IBD & Intestinal Disorders

International researchers have uncovered potentially diagnostic gut microbiome signatures and metabolic pathways associated specifically with ulcerative colitis (UC) and Crohn’s disease (CD).

Targeted droplet digital polymerase chain reaction (ddPCR)‒based quantification of bacterial species led to convenient inflammatory bowel disease (IBD) diagnostic assays that “are sufficiently robust, sensitive and cost-effective for clinical application,” the investigators wrote in a recent study published in Nature Medicine.

“Although traditional modalities used for diagnosis of IBD, including colonoscopy and cross-sectional imaging, are well established, the inconvenience of bowel preparation and radiation represents relevant concerns,” senior author Siew C. Ng, MBBS, PhD, a professor in the Department of Medicine and Therapeutics at the Chinese University of Hong Kong, said in an interview. “Furthermore, existing serological and fecal markers indicate inflammation but lack specificity for IBD.”

Identifying reproducible bacterial biomarkers specific to CD and IBD should enable precise and personalized approaches to detection and management.

As a starting point, the researchers hypothesized that changes in the gut microbiome of IBD patients may reflect underlying functional associations, if not causes, of the disease, said Ng, who is also director of Hong Kong’s Microbiota I-Center (MagIC). “Unlike inflammation, which is a manifestation of the disease, the gut microbiome may serve as a more reliable biomarker less affected by the disease’s fluctuating cycle.”

The study findings showed that bacterial markers remain consistent even during the inactive disease phase. Additionally, the results are reproducible across different populations, suggesting that these markers are true indicators of IBD, she added. “With a better performance than the commonly used noninvasive test, fecal calprotectin, we believe the test will be a valuable addition to clinician’s toolbox and a strong option for first-line diagnostics.”

 

The Study

The group used metagenomic data from 5979 fecal samples from persons with and without IBD from different regions (including the United States) and of different ethnicities. Identifying several microbiota alterations in IBD, they selected bacterial species to construct diagnostic models for UC (n = 10) and CD (n = 9). Some species were deleted and some were enriched in IBD.

Metagenomic findings confirmed, for example, enrichments of Escherichia coli and Bacteroides fragilis in the guts of CD patients, with adherent invasive E coli present in more than half of these. This pathogen has been linked to mucosal dysbiosis and functional alteration, and has been associated with disease activity and endoscopic recurrence following surgery. B fragilis may induce intestinal inflammation through toxin production.

The researchers also identified a new oral bacterium, Actinomyces species oral taxon 181, which was significantly enriched in stool samples with both CD and UC.

The diagnostic models achieved areas under the curve of >.90 for distinguishing IBD patients from controls in the discovery cohort and maintained satisfactory performance in transethnic validation cohorts from eight populations.

Ng’s group further developed a multiplex droplet digital PCR test targeting selected IBD-associated bacterial species. Models based on this test showed numerically higher performance than fecal calprotectin in discriminating UC and CD samples from controls. These universally IBD-associated bacteria suggest the potential applicability of a biomarker panel for noninvasive diagnosis.

Commenting on the paper but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston and associate professor of medicine at Harvard Medical School, called it “a very important study that highlights the potential role of a microbiome-based diagnostic for screening. It could have application in a wide variety of settings and is very promising.”

More work, however, is necessary to clarify such testing’s role. “The study’s validation in independent cohorts is an important strength, but the sizes of those cohorts are still quite small,” he said in an interview. “It’s important to understand its accuracy across a spectrum of IBD phenotypes and severity.”

Furthermore, endoscopic evaluation at diagnosis is important to establish severity and extent of disease. “It’s not clear this diagnostic biomarker can help supplant that role. But I see potential value to it for patients for whom we may not be considering endoscopy yet but who would like to risk-stratify.”

 

The Test’s Future

“We expect to see a real shift in clinical practice,” Ng said. “As a cost-effective test, it will help millions of people dealing with nonspecific gastrointestinal symptoms get the diagnoses they need.” Because the bacterial test can identify IBD at an inactive stage, it has the potential for early diagnosis. “This capability allows clinicians to initiate treatment sooner, helping to prevent progression from subclinical to clinical stages of the disease.”

The next research steps involve prospective studies with a larger and more diverse group of patients with various gastrointestinal symptoms. “This will enable a comprehensive evaluation of bacterial biomarkers in real-world populations,” she said. In vivo and in vitro experiments are expected to provide mechanistic insights into the causal role of these bacteria and metabolic dysregulations in the pathogenesis of IBD, as well as their future clinical utility in disease monitoring and predicting treatment response.

Her group plans to work with the biotech industry and regulatory agencies to transform these biomarkers into an approved test kit. “The rollout is likely to be gradual, but we’re optimistic that supportive international and national guidelines will be developed and will pave the way for widespread implementation.”

This study was supported by various academic, charitable, and governmental research-funding bodies, including the governments of Hong Kong and the People’s Republic of China. Ng has served as an advisory board member or speaker for Pfizer, Ferring, Janssen, AbbVie, Tillotts, Menarini, and Takeda. She has received research grants through her institutions from Olympus, Ferring, and AbbVie and is a founding member and shareholder of GenieBiome. She receives patent royalties through her institutions, including MagIC, which holds patents on the therapeutic and diagnostic use of the microbiome in IBD. Several co-authors reported various relationships, including patent holding, with private-sector companies. Ananthakrishnan had no relevant competing interests.

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

International researchers have uncovered potentially diagnostic gut microbiome signatures and metabolic pathways associated specifically with ulcerative colitis (UC) and Crohn’s disease (CD).

Targeted droplet digital polymerase chain reaction (ddPCR)‒based quantification of bacterial species led to convenient inflammatory bowel disease (IBD) diagnostic assays that “are sufficiently robust, sensitive and cost-effective for clinical application,” the investigators wrote in a recent study published in Nature Medicine.

“Although traditional modalities used for diagnosis of IBD, including colonoscopy and cross-sectional imaging, are well established, the inconvenience of bowel preparation and radiation represents relevant concerns,” senior author Siew C. Ng, MBBS, PhD, a professor in the Department of Medicine and Therapeutics at the Chinese University of Hong Kong, said in an interview. “Furthermore, existing serological and fecal markers indicate inflammation but lack specificity for IBD.”

Identifying reproducible bacterial biomarkers specific to CD and IBD should enable precise and personalized approaches to detection and management.

As a starting point, the researchers hypothesized that changes in the gut microbiome of IBD patients may reflect underlying functional associations, if not causes, of the disease, said Ng, who is also director of Hong Kong’s Microbiota I-Center (MagIC). “Unlike inflammation, which is a manifestation of the disease, the gut microbiome may serve as a more reliable biomarker less affected by the disease’s fluctuating cycle.”

The study findings showed that bacterial markers remain consistent even during the inactive disease phase. Additionally, the results are reproducible across different populations, suggesting that these markers are true indicators of IBD, she added. “With a better performance than the commonly used noninvasive test, fecal calprotectin, we believe the test will be a valuable addition to clinician’s toolbox and a strong option for first-line diagnostics.”

 

The Study

The group used metagenomic data from 5979 fecal samples from persons with and without IBD from different regions (including the United States) and of different ethnicities. Identifying several microbiota alterations in IBD, they selected bacterial species to construct diagnostic models for UC (n = 10) and CD (n = 9). Some species were deleted and some were enriched in IBD.

Metagenomic findings confirmed, for example, enrichments of Escherichia coli and Bacteroides fragilis in the guts of CD patients, with adherent invasive E coli present in more than half of these. This pathogen has been linked to mucosal dysbiosis and functional alteration, and has been associated with disease activity and endoscopic recurrence following surgery. B fragilis may induce intestinal inflammation through toxin production.

The researchers also identified a new oral bacterium, Actinomyces species oral taxon 181, which was significantly enriched in stool samples with both CD and UC.

The diagnostic models achieved areas under the curve of >.90 for distinguishing IBD patients from controls in the discovery cohort and maintained satisfactory performance in transethnic validation cohorts from eight populations.

Ng’s group further developed a multiplex droplet digital PCR test targeting selected IBD-associated bacterial species. Models based on this test showed numerically higher performance than fecal calprotectin in discriminating UC and CD samples from controls. These universally IBD-associated bacteria suggest the potential applicability of a biomarker panel for noninvasive diagnosis.

Commenting on the paper but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston and associate professor of medicine at Harvard Medical School, called it “a very important study that highlights the potential role of a microbiome-based diagnostic for screening. It could have application in a wide variety of settings and is very promising.”

More work, however, is necessary to clarify such testing’s role. “The study’s validation in independent cohorts is an important strength, but the sizes of those cohorts are still quite small,” he said in an interview. “It’s important to understand its accuracy across a spectrum of IBD phenotypes and severity.”

Furthermore, endoscopic evaluation at diagnosis is important to establish severity and extent of disease. “It’s not clear this diagnostic biomarker can help supplant that role. But I see potential value to it for patients for whom we may not be considering endoscopy yet but who would like to risk-stratify.”

 

The Test’s Future

“We expect to see a real shift in clinical practice,” Ng said. “As a cost-effective test, it will help millions of people dealing with nonspecific gastrointestinal symptoms get the diagnoses they need.” Because the bacterial test can identify IBD at an inactive stage, it has the potential for early diagnosis. “This capability allows clinicians to initiate treatment sooner, helping to prevent progression from subclinical to clinical stages of the disease.”

The next research steps involve prospective studies with a larger and more diverse group of patients with various gastrointestinal symptoms. “This will enable a comprehensive evaluation of bacterial biomarkers in real-world populations,” she said. In vivo and in vitro experiments are expected to provide mechanistic insights into the causal role of these bacteria and metabolic dysregulations in the pathogenesis of IBD, as well as their future clinical utility in disease monitoring and predicting treatment response.

Her group plans to work with the biotech industry and regulatory agencies to transform these biomarkers into an approved test kit. “The rollout is likely to be gradual, but we’re optimistic that supportive international and national guidelines will be developed and will pave the way for widespread implementation.”

This study was supported by various academic, charitable, and governmental research-funding bodies, including the governments of Hong Kong and the People’s Republic of China. Ng has served as an advisory board member or speaker for Pfizer, Ferring, Janssen, AbbVie, Tillotts, Menarini, and Takeda. She has received research grants through her institutions from Olympus, Ferring, and AbbVie and is a founding member and shareholder of GenieBiome. She receives patent royalties through her institutions, including MagIC, which holds patents on the therapeutic and diagnostic use of the microbiome in IBD. Several co-authors reported various relationships, including patent holding, with private-sector companies. Ananthakrishnan had no relevant competing interests.

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

International researchers have uncovered potentially diagnostic gut microbiome signatures and metabolic pathways associated specifically with ulcerative colitis (UC) and Crohn’s disease (CD).

Targeted droplet digital polymerase chain reaction (ddPCR)‒based quantification of bacterial species led to convenient inflammatory bowel disease (IBD) diagnostic assays that “are sufficiently robust, sensitive and cost-effective for clinical application,” the investigators wrote in a recent study published in Nature Medicine.

“Although traditional modalities used for diagnosis of IBD, including colonoscopy and cross-sectional imaging, are well established, the inconvenience of bowel preparation and radiation represents relevant concerns,” senior author Siew C. Ng, MBBS, PhD, a professor in the Department of Medicine and Therapeutics at the Chinese University of Hong Kong, said in an interview. “Furthermore, existing serological and fecal markers indicate inflammation but lack specificity for IBD.”

Identifying reproducible bacterial biomarkers specific to CD and IBD should enable precise and personalized approaches to detection and management.

As a starting point, the researchers hypothesized that changes in the gut microbiome of IBD patients may reflect underlying functional associations, if not causes, of the disease, said Ng, who is also director of Hong Kong’s Microbiota I-Center (MagIC). “Unlike inflammation, which is a manifestation of the disease, the gut microbiome may serve as a more reliable biomarker less affected by the disease’s fluctuating cycle.”

The study findings showed that bacterial markers remain consistent even during the inactive disease phase. Additionally, the results are reproducible across different populations, suggesting that these markers are true indicators of IBD, she added. “With a better performance than the commonly used noninvasive test, fecal calprotectin, we believe the test will be a valuable addition to clinician’s toolbox and a strong option for first-line diagnostics.”

 

The Study

The group used metagenomic data from 5979 fecal samples from persons with and without IBD from different regions (including the United States) and of different ethnicities. Identifying several microbiota alterations in IBD, they selected bacterial species to construct diagnostic models for UC (n = 10) and CD (n = 9). Some species were deleted and some were enriched in IBD.

Metagenomic findings confirmed, for example, enrichments of Escherichia coli and Bacteroides fragilis in the guts of CD patients, with adherent invasive E coli present in more than half of these. This pathogen has been linked to mucosal dysbiosis and functional alteration, and has been associated with disease activity and endoscopic recurrence following surgery. B fragilis may induce intestinal inflammation through toxin production.

The researchers also identified a new oral bacterium, Actinomyces species oral taxon 181, which was significantly enriched in stool samples with both CD and UC.

The diagnostic models achieved areas under the curve of >.90 for distinguishing IBD patients from controls in the discovery cohort and maintained satisfactory performance in transethnic validation cohorts from eight populations.

Ng’s group further developed a multiplex droplet digital PCR test targeting selected IBD-associated bacterial species. Models based on this test showed numerically higher performance than fecal calprotectin in discriminating UC and CD samples from controls. These universally IBD-associated bacteria suggest the potential applicability of a biomarker panel for noninvasive diagnosis.

Commenting on the paper but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston and associate professor of medicine at Harvard Medical School, called it “a very important study that highlights the potential role of a microbiome-based diagnostic for screening. It could have application in a wide variety of settings and is very promising.”

More work, however, is necessary to clarify such testing’s role. “The study’s validation in independent cohorts is an important strength, but the sizes of those cohorts are still quite small,” he said in an interview. “It’s important to understand its accuracy across a spectrum of IBD phenotypes and severity.”

Furthermore, endoscopic evaluation at diagnosis is important to establish severity and extent of disease. “It’s not clear this diagnostic biomarker can help supplant that role. But I see potential value to it for patients for whom we may not be considering endoscopy yet but who would like to risk-stratify.”

 

The Test’s Future

“We expect to see a real shift in clinical practice,” Ng said. “As a cost-effective test, it will help millions of people dealing with nonspecific gastrointestinal symptoms get the diagnoses they need.” Because the bacterial test can identify IBD at an inactive stage, it has the potential for early diagnosis. “This capability allows clinicians to initiate treatment sooner, helping to prevent progression from subclinical to clinical stages of the disease.”

The next research steps involve prospective studies with a larger and more diverse group of patients with various gastrointestinal symptoms. “This will enable a comprehensive evaluation of bacterial biomarkers in real-world populations,” she said. In vivo and in vitro experiments are expected to provide mechanistic insights into the causal role of these bacteria and metabolic dysregulations in the pathogenesis of IBD, as well as their future clinical utility in disease monitoring and predicting treatment response.

Her group plans to work with the biotech industry and regulatory agencies to transform these biomarkers into an approved test kit. “The rollout is likely to be gradual, but we’re optimistic that supportive international and national guidelines will be developed and will pave the way for widespread implementation.”

This study was supported by various academic, charitable, and governmental research-funding bodies, including the governments of Hong Kong and the People’s Republic of China. Ng has served as an advisory board member or speaker for Pfizer, Ferring, Janssen, AbbVie, Tillotts, Menarini, and Takeda. She has received research grants through her institutions from Olympus, Ferring, and AbbVie and is a founding member and shareholder of GenieBiome. She receives patent royalties through her institutions, including MagIC, which holds patents on the therapeutic and diagnostic use of the microbiome in IBD. Several co-authors reported various relationships, including patent holding, with private-sector companies. Ananthakrishnan had no relevant competing interests.

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

In a rapidly expanding therapeutic landscape, the American Gastroenterological Association (AGA) has issued updated practice guidelines for the pharmacological management of moderate to severe ulcerative colitis (UC) in adult outpatients.

“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.

 

Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.

“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.

 

The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”

One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated. 

“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.

The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.

 

Specifics

Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.

The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.

The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.

Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:

• Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
• Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
• Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
• For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
• In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
• The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
• The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
• Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
• The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
• For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.

According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.

However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”

Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”

 

The Future

The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.

The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.

They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.

The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.

These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.

A version of this article appeared on Medscape.com.

In a rapidly expanding therapeutic landscape, the American Gastroenterological Association (AGA) has issued updated practice guidelines for the pharmacological management of moderate to severe ulcerative colitis (UC) in adult outpatients.

“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.

 

Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.

“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.

 

The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”

One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated. 

“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.

The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.

 

Specifics

Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.

The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.

The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.

Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:

• Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
• Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
• Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
• For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
• In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
• The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
• The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
• Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
• The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
• For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.

According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.

However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”

Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”

 

The Future

The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.

The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.

They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.

The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.

These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.

A version of this article appeared on Medscape.com.

In a rapidly expanding therapeutic landscape, the American Gastroenterological Association (AGA) has issued updated practice guidelines for the pharmacological management of moderate to severe ulcerative colitis (UC) in adult outpatients.

“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.

 

Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.

“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.

 

The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”

One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated. 

“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.

The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.

 

Specifics

Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.

The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.

The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.

Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:

• Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
• Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
• Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
• For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
• In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
• The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
• The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
• Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
• The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
• For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.

According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.

However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”

Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”

 

The Future

The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.

The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.

They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.

The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.

These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.

A version of this article appeared on Medscape.com.

PHILADELPHIA – The addition of bezlotoxumab to fecal microbiota transplantation (FMT) does not provide any clear added benefit in patients with inflammatory bowel disease (IBD) and recurrent Clostridioides difficile infection (rCDI), according to a randomized controlled trial.

“Given the high efficacy of FMT, the addition of bezlotoxumab may not provide a further reduction in CDI recurrence,” said study author Jessica R. Allegretti, MD, MPH, AGAF, with Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.

Allegretti presented the findings during a plenary session at the annual meeting of the American College of Gastroenterology (ACG).

Brigham and Women's Hospital

Common and Deadly

CDI is the most common cause of healthcare-associated infection in the United States, leading to roughly 4.8 billion in excess healthcare costs. There are an estimated 500,000 cases each year in the United States, with roughly 30,000 of those cases leading to death.

Patients with IBD have a prevalence of CDI that is 2.5- to 8-fold higher than in peers without IBD, and they also have 4.5-fold higher risk of recurrence. Sequelae of CDI in IBD include exacerbations of IBD, increased hospitalizations, escalation of IBD therapy, and colectomy.

FMT has been shown to be safe and effective in patients with IBD and rCDI.

Bezlotoxumab — a fully human monoclonal antibody that binds to C difficile toxin B — was approved by the US Food and Drug Administration (FDA) in 2016 to reduce the recurrence of CDI in patients aged 18 years and older.

However, there is only limited data on the value of combining these two strategies.

Allegretti and colleagues conducted a multicenter randomized controlled trial to evaluate the impact of FMT in combination with bezlotoxumab in patients with IBD and rCDI.

They enrolled 61 patients (mean age, 38 years, 54% men) with two or more episodes of CDI who received a single colonoscopic FMT. Twenty patients had Crohn’s disease, and 41 had ulcerative colitis.

Thirty patients were randomly allocated to receive a single bezlotoxumab infusion and 31 to receive a placebo infusion prior to FMT.

A total of five participants (8%) experienced a CDI recurrence with confirmed EIA+ stool –4 in the treatment group and 1 in the placebo group (13% vs 3%, P = .15).

Participants in the treatment group had higher odds of CDI recurrence, though this was not statistically significant (odds ratio [OR], 4.6; 95% CI, 0.5-43.9), Allegretti reported.

With regards to C difficile colonization, more patients in the treatment group were decolonized compared with placebo at week 1 (82% vs 68%, P = .22) and at week 12 (83% vs 72%, P = .34). 

Steroid use at the time of FMT was associated with a significant increased risk of ongoing colonization of C difficile at week 12 post-FMT (OR, 4.90; 95% CI, 1.18-20.37; P = .03).

While there were no significant differences in IBD outcomes between groups, there were numerically higher rates of IBD improvement in the treatment group compared to the placebo group 56% vs 46%.

Only one patient had IBD worsen, and this patient was in the placebo group. There were no de novo IBD flares.

FMT alone and with bezlotoxumab were both safe and well tolerated. Two serious adverse events were reported; neither were deemed to be treatment-related.

“This is the first clinical trial to assess the clinical effect of FMT in combination with bezlotoxumab in patients with IBD and rCDI. The data suggest no clear efficacy benefit to this combination compared to FMT alone,” Allegretti told attendees.

“This finding is not surprising given the high rate of efficacy of FMT,” said Ashwin N. Ananthakrishnan, MD, MPH, AGAF, with Massachusetts General Hospital and Harvard Medical School, Boston, who was not involved in the study.

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

PHILADELPHIA – The addition of bezlotoxumab to fecal microbiota transplantation (FMT) does not provide any clear added benefit in patients with inflammatory bowel disease (IBD) and recurrent Clostridioides difficile infection (rCDI), according to a randomized controlled trial.

“Given the high efficacy of FMT, the addition of bezlotoxumab may not provide a further reduction in CDI recurrence,” said study author Jessica R. Allegretti, MD, MPH, AGAF, with Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.

Allegretti presented the findings during a plenary session at the annual meeting of the American College of Gastroenterology (ACG).

Brigham and Women's Hospital

Common and Deadly

CDI is the most common cause of healthcare-associated infection in the United States, leading to roughly 4.8 billion in excess healthcare costs. There are an estimated 500,000 cases each year in the United States, with roughly 30,000 of those cases leading to death.

Patients with IBD have a prevalence of CDI that is 2.5- to 8-fold higher than in peers without IBD, and they also have 4.5-fold higher risk of recurrence. Sequelae of CDI in IBD include exacerbations of IBD, increased hospitalizations, escalation of IBD therapy, and colectomy.

FMT has been shown to be safe and effective in patients with IBD and rCDI.

Bezlotoxumab — a fully human monoclonal antibody that binds to C difficile toxin B — was approved by the US Food and Drug Administration (FDA) in 2016 to reduce the recurrence of CDI in patients aged 18 years and older.

However, there is only limited data on the value of combining these two strategies.

Allegretti and colleagues conducted a multicenter randomized controlled trial to evaluate the impact of FMT in combination with bezlotoxumab in patients with IBD and rCDI.

They enrolled 61 patients (mean age, 38 years, 54% men) with two or more episodes of CDI who received a single colonoscopic FMT. Twenty patients had Crohn’s disease, and 41 had ulcerative colitis.

Thirty patients were randomly allocated to receive a single bezlotoxumab infusion and 31 to receive a placebo infusion prior to FMT.

A total of five participants (8%) experienced a CDI recurrence with confirmed EIA+ stool –4 in the treatment group and 1 in the placebo group (13% vs 3%, P = .15).

Participants in the treatment group had higher odds of CDI recurrence, though this was not statistically significant (odds ratio [OR], 4.6; 95% CI, 0.5-43.9), Allegretti reported.

With regards to C difficile colonization, more patients in the treatment group were decolonized compared with placebo at week 1 (82% vs 68%, P = .22) and at week 12 (83% vs 72%, P = .34). 

Steroid use at the time of FMT was associated with a significant increased risk of ongoing colonization of C difficile at week 12 post-FMT (OR, 4.90; 95% CI, 1.18-20.37; P = .03).

While there were no significant differences in IBD outcomes between groups, there were numerically higher rates of IBD improvement in the treatment group compared to the placebo group 56% vs 46%.

Only one patient had IBD worsen, and this patient was in the placebo group. There were no de novo IBD flares.

FMT alone and with bezlotoxumab were both safe and well tolerated. Two serious adverse events were reported; neither were deemed to be treatment-related.

“This is the first clinical trial to assess the clinical effect of FMT in combination with bezlotoxumab in patients with IBD and rCDI. The data suggest no clear efficacy benefit to this combination compared to FMT alone,” Allegretti told attendees.

“This finding is not surprising given the high rate of efficacy of FMT,” said Ashwin N. Ananthakrishnan, MD, MPH, AGAF, with Massachusetts General Hospital and Harvard Medical School, Boston, who was not involved in the study.

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

PHILADELPHIA – The addition of bezlotoxumab to fecal microbiota transplantation (FMT) does not provide any clear added benefit in patients with inflammatory bowel disease (IBD) and recurrent Clostridioides difficile infection (rCDI), according to a randomized controlled trial.

“Given the high efficacy of FMT, the addition of bezlotoxumab may not provide a further reduction in CDI recurrence,” said study author Jessica R. Allegretti, MD, MPH, AGAF, with Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.

Allegretti presented the findings during a plenary session at the annual meeting of the American College of Gastroenterology (ACG).

Brigham and Women's Hospital

Common and Deadly

CDI is the most common cause of healthcare-associated infection in the United States, leading to roughly 4.8 billion in excess healthcare costs. There are an estimated 500,000 cases each year in the United States, with roughly 30,000 of those cases leading to death.

Patients with IBD have a prevalence of CDI that is 2.5- to 8-fold higher than in peers without IBD, and they also have 4.5-fold higher risk of recurrence. Sequelae of CDI in IBD include exacerbations of IBD, increased hospitalizations, escalation of IBD therapy, and colectomy.

FMT has been shown to be safe and effective in patients with IBD and rCDI.

Bezlotoxumab — a fully human monoclonal antibody that binds to C difficile toxin B — was approved by the US Food and Drug Administration (FDA) in 2016 to reduce the recurrence of CDI in patients aged 18 years and older.

However, there is only limited data on the value of combining these two strategies.

Allegretti and colleagues conducted a multicenter randomized controlled trial to evaluate the impact of FMT in combination with bezlotoxumab in patients with IBD and rCDI.

They enrolled 61 patients (mean age, 38 years, 54% men) with two or more episodes of CDI who received a single colonoscopic FMT. Twenty patients had Crohn’s disease, and 41 had ulcerative colitis.

Thirty patients were randomly allocated to receive a single bezlotoxumab infusion and 31 to receive a placebo infusion prior to FMT.

A total of five participants (8%) experienced a CDI recurrence with confirmed EIA+ stool –4 in the treatment group and 1 in the placebo group (13% vs 3%, P = .15).

Participants in the treatment group had higher odds of CDI recurrence, though this was not statistically significant (odds ratio [OR], 4.6; 95% CI, 0.5-43.9), Allegretti reported.

With regards to C difficile colonization, more patients in the treatment group were decolonized compared with placebo at week 1 (82% vs 68%, P = .22) and at week 12 (83% vs 72%, P = .34). 

Steroid use at the time of FMT was associated with a significant increased risk of ongoing colonization of C difficile at week 12 post-FMT (OR, 4.90; 95% CI, 1.18-20.37; P = .03).

While there were no significant differences in IBD outcomes between groups, there were numerically higher rates of IBD improvement in the treatment group compared to the placebo group 56% vs 46%.

Only one patient had IBD worsen, and this patient was in the placebo group. There were no de novo IBD flares.

FMT alone and with bezlotoxumab were both safe and well tolerated. Two serious adverse events were reported; neither were deemed to be treatment-related.

“This is the first clinical trial to assess the clinical effect of FMT in combination with bezlotoxumab in patients with IBD and rCDI. The data suggest no clear efficacy benefit to this combination compared to FMT alone,” Allegretti told attendees.

“This finding is not surprising given the high rate of efficacy of FMT,” said Ashwin N. Ananthakrishnan, MD, MPH, AGAF, with Massachusetts General Hospital and Harvard Medical School, Boston, who was not involved in the study.

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

Many patients with Crohn’s disease (CD) have a heightened immune response to flagellins expressed by commensal gut bacteria Lachnospiraceae, with seroreactivity appearing up to 5 years prior to development of Crohn’s complications, according to investigators.

These findings suggest that the flagellin cytometric bead array used in the present study could serve as a simple diagnostic and prognostic tool for patients with CD, and point to a new therapeutic target, lead author Qing Zhao, MD, PhD, of the University of Alabama at Birmingham, and colleagues reported.

Qing Zhao

Previously, Zhao and colleagues found that about 30% of patients with CD had elevated IgG responses to multiple Lachnospiraceae flagellins, and stronger reactivity was associated with higher flagellin-specific CD4+ T cells in circulation.

“In this study, we aimed to identify immunodominant B cell peptide epitopes shared among Lachnospiraceae bacterial flagellins in patients with CD and to correlate this immune reactivity with the clinical disease course,” the investigators wrote in Gastroenterology.

To this end, the investigators analyzed serum samples from adult CD patients, pediatric CD patients, and healthy infants without inflammatory bowel disease, with data derived from multiple sources. Adult patients with CD were part of a regional cohort recruited at the University of Alabama at Birmingham, while pediatric patients with CD came from the RISK Stratification Study, a multisite cohort study across the United States and Canada. Samples from healthy infants were collected from three diverse geographic locations: Uganda, Sweden, and the United States, providing a broad comparison of immune responses to Lachnospiraceae flagellin across populations.

Samples were analyzed via two main methods: a flagellin peptide microarray and a cytometric bead array. The microarray, comprising sequential Lachnospiraceae-derived peptides, enabled identification of IgG responses specific to individual bacterial peptides. The cytometric bead array allowed for multiplexed detection of IgG, IgA, and IgM antibodies to these peptides, quantifying immune reactivity and enabling correlation with clinical disease data.

This approach revealed that nearly half of patients with CD — both adults and children — had a strong IgG immune response targeting a specific bacterial peptide in the Lachnospiraceae flagellin hinge region. This response was linked to an increased risk of disease complications over time, suggesting the peptide’s potential as a biomarker for CD severity and progression, according to the investigators.

Of note, healthy infants also exhibited an elevated IgG response to the same bacterial peptide at around 1 year of age, but this response declined as they grew older, in contrast to its persistence in CD patients. This difference points to a possible failure in immune tolerance in CD, where the natural immune response to gut bacteria in infancy may become dysregulated, Zhao and colleagues explained.

“The flagellin cytometric bead array used in this study holds potential for a simplified yet robust diagnostic and prognostic assay for Crohn’s disease,” they concluded. “Given that reactivity to the dominant flagellin epitope is strongly associated with the development of disease complications, this technique may also assist in identifying patients with Crohn’s disease who would benefit from early therapy.”

Zhao and colleagues also called for future studies to characterize the role of flagellin hinge peptide–specific IgG antibodies in CD pathogenesis, and to explore the hinge peptide as a potential therapeutic target.The study was supported by a Synergy Award from the Kenneth Rainin Foundation, a Career Development Award from the Crohn’s and Colitis Foundation, and grants from the Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor and the University of Alabama at Birmingham hold a patent on Lachnospiraceae A4 Fla2, licensed for clinical application by Prometheus Laboratories. Four study coauthors have filed a patent for the flagellin peptide cytometric bead array. One coauthor serves as the founder and chief scientific officer of ImmPrev Bio, a company developing an antigen-directed immunotherapy for Crohn’s disease.

Many patients with Crohn’s disease (CD) have a heightened immune response to flagellins expressed by commensal gut bacteria Lachnospiraceae, with seroreactivity appearing up to 5 years prior to development of Crohn’s complications, according to investigators.

These findings suggest that the flagellin cytometric bead array used in the present study could serve as a simple diagnostic and prognostic tool for patients with CD, and point to a new therapeutic target, lead author Qing Zhao, MD, PhD, of the University of Alabama at Birmingham, and colleagues reported.

Qing Zhao

Previously, Zhao and colleagues found that about 30% of patients with CD had elevated IgG responses to multiple Lachnospiraceae flagellins, and stronger reactivity was associated with higher flagellin-specific CD4+ T cells in circulation.

“In this study, we aimed to identify immunodominant B cell peptide epitopes shared among Lachnospiraceae bacterial flagellins in patients with CD and to correlate this immune reactivity with the clinical disease course,” the investigators wrote in Gastroenterology.

To this end, the investigators analyzed serum samples from adult CD patients, pediatric CD patients, and healthy infants without inflammatory bowel disease, with data derived from multiple sources. Adult patients with CD were part of a regional cohort recruited at the University of Alabama at Birmingham, while pediatric patients with CD came from the RISK Stratification Study, a multisite cohort study across the United States and Canada. Samples from healthy infants were collected from three diverse geographic locations: Uganda, Sweden, and the United States, providing a broad comparison of immune responses to Lachnospiraceae flagellin across populations.

Samples were analyzed via two main methods: a flagellin peptide microarray and a cytometric bead array. The microarray, comprising sequential Lachnospiraceae-derived peptides, enabled identification of IgG responses specific to individual bacterial peptides. The cytometric bead array allowed for multiplexed detection of IgG, IgA, and IgM antibodies to these peptides, quantifying immune reactivity and enabling correlation with clinical disease data.

This approach revealed that nearly half of patients with CD — both adults and children — had a strong IgG immune response targeting a specific bacterial peptide in the Lachnospiraceae flagellin hinge region. This response was linked to an increased risk of disease complications over time, suggesting the peptide’s potential as a biomarker for CD severity and progression, according to the investigators.

Of note, healthy infants also exhibited an elevated IgG response to the same bacterial peptide at around 1 year of age, but this response declined as they grew older, in contrast to its persistence in CD patients. This difference points to a possible failure in immune tolerance in CD, where the natural immune response to gut bacteria in infancy may become dysregulated, Zhao and colleagues explained.

“The flagellin cytometric bead array used in this study holds potential for a simplified yet robust diagnostic and prognostic assay for Crohn’s disease,” they concluded. “Given that reactivity to the dominant flagellin epitope is strongly associated with the development of disease complications, this technique may also assist in identifying patients with Crohn’s disease who would benefit from early therapy.”

Zhao and colleagues also called for future studies to characterize the role of flagellin hinge peptide–specific IgG antibodies in CD pathogenesis, and to explore the hinge peptide as a potential therapeutic target.The study was supported by a Synergy Award from the Kenneth Rainin Foundation, a Career Development Award from the Crohn’s and Colitis Foundation, and grants from the Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor and the University of Alabama at Birmingham hold a patent on Lachnospiraceae A4 Fla2, licensed for clinical application by Prometheus Laboratories. Four study coauthors have filed a patent for the flagellin peptide cytometric bead array. One coauthor serves as the founder and chief scientific officer of ImmPrev Bio, a company developing an antigen-directed immunotherapy for Crohn’s disease.

Many patients with Crohn’s disease (CD) have a heightened immune response to flagellins expressed by commensal gut bacteria Lachnospiraceae, with seroreactivity appearing up to 5 years prior to development of Crohn’s complications, according to investigators.

These findings suggest that the flagellin cytometric bead array used in the present study could serve as a simple diagnostic and prognostic tool for patients with CD, and point to a new therapeutic target, lead author Qing Zhao, MD, PhD, of the University of Alabama at Birmingham, and colleagues reported.

Qing Zhao

Previously, Zhao and colleagues found that about 30% of patients with CD had elevated IgG responses to multiple Lachnospiraceae flagellins, and stronger reactivity was associated with higher flagellin-specific CD4+ T cells in circulation.

“In this study, we aimed to identify immunodominant B cell peptide epitopes shared among Lachnospiraceae bacterial flagellins in patients with CD and to correlate this immune reactivity with the clinical disease course,” the investigators wrote in Gastroenterology.

To this end, the investigators analyzed serum samples from adult CD patients, pediatric CD patients, and healthy infants without inflammatory bowel disease, with data derived from multiple sources. Adult patients with CD were part of a regional cohort recruited at the University of Alabama at Birmingham, while pediatric patients with CD came from the RISK Stratification Study, a multisite cohort study across the United States and Canada. Samples from healthy infants were collected from three diverse geographic locations: Uganda, Sweden, and the United States, providing a broad comparison of immune responses to Lachnospiraceae flagellin across populations.

Samples were analyzed via two main methods: a flagellin peptide microarray and a cytometric bead array. The microarray, comprising sequential Lachnospiraceae-derived peptides, enabled identification of IgG responses specific to individual bacterial peptides. The cytometric bead array allowed for multiplexed detection of IgG, IgA, and IgM antibodies to these peptides, quantifying immune reactivity and enabling correlation with clinical disease data.

This approach revealed that nearly half of patients with CD — both adults and children — had a strong IgG immune response targeting a specific bacterial peptide in the Lachnospiraceae flagellin hinge region. This response was linked to an increased risk of disease complications over time, suggesting the peptide’s potential as a biomarker for CD severity and progression, according to the investigators.

Of note, healthy infants also exhibited an elevated IgG response to the same bacterial peptide at around 1 year of age, but this response declined as they grew older, in contrast to its persistence in CD patients. This difference points to a possible failure in immune tolerance in CD, where the natural immune response to gut bacteria in infancy may become dysregulated, Zhao and colleagues explained.

“The flagellin cytometric bead array used in this study holds potential for a simplified yet robust diagnostic and prognostic assay for Crohn’s disease,” they concluded. “Given that reactivity to the dominant flagellin epitope is strongly associated with the development of disease complications, this technique may also assist in identifying patients with Crohn’s disease who would benefit from early therapy.”

Zhao and colleagues also called for future studies to characterize the role of flagellin hinge peptide–specific IgG antibodies in CD pathogenesis, and to explore the hinge peptide as a potential therapeutic target.The study was supported by a Synergy Award from the Kenneth Rainin Foundation, a Career Development Award from the Crohn’s and Colitis Foundation, and grants from the Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor and the University of Alabama at Birmingham hold a patent on Lachnospiraceae A4 Fla2, licensed for clinical application by Prometheus Laboratories. Four study coauthors have filed a patent for the flagellin peptide cytometric bead array. One coauthor serves as the founder and chief scientific officer of ImmPrev Bio, a company developing an antigen-directed immunotherapy for Crohn’s disease.

VIENNA — Guselkumab has been shown to be efficacious vs placebo in patients with moderately to severely active Crohn’s disease (CD), regardless of prior biologic therapy exposure, according to a pooled analysis of the two phase 3 double-blind GALAXI 2 and 3 studies.

“We found that guselkumab was effective in both biologic-naive and biologic-inadequate subpopulations,” said coinvestigator Bruce E. Sands, MD, AGAF, gastroenterologist from Icahn School of Medicine at Mount Sinai, New York City.

These latest results add to the primary results of these studies reported earlier in 2024 that guselkumab was shown to be superior to both placebo and ustekinumab in the same patient population with moderately to severely active CD.

Sands reported the new data in a presentation at the United European Gastroenterology (UEG) Week 2024.

Guselkumab potently blocks interleukin (IL)–23 and binds to CD64, a receptor on cells that produce IL-23. The dual-acting IL-23p19 subunit inhibitor agent is currently under review by the Food and Drug Administration (FDA) for moderately to severely active CD. In September, guselkumab (Tremfya, Johnson & Johnson) was approved for use in moderately to severely active ulcerative colitis.
 

GALAXI 2 and 3 Pooled Dataset

In the two independent, identically designed GALAXI 2 and 3 studies, patients were randomized to guselkumab treatment at either 200 mg intravenous (IV) induction at weeks 0, 4, and 8, followed by 200 mg subcutaneous maintenance every 4 weeks, starting at week 12, or 200 mg IV induction at weeks 0, 4, and 8, followed by 100 mg subcutaneous maintenance every 8 weeks, starting at week 16; or to ustekinumab; or to placebo.

Participants were required to remain on their treatment of initial randomization for a long-term extension study (up to 5 years) looking at clinical, endoscopic, and safety outcomes, except for participants on placebo who were allowed to switch to ustekinumab if clinical response was not met at week 12.

Inclusion criteria for the studies comprised a Crohn’s Disease Activity Index score between 220 and 450, a mean daily stool frequency count > 3 or an abdominal pain score > 1, and a simple endoscopic score for CD score ≥ 6. Participants were also required to have shown an inadequate response or intolerance to oral corticosteroids, 6-mercaptopurine/azathioprine/methotrexate, or biologic therapies.

The pooled dataset included patients on either dose of guselkumab and patients on placebo (total n = 730). Of these, 52% of participants had shown a prior inadequate response to a biologic, 42% were biologic naive, and 6% had prior exposure to biologics but no documented failure. Patients on ustekinumab were not included in this analysis.

Almost all patients (97%) in the biologic-inadequate response group had previously received at least one anti–tumor necrosis factor agent, and around 15% had received vedolizumab. As expected, the biologic-inadequate responders were a lot sicker than the biologic-naive patients, Sands reported.

The composite co–primary endpoints for each guselkumab regimen vs placebo were clinical response at week 12 plus clinical remission at week 48, and clinical response at week 12 plus endoscopic response at week 48.

The major secondary endpoints comprised clinical remission at week 12 and endoscopic response also at week 12.
 

Short- and Long-Term Endpoints in Both Subgroups

In the biologic-naive subgroup, 54.7% of patients receiving the 200-mg dose regimen of guselkumab and 51.7% of those receiving the 100-mg dose regimen showed a clinical response at week 12 plus clinical remission at week 48, compared with 11.5% in the placebo group (P < .001 for both compared with placebo).

In the biologic-inadequate response group, 49.7% of those receiving the 200-mg dose regimen of guselkumab and 45.8% on the 100-mg dose regimen reached the composite endpoint, compared with the placebo response of 12.8% (P < .001 for both compared with placebo).

“You can see a slight decrease in response in the biologic-inadequate responders, but on the whole, the confidence intervals are highly overlapping,” said Sands.

Turning to major secondary endpoints at week 12, clinical remission was reached by 49.6% of the biologic-naive group on the 200-mg guselkumab regimen vs 16.4% on placebo, and by 46.0% of the biologic-inadequate group on the 200-mg regimen vs 19.2% on placebo (P < .001 for both subgroups). Endoscopic response was achieved by 46.3% of patients in the biologic-naive group and 29.0% in the biologic-inadequate group on the 200-mg regimen vs 18.0% and 6.4%, respectively, on placebo (P < .001 for both subgroups).

Sands noted that the drug has an excellent safety profile.

“These data show the drug works for naive patients who have failed conventional therapies, as well as for those who have failed biologic therapies,” so it could be used as a first- or second-line biologic, he added.

Sands reported potential conflicts of interest with AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Microbiotica, Mobius Care, Morphic Therapeutic, MRM Health, Pfizer, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Reistone Biopharma, Sun Pharma, Surrozen, Target RWE, Takeda, Teva, Theravance Biopharma, TLL Pharmaceutical, Tr1X, UNION Therapeutics, and Ventyx Biosciences.

A version of this article appeared on Medscape.com.

VIENNA — Guselkumab has been shown to be efficacious vs placebo in patients with moderately to severely active Crohn’s disease (CD), regardless of prior biologic therapy exposure, according to a pooled analysis of the two phase 3 double-blind GALAXI 2 and 3 studies.

“We found that guselkumab was effective in both biologic-naive and biologic-inadequate subpopulations,” said coinvestigator Bruce E. Sands, MD, AGAF, gastroenterologist from Icahn School of Medicine at Mount Sinai, New York City.

These latest results add to the primary results of these studies reported earlier in 2024 that guselkumab was shown to be superior to both placebo and ustekinumab in the same patient population with moderately to severely active CD.

Sands reported the new data in a presentation at the United European Gastroenterology (UEG) Week 2024.

Guselkumab potently blocks interleukin (IL)–23 and binds to CD64, a receptor on cells that produce IL-23. The dual-acting IL-23p19 subunit inhibitor agent is currently under review by the Food and Drug Administration (FDA) for moderately to severely active CD. In September, guselkumab (Tremfya, Johnson & Johnson) was approved for use in moderately to severely active ulcerative colitis.
 

GALAXI 2 and 3 Pooled Dataset

In the two independent, identically designed GALAXI 2 and 3 studies, patients were randomized to guselkumab treatment at either 200 mg intravenous (IV) induction at weeks 0, 4, and 8, followed by 200 mg subcutaneous maintenance every 4 weeks, starting at week 12, or 200 mg IV induction at weeks 0, 4, and 8, followed by 100 mg subcutaneous maintenance every 8 weeks, starting at week 16; or to ustekinumab; or to placebo.

Participants were required to remain on their treatment of initial randomization for a long-term extension study (up to 5 years) looking at clinical, endoscopic, and safety outcomes, except for participants on placebo who were allowed to switch to ustekinumab if clinical response was not met at week 12.

Inclusion criteria for the studies comprised a Crohn’s Disease Activity Index score between 220 and 450, a mean daily stool frequency count > 3 or an abdominal pain score > 1, and a simple endoscopic score for CD score ≥ 6. Participants were also required to have shown an inadequate response or intolerance to oral corticosteroids, 6-mercaptopurine/azathioprine/methotrexate, or biologic therapies.

The pooled dataset included patients on either dose of guselkumab and patients on placebo (total n = 730). Of these, 52% of participants had shown a prior inadequate response to a biologic, 42% were biologic naive, and 6% had prior exposure to biologics but no documented failure. Patients on ustekinumab were not included in this analysis.

Almost all patients (97%) in the biologic-inadequate response group had previously received at least one anti–tumor necrosis factor agent, and around 15% had received vedolizumab. As expected, the biologic-inadequate responders were a lot sicker than the biologic-naive patients, Sands reported.

The composite co–primary endpoints for each guselkumab regimen vs placebo were clinical response at week 12 plus clinical remission at week 48, and clinical response at week 12 plus endoscopic response at week 48.

The major secondary endpoints comprised clinical remission at week 12 and endoscopic response also at week 12.
 

Short- and Long-Term Endpoints in Both Subgroups

In the biologic-naive subgroup, 54.7% of patients receiving the 200-mg dose regimen of guselkumab and 51.7% of those receiving the 100-mg dose regimen showed a clinical response at week 12 plus clinical remission at week 48, compared with 11.5% in the placebo group (P < .001 for both compared with placebo).

In the biologic-inadequate response group, 49.7% of those receiving the 200-mg dose regimen of guselkumab and 45.8% on the 100-mg dose regimen reached the composite endpoint, compared with the placebo response of 12.8% (P < .001 for both compared with placebo).

“You can see a slight decrease in response in the biologic-inadequate responders, but on the whole, the confidence intervals are highly overlapping,” said Sands.

Turning to major secondary endpoints at week 12, clinical remission was reached by 49.6% of the biologic-naive group on the 200-mg guselkumab regimen vs 16.4% on placebo, and by 46.0% of the biologic-inadequate group on the 200-mg regimen vs 19.2% on placebo (P < .001 for both subgroups). Endoscopic response was achieved by 46.3% of patients in the biologic-naive group and 29.0% in the biologic-inadequate group on the 200-mg regimen vs 18.0% and 6.4%, respectively, on placebo (P < .001 for both subgroups).

Sands noted that the drug has an excellent safety profile.

“These data show the drug works for naive patients who have failed conventional therapies, as well as for those who have failed biologic therapies,” so it could be used as a first- or second-line biologic, he added.

Sands reported potential conflicts of interest with AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Microbiotica, Mobius Care, Morphic Therapeutic, MRM Health, Pfizer, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Reistone Biopharma, Sun Pharma, Surrozen, Target RWE, Takeda, Teva, Theravance Biopharma, TLL Pharmaceutical, Tr1X, UNION Therapeutics, and Ventyx Biosciences.

A version of this article appeared on Medscape.com.

VIENNA — Guselkumab has been shown to be efficacious vs placebo in patients with moderately to severely active Crohn’s disease (CD), regardless of prior biologic therapy exposure, according to a pooled analysis of the two phase 3 double-blind GALAXI 2 and 3 studies.

“We found that guselkumab was effective in both biologic-naive and biologic-inadequate subpopulations,” said coinvestigator Bruce E. Sands, MD, AGAF, gastroenterologist from Icahn School of Medicine at Mount Sinai, New York City.

These latest results add to the primary results of these studies reported earlier in 2024 that guselkumab was shown to be superior to both placebo and ustekinumab in the same patient population with moderately to severely active CD.

Sands reported the new data in a presentation at the United European Gastroenterology (UEG) Week 2024.

Guselkumab potently blocks interleukin (IL)–23 and binds to CD64, a receptor on cells that produce IL-23. The dual-acting IL-23p19 subunit inhibitor agent is currently under review by the Food and Drug Administration (FDA) for moderately to severely active CD. In September, guselkumab (Tremfya, Johnson & Johnson) was approved for use in moderately to severely active ulcerative colitis.
 

GALAXI 2 and 3 Pooled Dataset

In the two independent, identically designed GALAXI 2 and 3 studies, patients were randomized to guselkumab treatment at either 200 mg intravenous (IV) induction at weeks 0, 4, and 8, followed by 200 mg subcutaneous maintenance every 4 weeks, starting at week 12, or 200 mg IV induction at weeks 0, 4, and 8, followed by 100 mg subcutaneous maintenance every 8 weeks, starting at week 16; or to ustekinumab; or to placebo.

Participants were required to remain on their treatment of initial randomization for a long-term extension study (up to 5 years) looking at clinical, endoscopic, and safety outcomes, except for participants on placebo who were allowed to switch to ustekinumab if clinical response was not met at week 12.

Inclusion criteria for the studies comprised a Crohn’s Disease Activity Index score between 220 and 450, a mean daily stool frequency count > 3 or an abdominal pain score > 1, and a simple endoscopic score for CD score ≥ 6. Participants were also required to have shown an inadequate response or intolerance to oral corticosteroids, 6-mercaptopurine/azathioprine/methotrexate, or biologic therapies.

The pooled dataset included patients on either dose of guselkumab and patients on placebo (total n = 730). Of these, 52% of participants had shown a prior inadequate response to a biologic, 42% were biologic naive, and 6% had prior exposure to biologics but no documented failure. Patients on ustekinumab were not included in this analysis.

Almost all patients (97%) in the biologic-inadequate response group had previously received at least one anti–tumor necrosis factor agent, and around 15% had received vedolizumab. As expected, the biologic-inadequate responders were a lot sicker than the biologic-naive patients, Sands reported.

The composite co–primary endpoints for each guselkumab regimen vs placebo were clinical response at week 12 plus clinical remission at week 48, and clinical response at week 12 plus endoscopic response at week 48.

The major secondary endpoints comprised clinical remission at week 12 and endoscopic response also at week 12.
 

Short- and Long-Term Endpoints in Both Subgroups

In the biologic-naive subgroup, 54.7% of patients receiving the 200-mg dose regimen of guselkumab and 51.7% of those receiving the 100-mg dose regimen showed a clinical response at week 12 plus clinical remission at week 48, compared with 11.5% in the placebo group (P < .001 for both compared with placebo).

In the biologic-inadequate response group, 49.7% of those receiving the 200-mg dose regimen of guselkumab and 45.8% on the 100-mg dose regimen reached the composite endpoint, compared with the placebo response of 12.8% (P < .001 for both compared with placebo).

“You can see a slight decrease in response in the biologic-inadequate responders, but on the whole, the confidence intervals are highly overlapping,” said Sands.

Turning to major secondary endpoints at week 12, clinical remission was reached by 49.6% of the biologic-naive group on the 200-mg guselkumab regimen vs 16.4% on placebo, and by 46.0% of the biologic-inadequate group on the 200-mg regimen vs 19.2% on placebo (P < .001 for both subgroups). Endoscopic response was achieved by 46.3% of patients in the biologic-naive group and 29.0% in the biologic-inadequate group on the 200-mg regimen vs 18.0% and 6.4%, respectively, on placebo (P < .001 for both subgroups).

Sands noted that the drug has an excellent safety profile.

“These data show the drug works for naive patients who have failed conventional therapies, as well as for those who have failed biologic therapies,” so it could be used as a first- or second-line biologic, he added.

Sands reported potential conflicts of interest with AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Microbiotica, Mobius Care, Morphic Therapeutic, MRM Health, Pfizer, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Reistone Biopharma, Sun Pharma, Surrozen, Target RWE, Takeda, Teva, Theravance Biopharma, TLL Pharmaceutical, Tr1X, UNION Therapeutics, and Ventyx Biosciences.

A version of this article appeared on Medscape.com.