added that a better understanding is needed of how semaglutide works in patients with MASH cirrhosis since the previous small study was unsuccessful. “But this may need to be repeated as the published study was underpowered. Outcomes in the ESSENCE trial will help to clarify whether semaglutide will improve clinical outcomes beyond improving liver histology.”

According to Newsome, GLP-1s will become the backbone of therapy in MASH given their range of metabolic and liver benefit. But questions remain, he said. “Will there be further improvements with longer treatment with semaglutide? What noninvasive tests should we use to determine treatment success? Which patients will benefit from combination treatment?”

This study was supported by Novo Nordisk, the manufacturer of Wegovy. Sanyal reported having various financial relationships with multiple private-sector companies, including Novo Nordisk. Newsome reported consulting for Novo Nordisk and Boehringer Ingelheim. Several study coauthors reported having similar relationships with pharmaceutical companies or employment with Novo Nordisk. Chalasani declared being involved in several MASH clinical trials conducted by other pharmaceutical companies.

A version of this article appeared on Medscape.com.

An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.

Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.

The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.

Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.

 

The Study

In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.

The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.

High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 

Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.

Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels. 

Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.

Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers. 

The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.

This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.

Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.

A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
 

An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.

Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.

The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.

Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.

 

The Study

In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.

The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.

High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 

Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.

Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels. 

Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.

Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers. 

The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.

This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.

Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.

A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
 

An experimental study in zebrafish has suggested the decades-old, first-generation antihistamine chlorcyclizine and/or other antihistamines may be a strategy for treating erythropoietic protoporphyria (EPP)-associated liver disease by decreasing hepatic protoporphorin IX (PP-IX) accumulation.

Currently, liver transplantation is the primary treatment for this rare, painful, and life-threatening genetic disease, which is caused by excessive PP-IX accumulation and affects about 4000 people in the United States.

The findings could eventually lead to a simpler treatment that prevent shepatic damage at a much earlier stage, according to researchers led by M. Bishr Omary, MD, PhD, a professor in the Center for Advanced Biotechnology and Medicine and Robert Wood Johnson Medical School at Rutgers University in Piscataway, New Jersey.

Reporting in Cellular and Molecular Gastroenterology and Hepatology, the investigators found that chlorcyclizine reduced PP-IX levels. EPP is caused by mutations leading to deficiency of the enzyme ferrochelatase, which inserts iron into PP-IX to generate heme. The resulting condition is characterized by PP-IX accumulation, skin photosensitivity, cholestasis, and end-stage liver disease. “Despite available drugs that address photosensitivity, the treatment of EPP-related liver disease remains an unmet need,” Omary and colleagues wrote.

 

The Study

In order to trigger PP-IX overproduction and accumulation, the investigators administered delta-aminolevulinic acid and deferoxamine to zebrafish. These freshwater tropical fish share many physiological characteristics with humans and have been used to model human disease and develop drugs. Furthermore, these fish are transparent at the larval stage, allowing quantification and visualization of porphyrin, which is fluorescent.

The researchers had screened some 2500 approved and bioactive compounds and identified chlorcyclizine as a potent PP-IX–lowering agent.

High-throughput compound screening of ALA + DFO-treated zebrafish found that the HH-1 blocker reduced zebrafish liver PP-IX levels. The effect of chlorcyclizine was validated in porphyrin-loaded primary mouse hepatocytes, transgenic mice, and mice fed the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydrocollidine. 

Plasma and tissue PP-IX were measured by fluorescence; livers were analyzed by histology, immunoblotting, and quantitative polymerase chain reaction.

Chlorcyclizine-treated zebrafish larvae as well as the two types of mice all showed reduced hepatic PP-IX levels compared with controls. While the neurotransmitter played an important role in PP-IX accumulation in porphyrin-stressed hepatocytes, blockading notably decreased PP-IX levels. 

Detailed analysis showed that chlorcyclizine appeared to work through multiple mechanisms, helping the liver clear toxic porphyrin buildup and reducing inflammation. It also decreased the presence of histamine-producing mast cells. The result was less liver injury, decreased porphyrin-triggered protein aggregation and oxidation, and increased clearance of s PP-I in stool.

Interestingly, in both mouse models, chlorcyclizine lowered PP-IX levels in female but not male mice in liver, erythrocytes, and bone marrow. This sex-specific effect appeared to be related to the greater speed at which male murines metabolize the drug, the authors explained in a news release. In rats, for example, the metabolism of chlorcyclizine is 8 times higher in male than in female livers. 

The investigators plan to launch a clinical trial in EPP patients to evaluate the effectiveness of chlorcyclizine for both liver and skin involvement. And a phase 2 trial is already underway testing the antacid cimetidine for treating EPP skin manifestations. It is possible that the different antihistamines may act additively or synergistically.

This work was supported by National Institutes of Health (NIH) grants and the Henry and Mala Dorfman Family Professorship of Pediatric Hematology/Oncology.

Omary is a member of the NIH/National Institute of Diabetes and Digestive and Kidney Diseases Data and Safety Monitoring Board of the Porphyrias Consortium.

A provisional patent application has been submitted for the use of H1-receptor blockers with or without receptor blockers to treat protoporphyrias associated with PP-IX accumulation.
 

An irritable bowel syndrome (IBS) elimination diet based on a novel IBS–specific, immunoglobulin G (IgG) was superior to a sham diet for abdominal pain, an 8-center, randomized double-blind controlled trial found.

While elimination diets can provide a personalized approach to dietary therapy, existing studies have had serious methodological issues, noted lead author Prashant Singh, MBBS, of the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Mich., and colleagues in Gastroenterology.

For example, previous studies on IgG-based diets used assays developed without determining IBS trigger foods or establishing a 95% confidence interval–based cutoff using a healthy control comparison group.

 

Study Details

From June 2018 to December 2021, 238 IBS patients testing positive for at least one food on 18-food IgG ELISA (enzyme-linked immunosorbent assay) testing and an average daily abdominal pain intensity score of 3.0 to 7.5 on an 11.0-point scale during a 2-week run-in period were randomized for 8 weeks to an experimental antibody-guided diet or to a sham diet. The primary outcome was a 30% decrease in abdominal pain intensity (API) for 2 of the last 4 weeks of treatment.

The overall study population had a mean age of about 40 years, and more than three-quarters were female. The 3 IBS types – constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), and mixed bowel habits-predominant (IBS-M) – accounted for about a third each in both arms.

The experimental diet eliminated foods based on a positive ELISA result. Its sham counterpart had the same number of foods removed as the number of positive-testing food sensitivities, but the foods eliminated in the sham diet had tested negative on the IgG assay.

Participants reported daily abdominal pain intensity, bloating, and stool consistency, and frequency. They also reported dietary compliance and daily medication use.

Of the 238 randomized adults, 223 were included in the modified intention-to-treat analysis. A significantly greater proportion of subjects in the experimental group met the primary outcome than those in the sham group: 59.6% vs 42.1%, P = .02). “This highlights the potential effectiveness of a personalized elimination diet based on a novel IBS-specific IgG assay,” the authors wrote.

Symptom improvement between arms began to separate out at around 2 weeks, suggesting the effect of the experimental diet was relatively rapid in onset, and continued for at least 8 weeks. The durability of response, however, needs to be assessed in future studies “and it is unclear if there is a role for repeat IgG testing to monitor treatment response,” the authors wrote.

Subgroup analysis revealed that a higher proportion of those with IBS-C and IBS-M in the experimental diet group met the primary endpoint vs the sham group: 67.1% vs 35.8% and 66% vs 29.5%, respectively.

Interestingly, more patients in the experimental arm were noncompliant with their diet. “It is possible that subjects found the experimental diet more difficult to comply with compared with the sham diet or that because the experimental diet was more likely to improve symptoms, dietary indiscretion may have been more common in this group (a phenomenon seen with other elimination diets such as gluten-free diet in celiac disease),” the authors wrote.

Adverse events, deemed unrelated to either regimen, were 3 in the experimental arm vs 8 in the sham arm, which had 2 urinary tract infections.

The authors called for a larger, adequately powered study to assess the efficacy of an elimination diet based on this novel immunoglobulin G assay in patients with IBS-C and IBS-M. Future studies should perform detailed adherence assessments using food diaries.

“Mechanisms of how immunoglobulin G-antibody response to food antigen generates symptoms in irritable bowel syndrome are not well understood. Delineating this might provide new insights into food-related irritable bowel syndrome pathophysiology,” they concluded.

This study was funded by Biomerica Inc.

An irritable bowel syndrome (IBS) elimination diet based on a novel IBS–specific, immunoglobulin G (IgG) was superior to a sham diet for abdominal pain, an 8-center, randomized double-blind controlled trial found.

While elimination diets can provide a personalized approach to dietary therapy, existing studies have had serious methodological issues, noted lead author Prashant Singh, MBBS, of the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Mich., and colleagues in Gastroenterology.

For example, previous studies on IgG-based diets used assays developed without determining IBS trigger foods or establishing a 95% confidence interval–based cutoff using a healthy control comparison group.

 

Study Details

From June 2018 to December 2021, 238 IBS patients testing positive for at least one food on 18-food IgG ELISA (enzyme-linked immunosorbent assay) testing and an average daily abdominal pain intensity score of 3.0 to 7.5 on an 11.0-point scale during a 2-week run-in period were randomized for 8 weeks to an experimental antibody-guided diet or to a sham diet. The primary outcome was a 30% decrease in abdominal pain intensity (API) for 2 of the last 4 weeks of treatment.

The overall study population had a mean age of about 40 years, and more than three-quarters were female. The 3 IBS types – constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), and mixed bowel habits-predominant (IBS-M) – accounted for about a third each in both arms.

The experimental diet eliminated foods based on a positive ELISA result. Its sham counterpart had the same number of foods removed as the number of positive-testing food sensitivities, but the foods eliminated in the sham diet had tested negative on the IgG assay.

Participants reported daily abdominal pain intensity, bloating, and stool consistency, and frequency. They also reported dietary compliance and daily medication use.

Of the 238 randomized adults, 223 were included in the modified intention-to-treat analysis. A significantly greater proportion of subjects in the experimental group met the primary outcome than those in the sham group: 59.6% vs 42.1%, P = .02). “This highlights the potential effectiveness of a personalized elimination diet based on a novel IBS-specific IgG assay,” the authors wrote.

Symptom improvement between arms began to separate out at around 2 weeks, suggesting the effect of the experimental diet was relatively rapid in onset, and continued for at least 8 weeks. The durability of response, however, needs to be assessed in future studies “and it is unclear if there is a role for repeat IgG testing to monitor treatment response,” the authors wrote.

Subgroup analysis revealed that a higher proportion of those with IBS-C and IBS-M in the experimental diet group met the primary endpoint vs the sham group: 67.1% vs 35.8% and 66% vs 29.5%, respectively.

Interestingly, more patients in the experimental arm were noncompliant with their diet. “It is possible that subjects found the experimental diet more difficult to comply with compared with the sham diet or that because the experimental diet was more likely to improve symptoms, dietary indiscretion may have been more common in this group (a phenomenon seen with other elimination diets such as gluten-free diet in celiac disease),” the authors wrote.

Adverse events, deemed unrelated to either regimen, were 3 in the experimental arm vs 8 in the sham arm, which had 2 urinary tract infections.

The authors called for a larger, adequately powered study to assess the efficacy of an elimination diet based on this novel immunoglobulin G assay in patients with IBS-C and IBS-M. Future studies should perform detailed adherence assessments using food diaries.

“Mechanisms of how immunoglobulin G-antibody response to food antigen generates symptoms in irritable bowel syndrome are not well understood. Delineating this might provide new insights into food-related irritable bowel syndrome pathophysiology,” they concluded.

This study was funded by Biomerica Inc.

An irritable bowel syndrome (IBS) elimination diet based on a novel IBS–specific, immunoglobulin G (IgG) was superior to a sham diet for abdominal pain, an 8-center, randomized double-blind controlled trial found.

While elimination diets can provide a personalized approach to dietary therapy, existing studies have had serious methodological issues, noted lead author Prashant Singh, MBBS, of the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Mich., and colleagues in Gastroenterology.

For example, previous studies on IgG-based diets used assays developed without determining IBS trigger foods or establishing a 95% confidence interval–based cutoff using a healthy control comparison group.

 

Study Details

From June 2018 to December 2021, 238 IBS patients testing positive for at least one food on 18-food IgG ELISA (enzyme-linked immunosorbent assay) testing and an average daily abdominal pain intensity score of 3.0 to 7.5 on an 11.0-point scale during a 2-week run-in period were randomized for 8 weeks to an experimental antibody-guided diet or to a sham diet. The primary outcome was a 30% decrease in abdominal pain intensity (API) for 2 of the last 4 weeks of treatment.

The overall study population had a mean age of about 40 years, and more than three-quarters were female. The 3 IBS types – constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), and mixed bowel habits-predominant (IBS-M) – accounted for about a third each in both arms.

The experimental diet eliminated foods based on a positive ELISA result. Its sham counterpart had the same number of foods removed as the number of positive-testing food sensitivities, but the foods eliminated in the sham diet had tested negative on the IgG assay.

Participants reported daily abdominal pain intensity, bloating, and stool consistency, and frequency. They also reported dietary compliance and daily medication use.

Of the 238 randomized adults, 223 were included in the modified intention-to-treat analysis. A significantly greater proportion of subjects in the experimental group met the primary outcome than those in the sham group: 59.6% vs 42.1%, P = .02). “This highlights the potential effectiveness of a personalized elimination diet based on a novel IBS-specific IgG assay,” the authors wrote.

Symptom improvement between arms began to separate out at around 2 weeks, suggesting the effect of the experimental diet was relatively rapid in onset, and continued for at least 8 weeks. The durability of response, however, needs to be assessed in future studies “and it is unclear if there is a role for repeat IgG testing to monitor treatment response,” the authors wrote.

Subgroup analysis revealed that a higher proportion of those with IBS-C and IBS-M in the experimental diet group met the primary endpoint vs the sham group: 67.1% vs 35.8% and 66% vs 29.5%, respectively.

Interestingly, more patients in the experimental arm were noncompliant with their diet. “It is possible that subjects found the experimental diet more difficult to comply with compared with the sham diet or that because the experimental diet was more likely to improve symptoms, dietary indiscretion may have been more common in this group (a phenomenon seen with other elimination diets such as gluten-free diet in celiac disease),” the authors wrote.

Adverse events, deemed unrelated to either regimen, were 3 in the experimental arm vs 8 in the sham arm, which had 2 urinary tract infections.

The authors called for a larger, adequately powered study to assess the efficacy of an elimination diet based on this novel immunoglobulin G assay in patients with IBS-C and IBS-M. Future studies should perform detailed adherence assessments using food diaries.

“Mechanisms of how immunoglobulin G-antibody response to food antigen generates symptoms in irritable bowel syndrome are not well understood. Delineating this might provide new insights into food-related irritable bowel syndrome pathophysiology,” they concluded.

This study was funded by Biomerica Inc.

SAN DIEGO — In treating pancreas divisum, the common use of endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy showed no significant benefit over a sham procedure, suggesting that patients can be spared the intervention, which can carry risks of its own.

“This is a topic that has been debated for decades,” said first author Gregory A. Coté, MD, AGAF, Division Head, professor of medicine, Division of Gastroenterology & Hepatology, Oregon Health & Science University, in Portland, Oregon.

“Many doctors believe the procedure helps and offer it because we have limited options to help our patients, whereas others believe the procedure is harmful and doesn’t help,” he explained in a press briefing for the late-breaking study, presented at Digestive Disease Week (DDW) 2025.

The study’s findings supported the latter argument.

“Patients who underwent ERCP with sphincterotomy were just as likely as those who did not have this procedure to develop acute pancreatitis again,” Coté reported.

While clinical guidelines currently recommend ERCP as treatment for pancreas divisum, “these guidelines are likely to change based on this study,” he said.

Pancreas divisum, occurring in about 7%-10% of people, is an anatomic variation that can represent an obstructive risk factor for acute recurrent pancreatitis.

The common use of ERCP with minor papilla endoscopic sphincterotomy to treat the condition is based on prior retrospective studies showing that in patients who did develop acute pancreatitis, up to 70% with the treatment never developed acute pancreatitis again. However, there have been no studies comparing the use of the treatment with a control group.

Coté and colleagues conducted the multicenter SHARP trial, in which 148 patients with pancreas divisum were enrolled between September 2018 and August 2024 and randomized to receive either ERCP with minor papilla endoscopic sphincterotomy (n = 75) or a sham treatment (n = 73).

The patients, who had a median age of 51 years, had a median of 3 acute pancreatitis episodes prior to randomization.

With a median follow-up of 33.5 months (range, 6-48 months), 34.7% of patients in the ERCP arm experienced an acute pancreatitis incident compared with 43.8% in the sham arm, for a hazard ratio of 0.83 after adjusting for duct size and the number of episodes, which was not a statistically significant difference (P = .27).

A subgroup analysis further showed no indication of a treatment effect based on factors including age, diabetes status, sex, alcohol or tobacco use, or other factors.

“Compared with a sham ERCP group, we found that minor papillotomy did not reduce the risk of acute pancreatitis, incident chronic pancreatitis, endocrine pancreatic insufficiency or diabetes, or pancreas-related pain events,” Coté said.

The findings are particularly important because the treatment itself is associated with some risks, he added.

“Ironically, the problem with this procedure is that it can cause acute pancreatitis in 10%-20% of patients and may instigate other issues later,” such as the development of scarring of the pancreas related to incisions in the procedure.

“No one wants to offer an expensive procedure that has its own risks if it doesn’t help,” Coté said.

Based on the findings, “pancreas divisum anatomy should no longer be considered an indication for ERCP, even for idiopathic acute pancreatitis,” he concluded.

A version of this article appeared on Medscape.com.

SAN DIEGO — In treating pancreas divisum, the common use of endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy showed no significant benefit over a sham procedure, suggesting that patients can be spared the intervention, which can carry risks of its own.

“This is a topic that has been debated for decades,” said first author Gregory A. Coté, MD, AGAF, Division Head, professor of medicine, Division of Gastroenterology & Hepatology, Oregon Health & Science University, in Portland, Oregon.

“Many doctors believe the procedure helps and offer it because we have limited options to help our patients, whereas others believe the procedure is harmful and doesn’t help,” he explained in a press briefing for the late-breaking study, presented at Digestive Disease Week (DDW) 2025.

The study’s findings supported the latter argument.

“Patients who underwent ERCP with sphincterotomy were just as likely as those who did not have this procedure to develop acute pancreatitis again,” Coté reported.

While clinical guidelines currently recommend ERCP as treatment for pancreas divisum, “these guidelines are likely to change based on this study,” he said.

Pancreas divisum, occurring in about 7%-10% of people, is an anatomic variation that can represent an obstructive risk factor for acute recurrent pancreatitis.

The common use of ERCP with minor papilla endoscopic sphincterotomy to treat the condition is based on prior retrospective studies showing that in patients who did develop acute pancreatitis, up to 70% with the treatment never developed acute pancreatitis again. However, there have been no studies comparing the use of the treatment with a control group.

Coté and colleagues conducted the multicenter SHARP trial, in which 148 patients with pancreas divisum were enrolled between September 2018 and August 2024 and randomized to receive either ERCP with minor papilla endoscopic sphincterotomy (n = 75) or a sham treatment (n = 73).

The patients, who had a median age of 51 years, had a median of 3 acute pancreatitis episodes prior to randomization.

With a median follow-up of 33.5 months (range, 6-48 months), 34.7% of patients in the ERCP arm experienced an acute pancreatitis incident compared with 43.8% in the sham arm, for a hazard ratio of 0.83 after adjusting for duct size and the number of episodes, which was not a statistically significant difference (P = .27).

A subgroup analysis further showed no indication of a treatment effect based on factors including age, diabetes status, sex, alcohol or tobacco use, or other factors.

“Compared with a sham ERCP group, we found that minor papillotomy did not reduce the risk of acute pancreatitis, incident chronic pancreatitis, endocrine pancreatic insufficiency or diabetes, or pancreas-related pain events,” Coté said.

The findings are particularly important because the treatment itself is associated with some risks, he added.

“Ironically, the problem with this procedure is that it can cause acute pancreatitis in 10%-20% of patients and may instigate other issues later,” such as the development of scarring of the pancreas related to incisions in the procedure.

“No one wants to offer an expensive procedure that has its own risks if it doesn’t help,” Coté said.

Based on the findings, “pancreas divisum anatomy should no longer be considered an indication for ERCP, even for idiopathic acute pancreatitis,” he concluded.

A version of this article appeared on Medscape.com.

SAN DIEGO — In treating pancreas divisum, the common use of endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy showed no significant benefit over a sham procedure, suggesting that patients can be spared the intervention, which can carry risks of its own.

“This is a topic that has been debated for decades,” said first author Gregory A. Coté, MD, AGAF, Division Head, professor of medicine, Division of Gastroenterology & Hepatology, Oregon Health & Science University, in Portland, Oregon.

“Many doctors believe the procedure helps and offer it because we have limited options to help our patients, whereas others believe the procedure is harmful and doesn’t help,” he explained in a press briefing for the late-breaking study, presented at Digestive Disease Week (DDW) 2025.

The study’s findings supported the latter argument.

“Patients who underwent ERCP with sphincterotomy were just as likely as those who did not have this procedure to develop acute pancreatitis again,” Coté reported.

While clinical guidelines currently recommend ERCP as treatment for pancreas divisum, “these guidelines are likely to change based on this study,” he said.

Pancreas divisum, occurring in about 7%-10% of people, is an anatomic variation that can represent an obstructive risk factor for acute recurrent pancreatitis.

The common use of ERCP with minor papilla endoscopic sphincterotomy to treat the condition is based on prior retrospective studies showing that in patients who did develop acute pancreatitis, up to 70% with the treatment never developed acute pancreatitis again. However, there have been no studies comparing the use of the treatment with a control group.

Coté and colleagues conducted the multicenter SHARP trial, in which 148 patients with pancreas divisum were enrolled between September 2018 and August 2024 and randomized to receive either ERCP with minor papilla endoscopic sphincterotomy (n = 75) or a sham treatment (n = 73).

The patients, who had a median age of 51 years, had a median of 3 acute pancreatitis episodes prior to randomization.

With a median follow-up of 33.5 months (range, 6-48 months), 34.7% of patients in the ERCP arm experienced an acute pancreatitis incident compared with 43.8% in the sham arm, for a hazard ratio of 0.83 after adjusting for duct size and the number of episodes, which was not a statistically significant difference (P = .27).

A subgroup analysis further showed no indication of a treatment effect based on factors including age, diabetes status, sex, alcohol or tobacco use, or other factors.

“Compared with a sham ERCP group, we found that minor papillotomy did not reduce the risk of acute pancreatitis, incident chronic pancreatitis, endocrine pancreatic insufficiency or diabetes, or pancreas-related pain events,” Coté said.

The findings are particularly important because the treatment itself is associated with some risks, he added.

“Ironically, the problem with this procedure is that it can cause acute pancreatitis in 10%-20% of patients and may instigate other issues later,” such as the development of scarring of the pancreas related to incisions in the procedure.

“No one wants to offer an expensive procedure that has its own risks if it doesn’t help,” Coté said.

Based on the findings, “pancreas divisum anatomy should no longer be considered an indication for ERCP, even for idiopathic acute pancreatitis,” he concluded.

A version of this article appeared on Medscape.com.

SAN DIEGO — The session started with a question that many in the audience at Digestive Disease Week (DDW) 2025 seemed to relate to: “How many of you find yourself squeezing workouts into a weekend after a hectic work week?”

Although regular exercise three or more times a week is often viewed as preferable, Shiyi Yu, MD, a resident physician in the Department of Gastroenterology at Guangdong Provincial People’s Hospital in Guangzhou, China, had good news for weekend warriors.

Both patterns reduce digestive disease almost equally.

Her study compared weekend warriors with those she called “active regulars” and sedentary folks to see how activity patterns affect digestive disease risks.

Her bottom line: “Your gut does not care about your schedule.”

The researchers analyzed wrist-based accelerometer data from 89,595 participants in the UK Biobank. To categorize participants as active or inactive, they used the World Health Organization 2020 guidelines for physical activity, which recommend at least 150-300 minutes of moderate-intensity aerobic physical activity or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination throughout the week. Median age of participants was 63.3 years and 48.8% were men.

They divided participants into three groups:

• About 43% were weekend warriors who met or exceeded 150 minutes of moderate to vigorous physical activity (MVPA), with 50% or more of total MVPA achieved in 1-2 days.
• About 23% were active regulars who met or exceeded 150 minutes a week but spread over more days.
• About 34% were inactive participants who were active less than 150 minutes a week.

The researchers followed the participants for a median of 7.9 years, looking for the incidence of multiple digestive diseases, identified using the International Classification of Diseases, 10th Revision, codes. These included diverticulosis, constipation, metabolic dysfunction–associated steatotic liver disease, cholelithiasis, and gastroesophageal reflux disease. 

Both activity patterns “showed similar risk reduction with no significant difference,” Yu said. At the threshold ≥ 150 minutes, for instance, hazard ratios for any digestive disease were 0.83 for weekend warriors and 0.79 for active regulars, compared with sedentary participants.

The analysis was repeated using a median threshold ≥ 230.4 minutes of MVPA a week, and the researchers found the same results.

As a validation cohort, the researchers used more than 6,000 participants from the National Institutes of Health’s All of Us Research Program with over 6 months of wrist-based accelerometer data.

A recent meta-epidemiology study found that the weekend warrior pattern offers other health benefits, including reducing the risk for cardiovascular disease mortality, mental disorders, and metabolic syndrome.

 

A Pleasant Surprise

The digestive disease study’s findings were “a surprise and a pleasant one,” said Aasma Shaukat, MD, MPH, AGAF, professor of medicine and a gastroenterologist at NYU Grossman School of Medicine, New York City.

“We often think if we’re not able to exercise regularly, then there’s no hope for us,” said Shaukat, who moderated the session. “But this implies that even if we have time only during the weekend to engage in physical activity, it still confers benefits in reducing our risk of any GI health disorder, as well as cardiovascular or other health disorders, compared to people inactive at baseline.”

“It gives us flexibility in terms of how we structure our exercise. Obviously, people should try to get into the habit of doing regular activity; it’s more sustainable. But a good alternative, according to this research, is that packing all of that in over the weekend seems to confer benefit. So all is not lost.”

Will this change her conversation with patients moving forward? Absolutely, Shaukat said. She generally recommends physical activity for at least 30 minutes three times a week. Now Shaukat said she can tell patients: “If that’s not possible, take that time out during the weekend for your health”.

This study was funded by grants from the National Natural Science Foundation of China and its Regional Innovation and Development Joint Foundation. Yu and Shaukat reported no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — The session started with a question that many in the audience at Digestive Disease Week (DDW) 2025 seemed to relate to: “How many of you find yourself squeezing workouts into a weekend after a hectic work week?”

Although regular exercise three or more times a week is often viewed as preferable, Shiyi Yu, MD, a resident physician in the Department of Gastroenterology at Guangdong Provincial People’s Hospital in Guangzhou, China, had good news for weekend warriors.

Both patterns reduce digestive disease almost equally.

Her study compared weekend warriors with those she called “active regulars” and sedentary folks to see how activity patterns affect digestive disease risks.

Her bottom line: “Your gut does not care about your schedule.”

The researchers analyzed wrist-based accelerometer data from 89,595 participants in the UK Biobank. To categorize participants as active or inactive, they used the World Health Organization 2020 guidelines for physical activity, which recommend at least 150-300 minutes of moderate-intensity aerobic physical activity or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination throughout the week. Median age of participants was 63.3 years and 48.8% were men.

They divided participants into three groups:

• About 43% were weekend warriors who met or exceeded 150 minutes of moderate to vigorous physical activity (MVPA), with 50% or more of total MVPA achieved in 1-2 days.
• About 23% were active regulars who met or exceeded 150 minutes a week but spread over more days.
• About 34% were inactive participants who were active less than 150 minutes a week.

The researchers followed the participants for a median of 7.9 years, looking for the incidence of multiple digestive diseases, identified using the International Classification of Diseases, 10th Revision, codes. These included diverticulosis, constipation, metabolic dysfunction–associated steatotic liver disease, cholelithiasis, and gastroesophageal reflux disease. 

Both activity patterns “showed similar risk reduction with no significant difference,” Yu said. At the threshold ≥ 150 minutes, for instance, hazard ratios for any digestive disease were 0.83 for weekend warriors and 0.79 for active regulars, compared with sedentary participants.

The analysis was repeated using a median threshold ≥ 230.4 minutes of MVPA a week, and the researchers found the same results.

As a validation cohort, the researchers used more than 6,000 participants from the National Institutes of Health’s All of Us Research Program with over 6 months of wrist-based accelerometer data.

A recent meta-epidemiology study found that the weekend warrior pattern offers other health benefits, including reducing the risk for cardiovascular disease mortality, mental disorders, and metabolic syndrome.

 

A Pleasant Surprise

The digestive disease study’s findings were “a surprise and a pleasant one,” said Aasma Shaukat, MD, MPH, AGAF, professor of medicine and a gastroenterologist at NYU Grossman School of Medicine, New York City.

“We often think if we’re not able to exercise regularly, then there’s no hope for us,” said Shaukat, who moderated the session. “But this implies that even if we have time only during the weekend to engage in physical activity, it still confers benefits in reducing our risk of any GI health disorder, as well as cardiovascular or other health disorders, compared to people inactive at baseline.”

“It gives us flexibility in terms of how we structure our exercise. Obviously, people should try to get into the habit of doing regular activity; it’s more sustainable. But a good alternative, according to this research, is that packing all of that in over the weekend seems to confer benefit. So all is not lost.”

Will this change her conversation with patients moving forward? Absolutely, Shaukat said. She generally recommends physical activity for at least 30 minutes three times a week. Now Shaukat said she can tell patients: “If that’s not possible, take that time out during the weekend for your health”.

This study was funded by grants from the National Natural Science Foundation of China and its Regional Innovation and Development Joint Foundation. Yu and Shaukat reported no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — The session started with a question that many in the audience at Digestive Disease Week (DDW) 2025 seemed to relate to: “How many of you find yourself squeezing workouts into a weekend after a hectic work week?”

Although regular exercise three or more times a week is often viewed as preferable, Shiyi Yu, MD, a resident physician in the Department of Gastroenterology at Guangdong Provincial People’s Hospital in Guangzhou, China, had good news for weekend warriors.

Both patterns reduce digestive disease almost equally.

Her study compared weekend warriors with those she called “active regulars” and sedentary folks to see how activity patterns affect digestive disease risks.

Her bottom line: “Your gut does not care about your schedule.”

The researchers analyzed wrist-based accelerometer data from 89,595 participants in the UK Biobank. To categorize participants as active or inactive, they used the World Health Organization 2020 guidelines for physical activity, which recommend at least 150-300 minutes of moderate-intensity aerobic physical activity or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination throughout the week. Median age of participants was 63.3 years and 48.8% were men.

They divided participants into three groups:

• About 43% were weekend warriors who met or exceeded 150 minutes of moderate to vigorous physical activity (MVPA), with 50% or more of total MVPA achieved in 1-2 days.
• About 23% were active regulars who met or exceeded 150 minutes a week but spread over more days.
• About 34% were inactive participants who were active less than 150 minutes a week.

The researchers followed the participants for a median of 7.9 years, looking for the incidence of multiple digestive diseases, identified using the International Classification of Diseases, 10th Revision, codes. These included diverticulosis, constipation, metabolic dysfunction–associated steatotic liver disease, cholelithiasis, and gastroesophageal reflux disease. 

Both activity patterns “showed similar risk reduction with no significant difference,” Yu said. At the threshold ≥ 150 minutes, for instance, hazard ratios for any digestive disease were 0.83 for weekend warriors and 0.79 for active regulars, compared with sedentary participants.

The analysis was repeated using a median threshold ≥ 230.4 minutes of MVPA a week, and the researchers found the same results.

As a validation cohort, the researchers used more than 6,000 participants from the National Institutes of Health’s All of Us Research Program with over 6 months of wrist-based accelerometer data.

A recent meta-epidemiology study found that the weekend warrior pattern offers other health benefits, including reducing the risk for cardiovascular disease mortality, mental disorders, and metabolic syndrome.

 

A Pleasant Surprise

The digestive disease study’s findings were “a surprise and a pleasant one,” said Aasma Shaukat, MD, MPH, AGAF, professor of medicine and a gastroenterologist at NYU Grossman School of Medicine, New York City.

“We often think if we’re not able to exercise regularly, then there’s no hope for us,” said Shaukat, who moderated the session. “But this implies that even if we have time only during the weekend to engage in physical activity, it still confers benefits in reducing our risk of any GI health disorder, as well as cardiovascular or other health disorders, compared to people inactive at baseline.”

“It gives us flexibility in terms of how we structure our exercise. Obviously, people should try to get into the habit of doing regular activity; it’s more sustainable. But a good alternative, according to this research, is that packing all of that in over the weekend seems to confer benefit. So all is not lost.”

Will this change her conversation with patients moving forward? Absolutely, Shaukat said. She generally recommends physical activity for at least 30 minutes three times a week. Now Shaukat said she can tell patients: “If that’s not possible, take that time out during the weekend for your health”.

This study was funded by grants from the National Natural Science Foundation of China and its Regional Innovation and Development Joint Foundation. Yu and Shaukat reported no disclosures.

A version of this article appeared on Medscape.com.

SAN DIEGO — Patients with obesity and type 2 diabetes treated with glucagon-like peptide 1 (GLP-1) receptor agonists had significantly reduced rates of colorectal cancer (CRC) risk and associated mortality compared with those undergoing bariatric surgery, new research showed.

CRC risk was also lower for patients taking GLP-1s than the general population.

“Our findings show we might need to evaluate these therapies beyond their glycemic or weight loss [effects],” said first author Omar Al Ta’ani, MD, of the Allegheny Health Network, Pittsburgh.

This supports future prospective studies examining GLP-1s for CRC reduction, added Ta’ani, who presented the results at Digestive Disease Week (DDW) 2025.

Patients with type 2 diabetes and obesity are known to have a higher risk for CRC, stemming from metabolic risk factors. Whereas prior studies suggested that GLP-1s decrease the risk for CRC compared with other antidiabetic medications, studies looking at the risk for CRC associated with bariatric surgery have had more mixed results, Ta’ani said.

For the comparison, Ta’ani and colleagues conducted a retrospective analysis of the TriNetX database, identifying patients with type 2 diabetes and obesity (body mass index [BMI] > 30) enrolled in the database between 2005 and 2019.

Overall, the study included 94,098 GLP-1 users and 24,969 patients who underwent bariatric surgery. Those with a prior history of CRC were excluded.

Using propensity score matching, patients treated with GLP-1s were matched 1:1 with patients who had bariatric surgery based on wide-ranging factors including age, race, gender, demographics, diseases, medications, personal and family history, and hemoglobin A1c.

After the propensity matching, each group included 21,022 patients. About 64% in each group were women; their median age was 53 years and about 65% were White.

Overall, the results showed that patients on GLP-1s had a significantly lower CRC risk compared with those who had bariatric surgery (adjusted hazard ratio [aHR], 0.29; P < .0001). The lower risk was also observed among those with high obesity (defined as BMI > 35) compared with those who had surgery (aHR, 0.39; P < .0001).

The results were consistent across genders; however, the differences between GLP-1s and bariatric surgery were not observed in the 18- to 45-year-old age group (BMI > 30, P = .0809; BMI > 35, P = .2318).

Compared with the general population, patients on GLP-1s also had a reduced risk for CRC (aHR, 0.28; P < .0001); however, the difference was not observed between the bariatric surgery group and the general population (aHR, 1.11; P = .3).

Among patients with type 2 diabetes with CRC and a BMI > 30, the 5-year mortality rate was lower in the GLP-1 group vs the bariatric surgery group (aHR, 0.42; P < .001).

Speculating on the mechanisms of GLP-1s that could result in a greater reduction in CRC risk, Ta’ani explained that the key pathways linking type 2 diabetes, obesity, and CRC include hyperinsulinemia, chronic inflammation, and impaired immune surveillance.

Studies have shown that GLP-1s may be more effective in addressing the collective pathways, he said. They “may improve insulin resistance and lower systemic inflammation.” 

Furthermore, GLP1s “inhibit tumor pathways like Wnt/beta-catenin and PI3K/Akt/mTOR signaling, which promote apoptosis and reduce tumor cell proliferation,” he added.

 

Bariatric Surgery Findings Questioned

Meanwhile, “bariatric surgery’s impact on CRC remains mixed,” said Ta’ani.

Commenting on the study, Vance L. Albaugh, MD, an assistant professor of metabolic surgery at the Metamor Institute, Pennington Biomedical Research Center, Baton Rouge, Louisiana, noted that prior studies, including a recent meta-analysis, suggest a potential benefit of bariatric surgery in cancer prevention.

“I think the [current study] is interesting, but it’s been pretty [well-reported] that bariatric surgery does decrease cancer incidence, so I find it questionable that this study shows the opposite of what’s in the literature,” Albaugh, an obesity medicine specialist and bariatric surgeon, said in an interview.

Ta’ani acknowledged the study’s important limitations, including that with a retrospective design, causality cannot be firmly established.

And, as noted by an audience member in the session’s Q&A, the study ended in 2019, which was before GLP-1s had taken off as anti-obesity drugs and before US Food and Drug Administration approvals for weight loss.

Participants were matched based on BMI, however, Ta’ani pointed out.

Albaugh agreed that the study ending in 2019 was a notable limitation. However, the relatively long study period — extending from 2005 to 2019 — was a strength.

“It’s nice to have a very long period to capture people who are diagnosed, because it takes a long time to develop CRC,” he said. “To evaluate effects [of more recent drug regimens], you would not be able to have the follow-up they had.”

Other study limitations included the need to adjust for ranges of obesity severity, said Albaugh. “The risk of colorectal cancer is probably much different for someone with a BMI of 60 vs a BMI of 30.” 

Ultimately, a key question the study results raise is whether GLP-1 drugs have protective effects above and beyond that of weight loss, he said.

“I think that’s a very exciting question and that’s what I think the researchers’ next work should really focus on.”

Ta’ani had no disclosures to report. Albaugh reported that he had consulted for Novo Nordisk.

A version of this article appeared on Medscape.com.

SAN DIEGO — Patients with obesity and type 2 diabetes treated with glucagon-like peptide 1 (GLP-1) receptor agonists had significantly reduced rates of colorectal cancer (CRC) risk and associated mortality compared with those undergoing bariatric surgery, new research showed.

CRC risk was also lower for patients taking GLP-1s than the general population.

“Our findings show we might need to evaluate these therapies beyond their glycemic or weight loss [effects],” said first author Omar Al Ta’ani, MD, of the Allegheny Health Network, Pittsburgh.

This supports future prospective studies examining GLP-1s for CRC reduction, added Ta’ani, who presented the results at Digestive Disease Week (DDW) 2025.

Patients with type 2 diabetes and obesity are known to have a higher risk for CRC, stemming from metabolic risk factors. Whereas prior studies suggested that GLP-1s decrease the risk for CRC compared with other antidiabetic medications, studies looking at the risk for CRC associated with bariatric surgery have had more mixed results, Ta’ani said.

For the comparison, Ta’ani and colleagues conducted a retrospective analysis of the TriNetX database, identifying patients with type 2 diabetes and obesity (body mass index [BMI] > 30) enrolled in the database between 2005 and 2019.

Overall, the study included 94,098 GLP-1 users and 24,969 patients who underwent bariatric surgery. Those with a prior history of CRC were excluded.

Using propensity score matching, patients treated with GLP-1s were matched 1:1 with patients who had bariatric surgery based on wide-ranging factors including age, race, gender, demographics, diseases, medications, personal and family history, and hemoglobin A1c.

After the propensity matching, each group included 21,022 patients. About 64% in each group were women; their median age was 53 years and about 65% were White.

Overall, the results showed that patients on GLP-1s had a significantly lower CRC risk compared with those who had bariatric surgery (adjusted hazard ratio [aHR], 0.29; P < .0001). The lower risk was also observed among those with high obesity (defined as BMI > 35) compared with those who had surgery (aHR, 0.39; P < .0001).

The results were consistent across genders; however, the differences between GLP-1s and bariatric surgery were not observed in the 18- to 45-year-old age group (BMI > 30, P = .0809; BMI > 35, P = .2318).

Compared with the general population, patients on GLP-1s also had a reduced risk for CRC (aHR, 0.28; P < .0001); however, the difference was not observed between the bariatric surgery group and the general population (aHR, 1.11; P = .3).

Among patients with type 2 diabetes with CRC and a BMI > 30, the 5-year mortality rate was lower in the GLP-1 group vs the bariatric surgery group (aHR, 0.42; P < .001).

Speculating on the mechanisms of GLP-1s that could result in a greater reduction in CRC risk, Ta’ani explained that the key pathways linking type 2 diabetes, obesity, and CRC include hyperinsulinemia, chronic inflammation, and impaired immune surveillance.

Studies have shown that GLP-1s may be more effective in addressing the collective pathways, he said. They “may improve insulin resistance and lower systemic inflammation.” 

Furthermore, GLP1s “inhibit tumor pathways like Wnt/beta-catenin and PI3K/Akt/mTOR signaling, which promote apoptosis and reduce tumor cell proliferation,” he added.

 

Bariatric Surgery Findings Questioned

Meanwhile, “bariatric surgery’s impact on CRC remains mixed,” said Ta’ani.

Commenting on the study, Vance L. Albaugh, MD, an assistant professor of metabolic surgery at the Metamor Institute, Pennington Biomedical Research Center, Baton Rouge, Louisiana, noted that prior studies, including a recent meta-analysis, suggest a potential benefit of bariatric surgery in cancer prevention.

“I think the [current study] is interesting, but it’s been pretty [well-reported] that bariatric surgery does decrease cancer incidence, so I find it questionable that this study shows the opposite of what’s in the literature,” Albaugh, an obesity medicine specialist and bariatric surgeon, said in an interview.

Ta’ani acknowledged the study’s important limitations, including that with a retrospective design, causality cannot be firmly established.

And, as noted by an audience member in the session’s Q&A, the study ended in 2019, which was before GLP-1s had taken off as anti-obesity drugs and before US Food and Drug Administration approvals for weight loss.

Participants were matched based on BMI, however, Ta’ani pointed out.

Albaugh agreed that the study ending in 2019 was a notable limitation. However, the relatively long study period — extending from 2005 to 2019 — was a strength.

“It’s nice to have a very long period to capture people who are diagnosed, because it takes a long time to develop CRC,” he said. “To evaluate effects [of more recent drug regimens], you would not be able to have the follow-up they had.”

Other study limitations included the need to adjust for ranges of obesity severity, said Albaugh. “The risk of colorectal cancer is probably much different for someone with a BMI of 60 vs a BMI of 30.” 

Ultimately, a key question the study results raise is whether GLP-1 drugs have protective effects above and beyond that of weight loss, he said.

“I think that’s a very exciting question and that’s what I think the researchers’ next work should really focus on.”

Ta’ani had no disclosures to report. Albaugh reported that he had consulted for Novo Nordisk.

A version of this article appeared on Medscape.com.

SAN DIEGO — Patients with obesity and type 2 diabetes treated with glucagon-like peptide 1 (GLP-1) receptor agonists had significantly reduced rates of colorectal cancer (CRC) risk and associated mortality compared with those undergoing bariatric surgery, new research showed.

CRC risk was also lower for patients taking GLP-1s than the general population.

“Our findings show we might need to evaluate these therapies beyond their glycemic or weight loss [effects],” said first author Omar Al Ta’ani, MD, of the Allegheny Health Network, Pittsburgh.

This supports future prospective studies examining GLP-1s for CRC reduction, added Ta’ani, who presented the results at Digestive Disease Week (DDW) 2025.

Patients with type 2 diabetes and obesity are known to have a higher risk for CRC, stemming from metabolic risk factors. Whereas prior studies suggested that GLP-1s decrease the risk for CRC compared with other antidiabetic medications, studies looking at the risk for CRC associated with bariatric surgery have had more mixed results, Ta’ani said.

For the comparison, Ta’ani and colleagues conducted a retrospective analysis of the TriNetX database, identifying patients with type 2 diabetes and obesity (body mass index [BMI] > 30) enrolled in the database between 2005 and 2019.

Overall, the study included 94,098 GLP-1 users and 24,969 patients who underwent bariatric surgery. Those with a prior history of CRC were excluded.

Using propensity score matching, patients treated with GLP-1s were matched 1:1 with patients who had bariatric surgery based on wide-ranging factors including age, race, gender, demographics, diseases, medications, personal and family history, and hemoglobin A1c.

After the propensity matching, each group included 21,022 patients. About 64% in each group were women; their median age was 53 years and about 65% were White.

Overall, the results showed that patients on GLP-1s had a significantly lower CRC risk compared with those who had bariatric surgery (adjusted hazard ratio [aHR], 0.29; P < .0001). The lower risk was also observed among those with high obesity (defined as BMI > 35) compared with those who had surgery (aHR, 0.39; P < .0001).

The results were consistent across genders; however, the differences between GLP-1s and bariatric surgery were not observed in the 18- to 45-year-old age group (BMI > 30, P = .0809; BMI > 35, P = .2318).

Compared with the general population, patients on GLP-1s also had a reduced risk for CRC (aHR, 0.28; P < .0001); however, the difference was not observed between the bariatric surgery group and the general population (aHR, 1.11; P = .3).

Among patients with type 2 diabetes with CRC and a BMI > 30, the 5-year mortality rate was lower in the GLP-1 group vs the bariatric surgery group (aHR, 0.42; P < .001).

Speculating on the mechanisms of GLP-1s that could result in a greater reduction in CRC risk, Ta’ani explained that the key pathways linking type 2 diabetes, obesity, and CRC include hyperinsulinemia, chronic inflammation, and impaired immune surveillance.

Studies have shown that GLP-1s may be more effective in addressing the collective pathways, he said. They “may improve insulin resistance and lower systemic inflammation.” 

Furthermore, GLP1s “inhibit tumor pathways like Wnt/beta-catenin and PI3K/Akt/mTOR signaling, which promote apoptosis and reduce tumor cell proliferation,” he added.

 

Bariatric Surgery Findings Questioned

Meanwhile, “bariatric surgery’s impact on CRC remains mixed,” said Ta’ani.

Commenting on the study, Vance L. Albaugh, MD, an assistant professor of metabolic surgery at the Metamor Institute, Pennington Biomedical Research Center, Baton Rouge, Louisiana, noted that prior studies, including a recent meta-analysis, suggest a potential benefit of bariatric surgery in cancer prevention.

“I think the [current study] is interesting, but it’s been pretty [well-reported] that bariatric surgery does decrease cancer incidence, so I find it questionable that this study shows the opposite of what’s in the literature,” Albaugh, an obesity medicine specialist and bariatric surgeon, said in an interview.

Ta’ani acknowledged the study’s important limitations, including that with a retrospective design, causality cannot be firmly established.

And, as noted by an audience member in the session’s Q&A, the study ended in 2019, which was before GLP-1s had taken off as anti-obesity drugs and before US Food and Drug Administration approvals for weight loss.

Participants were matched based on BMI, however, Ta’ani pointed out.

Albaugh agreed that the study ending in 2019 was a notable limitation. However, the relatively long study period — extending from 2005 to 2019 — was a strength.

“It’s nice to have a very long period to capture people who are diagnosed, because it takes a long time to develop CRC,” he said. “To evaluate effects [of more recent drug regimens], you would not be able to have the follow-up they had.”

Other study limitations included the need to adjust for ranges of obesity severity, said Albaugh. “The risk of colorectal cancer is probably much different for someone with a BMI of 60 vs a BMI of 30.” 

Ultimately, a key question the study results raise is whether GLP-1 drugs have protective effects above and beyond that of weight loss, he said.

“I think that’s a very exciting question and that’s what I think the researchers’ next work should really focus on.”

Ta’ani had no disclosures to report. Albaugh reported that he had consulted for Novo Nordisk.

A version of this article appeared on Medscape.com.

SAN DIEGO — Molecular residual disease (MRD) positivity, as detected via circulating tumor (ct) DNA following curative resection, was significantly associated with improved disease-free survival after chemotherapy in patients with stage II or III colorectal cancer (CRC), the results of the BESPOKE study showed.

“These findings highlight the value of utilizing ctDNA to select which patients should receive management chemotherapy and which patients can be potentially spared chemotherapy’s physical, emotional, and financial toxicities without compromising their long-term outcomes,” said first author Kim Magee of Natera, a clinical genetic testing company in Austin, Texas.

“ctDNA is emerging as the most powerful and prognostic biomarker in colorectal cancer,” said Magee, who presented the findings at Digestive Disease Week (DDW) 2025.

In stage II CRC, as many as 80% of patients are cured by surgery alone, while only about 5% benefit from chemotherapy. In stage III CRC, about half of patients are cured by surgery alone, while only 20% benefit from chemotherapy, and 30% recur despite chemotherapy, Magee explained.

The inability to pinpoint which patients will most benefit from chemotherapy means “we know we are needlessly treating [many] of these patients,” she said.

 

ctDNA Offers Insights Into Tumor’s Real-Time Status

Just as cells release fragments (cell-free DNA) into the blood as they regenerate, tumor cells also release fragments — ctDNA — which can represent a biomarker of a cancer’s current state, Magee explained.

Because the DNA fragments have a half-life of only about 2 hours, they represent a key snapshot in real time, “as opposed to imaging, which can take several weeks or months to show changes,” she said.

To determine the effects of ctDNA testing on treatment decisions and asymptomatic recurrence rates, Magee and colleagues analyzed data from the multicenter, prospective study, which used the Signatera (Natera) residual disease test.

The study included 1794 patients with resected stage II-III CRC who were treated with the standard of care between May 2020 and March 2023 who had complete clinical and laboratory data available.

ctDNA was collected 2-6 weeks post surgery and at surveillance months 2, 4, 6, and every 3 months through month 24.

Among the 1166 patients included in a final analysis, 694 (59.5%) patients received adjunctive chemotherapy, and 472 (40.5%) received no chemotherapy.

Among those with stage II CRC, a postoperative MRD positivity rate was 7.54%, while the rate in those with stage III disease was 28.35%.

Overall, 16.1% of patients had a recurrence by the trial end at 24 months.

The results showed that among patients who tested negative for ctDNA, the disease-free survival estimates were highly favorable, at 91.8% for stage II and 87.4% for stage III CRC.

Comparatively, for those who were ctDNA-positive, disease-free survival rates were just 45.9% and 35.5%, respectively, regardless of whether those patients received adjunctive chemotherapy.

At the study’s first ctDNA surveillance timepoint, patients who were ctDNA-positive with stage II and III CRC combined had substantially worse disease-free survival than patients who were ctDNA-negative (HR, 26.4; P < .0001).

 

Impact of Chemotherapy

Patients who were found to be MRD-positive on ctDNA testing and treated with chemotherapy had a 40.3% 2-year disease-free survival rate compared with just 24.7% among MRD-positive patients who did not receive chemotherapy.

Meanwhile, those who were MRD-negative and treated with chemotherapy had a substantially higher 2-year disease-free survival rate of 89.7% — nearly identical to the 89.5% observed in the no-chemotherapy group.

The findings underscored that “the adjuvant chemotherapy benefits were only observed among those who were ctDNA-positive,” Magee said.

“ctDNA can guide postsurgical treatment decisions by identifying which patients are most likely to benefit from chemotherapy, and in the surveillance setting, ctDNA can predict recurrence — usually ahead of scans,” she added. “This opens the opportunity to intervene and give those patients a second chance at cure.”

On the heels of major recent advances including CT, MRI, and PET-CT, “we believe that ctDNA represents the next major pivotal advancement in monitoring and eventually better understanding cancer diagnostics,” Magee said.

 

Commenting on the study, William M. Grady, MD, AGAF, medical director of the Fred Hutchinson Cancer Center Gastrointestinal Cancer Prevention Clinic, Seattle, said the BESPOKE trial represents a “well-done” study, adding to research underscoring that “MRD testing is a more accurate prognostic assay than the current standards of CT scan and CEA [carcinoembryonic antigen, a tumor marker] testing.”

However, “a limitation is that this is 2 years of follow-up, [while] 5-year follow-up data would be ideal,” he said in an interview, noting, importantly, that “a small number of patients who have no evidence of disease (NED) at 2 years develop recurrence by 5 years.”

Furthermore, more research demonstrating the outcomes of MRD detection is needed, Grady added.

“A caveat is that studies are still needed showing that if you change your care of patients based on the MRD result, that you improve outcomes,” he said. “These studies are being planned and initiated at this time, from my understanding.”

Oncologists treating patients with CRC are commonly performing MRD assessment with ctDNA assays; however, Grady noted that the practice is still not the standard of care.

Regarding the suggestion of ctDNA representing the next major, pivotal step in cancer monitoring, Grady responded that “I think this is aspirational, and further studies are needed to make this claim.”

However, “it does look like it has the promise to turn out to be true.”

Magee is an employee of Nater. Grady has been on the scientific advisory boards for Guardant Health and Freenome and has consulted for Karius.

A version of this article appeared on Medscape.com.

SAN DIEGO — Molecular residual disease (MRD) positivity, as detected via circulating tumor (ct) DNA following curative resection, was significantly associated with improved disease-free survival after chemotherapy in patients with stage II or III colorectal cancer (CRC), the results of the BESPOKE study showed.

“These findings highlight the value of utilizing ctDNA to select which patients should receive management chemotherapy and which patients can be potentially spared chemotherapy’s physical, emotional, and financial toxicities without compromising their long-term outcomes,” said first author Kim Magee of Natera, a clinical genetic testing company in Austin, Texas.

“ctDNA is emerging as the most powerful and prognostic biomarker in colorectal cancer,” said Magee, who presented the findings at Digestive Disease Week (DDW) 2025.

In stage II CRC, as many as 80% of patients are cured by surgery alone, while only about 5% benefit from chemotherapy. In stage III CRC, about half of patients are cured by surgery alone, while only 20% benefit from chemotherapy, and 30% recur despite chemotherapy, Magee explained.

The inability to pinpoint which patients will most benefit from chemotherapy means “we know we are needlessly treating [many] of these patients,” she said.

 

ctDNA Offers Insights Into Tumor’s Real-Time Status

Just as cells release fragments (cell-free DNA) into the blood as they regenerate, tumor cells also release fragments — ctDNA — which can represent a biomarker of a cancer’s current state, Magee explained.

Because the DNA fragments have a half-life of only about 2 hours, they represent a key snapshot in real time, “as opposed to imaging, which can take several weeks or months to show changes,” she said.

To determine the effects of ctDNA testing on treatment decisions and asymptomatic recurrence rates, Magee and colleagues analyzed data from the multicenter, prospective study, which used the Signatera (Natera) residual disease test.

The study included 1794 patients with resected stage II-III CRC who were treated with the standard of care between May 2020 and March 2023 who had complete clinical and laboratory data available.

ctDNA was collected 2-6 weeks post surgery and at surveillance months 2, 4, 6, and every 3 months through month 24.

Among the 1166 patients included in a final analysis, 694 (59.5%) patients received adjunctive chemotherapy, and 472 (40.5%) received no chemotherapy.

Among those with stage II CRC, a postoperative MRD positivity rate was 7.54%, while the rate in those with stage III disease was 28.35%.

Overall, 16.1% of patients had a recurrence by the trial end at 24 months.

The results showed that among patients who tested negative for ctDNA, the disease-free survival estimates were highly favorable, at 91.8% for stage II and 87.4% for stage III CRC.

Comparatively, for those who were ctDNA-positive, disease-free survival rates were just 45.9% and 35.5%, respectively, regardless of whether those patients received adjunctive chemotherapy.

At the study’s first ctDNA surveillance timepoint, patients who were ctDNA-positive with stage II and III CRC combined had substantially worse disease-free survival than patients who were ctDNA-negative (HR, 26.4; P < .0001).

 

Impact of Chemotherapy

Patients who were found to be MRD-positive on ctDNA testing and treated with chemotherapy had a 40.3% 2-year disease-free survival rate compared with just 24.7% among MRD-positive patients who did not receive chemotherapy.

Meanwhile, those who were MRD-negative and treated with chemotherapy had a substantially higher 2-year disease-free survival rate of 89.7% — nearly identical to the 89.5% observed in the no-chemotherapy group.

The findings underscored that “the adjuvant chemotherapy benefits were only observed among those who were ctDNA-positive,” Magee said.

“ctDNA can guide postsurgical treatment decisions by identifying which patients are most likely to benefit from chemotherapy, and in the surveillance setting, ctDNA can predict recurrence — usually ahead of scans,” she added. “This opens the opportunity to intervene and give those patients a second chance at cure.”

On the heels of major recent advances including CT, MRI, and PET-CT, “we believe that ctDNA represents the next major pivotal advancement in monitoring and eventually better understanding cancer diagnostics,” Magee said.

 

Commenting on the study, William M. Grady, MD, AGAF, medical director of the Fred Hutchinson Cancer Center Gastrointestinal Cancer Prevention Clinic, Seattle, said the BESPOKE trial represents a “well-done” study, adding to research underscoring that “MRD testing is a more accurate prognostic assay than the current standards of CT scan and CEA [carcinoembryonic antigen, a tumor marker] testing.”

However, “a limitation is that this is 2 years of follow-up, [while] 5-year follow-up data would be ideal,” he said in an interview, noting, importantly, that “a small number of patients who have no evidence of disease (NED) at 2 years develop recurrence by 5 years.”

Furthermore, more research demonstrating the outcomes of MRD detection is needed, Grady added.

“A caveat is that studies are still needed showing that if you change your care of patients based on the MRD result, that you improve outcomes,” he said. “These studies are being planned and initiated at this time, from my understanding.”

Oncologists treating patients with CRC are commonly performing MRD assessment with ctDNA assays; however, Grady noted that the practice is still not the standard of care.

Regarding the suggestion of ctDNA representing the next major, pivotal step in cancer monitoring, Grady responded that “I think this is aspirational, and further studies are needed to make this claim.”

However, “it does look like it has the promise to turn out to be true.”

Magee is an employee of Nater. Grady has been on the scientific advisory boards for Guardant Health and Freenome and has consulted for Karius.

A version of this article appeared on Medscape.com.

SAN DIEGO — Molecular residual disease (MRD) positivity, as detected via circulating tumor (ct) DNA following curative resection, was significantly associated with improved disease-free survival after chemotherapy in patients with stage II or III colorectal cancer (CRC), the results of the BESPOKE study showed.

“These findings highlight the value of utilizing ctDNA to select which patients should receive management chemotherapy and which patients can be potentially spared chemotherapy’s physical, emotional, and financial toxicities without compromising their long-term outcomes,” said first author Kim Magee of Natera, a clinical genetic testing company in Austin, Texas.

“ctDNA is emerging as the most powerful and prognostic biomarker in colorectal cancer,” said Magee, who presented the findings at Digestive Disease Week (DDW) 2025.

In stage II CRC, as many as 80% of patients are cured by surgery alone, while only about 5% benefit from chemotherapy. In stage III CRC, about half of patients are cured by surgery alone, while only 20% benefit from chemotherapy, and 30% recur despite chemotherapy, Magee explained.

The inability to pinpoint which patients will most benefit from chemotherapy means “we know we are needlessly treating [many] of these patients,” she said.

 

ctDNA Offers Insights Into Tumor’s Real-Time Status

Just as cells release fragments (cell-free DNA) into the blood as they regenerate, tumor cells also release fragments — ctDNA — which can represent a biomarker of a cancer’s current state, Magee explained.

Because the DNA fragments have a half-life of only about 2 hours, they represent a key snapshot in real time, “as opposed to imaging, which can take several weeks or months to show changes,” she said.

To determine the effects of ctDNA testing on treatment decisions and asymptomatic recurrence rates, Magee and colleagues analyzed data from the multicenter, prospective study, which used the Signatera (Natera) residual disease test.

The study included 1794 patients with resected stage II-III CRC who were treated with the standard of care between May 2020 and March 2023 who had complete clinical and laboratory data available.

ctDNA was collected 2-6 weeks post surgery and at surveillance months 2, 4, 6, and every 3 months through month 24.

Among the 1166 patients included in a final analysis, 694 (59.5%) patients received adjunctive chemotherapy, and 472 (40.5%) received no chemotherapy.

Among those with stage II CRC, a postoperative MRD positivity rate was 7.54%, while the rate in those with stage III disease was 28.35%.

Overall, 16.1% of patients had a recurrence by the trial end at 24 months.

The results showed that among patients who tested negative for ctDNA, the disease-free survival estimates were highly favorable, at 91.8% for stage II and 87.4% for stage III CRC.

Comparatively, for those who were ctDNA-positive, disease-free survival rates were just 45.9% and 35.5%, respectively, regardless of whether those patients received adjunctive chemotherapy.

At the study’s first ctDNA surveillance timepoint, patients who were ctDNA-positive with stage II and III CRC combined had substantially worse disease-free survival than patients who were ctDNA-negative (HR, 26.4; P < .0001).

 

Impact of Chemotherapy

Patients who were found to be MRD-positive on ctDNA testing and treated with chemotherapy had a 40.3% 2-year disease-free survival rate compared with just 24.7% among MRD-positive patients who did not receive chemotherapy.

Meanwhile, those who were MRD-negative and treated with chemotherapy had a substantially higher 2-year disease-free survival rate of 89.7% — nearly identical to the 89.5% observed in the no-chemotherapy group.

The findings underscored that “the adjuvant chemotherapy benefits were only observed among those who were ctDNA-positive,” Magee said.

“ctDNA can guide postsurgical treatment decisions by identifying which patients are most likely to benefit from chemotherapy, and in the surveillance setting, ctDNA can predict recurrence — usually ahead of scans,” she added. “This opens the opportunity to intervene and give those patients a second chance at cure.”

On the heels of major recent advances including CT, MRI, and PET-CT, “we believe that ctDNA represents the next major pivotal advancement in monitoring and eventually better understanding cancer diagnostics,” Magee said.

 

Commenting on the study, William M. Grady, MD, AGAF, medical director of the Fred Hutchinson Cancer Center Gastrointestinal Cancer Prevention Clinic, Seattle, said the BESPOKE trial represents a “well-done” study, adding to research underscoring that “MRD testing is a more accurate prognostic assay than the current standards of CT scan and CEA [carcinoembryonic antigen, a tumor marker] testing.”

However, “a limitation is that this is 2 years of follow-up, [while] 5-year follow-up data would be ideal,” he said in an interview, noting, importantly, that “a small number of patients who have no evidence of disease (NED) at 2 years develop recurrence by 5 years.”

Furthermore, more research demonstrating the outcomes of MRD detection is needed, Grady added.

“A caveat is that studies are still needed showing that if you change your care of patients based on the MRD result, that you improve outcomes,” he said. “These studies are being planned and initiated at this time, from my understanding.”

Oncologists treating patients with CRC are commonly performing MRD assessment with ctDNA assays; however, Grady noted that the practice is still not the standard of care.

Regarding the suggestion of ctDNA representing the next major, pivotal step in cancer monitoring, Grady responded that “I think this is aspirational, and further studies are needed to make this claim.”

However, “it does look like it has the promise to turn out to be true.”

Magee is an employee of Nater. Grady has been on the scientific advisory boards for Guardant Health and Freenome and has consulted for Karius.

A version of this article appeared on Medscape.com.