The monoclonal antibody therapy, developed at Cedars-Sinai, is called tulisokibart. The experimental treatment also recently showed promising results in a separate Phase II study in treating ulcerative colitis.

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases that affect the digestive tract and impact approximately 1% of the U.S. population. There is no cure, and response to current treatments is variable.

“These findings, together with the recently published positive results in ulcerative colitis, strongly support this approach as a completely new therapy for people with inflammatory bowel diseases,” said clinician-scientist and geneticist Dermot McGovern, MD, PhD, director of Translational Research in the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai and senior author of the study.

McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and the director of Precision Health at Cedars-Sinai, together with colleagues at Cedars-Sinai, helped develop tulisokibart.

“This mechanism was identified through both genetic and immunological work, the vast majority of which came from the inflammatory bowel diseases group at Cedars-Sinai,” he said.

In the Phase II-A trial, called APOLLO-CD, 55 adults with Crohn’s disease received tulisokibart in varying doses over 12 weeks. The results showed that nearly 50% of patients achieved clinical remission, compared to about 16% in historical studies.

The investigational therapy also may target fibrosis—a process that leads to narrowing in the gut and often requires surgery. Fibrosis is a major problem in Crohn’s disease and other diseases and cannot currently be prevented or reversed.

Stephan Targan, MD, former executive director of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai and a study author, said the therapy’s ability to target fibrosis has broad implications.

“Fibrosis is a major issue in many chronic medical conditions and can cause serious complications,” said Targan, the Feintech Family Chair in Inflammatory Bowel Disease. “So, there is great interest in seeing whether the drug we developed may have benefits even beyond inflammatory bowel disease.”

McGovern added that data from the APOLLO-CD study indicated that response to tulisokibart was rapid—patients’ inflammatory markers dropped within a week of beginning the therapy.

“This is promising news, because in addition to getting people well and helping them stay in remission, we want to help them get well as quickly as possible,” he said.

Also promising: Tulisokibart was developed with a diagnostic tool to help identify people who are most likely to benefit from the drug, which would introduce precision medicine to inflammatory bowel disease care.

McGovern, Targan and a team of researchers at Cedars-Sinai, including Janine Bilsborough, PhD, director of Inflammatory Bowel Disease Drug Discovery and Development, have long studied the role of TL1A in contributing to inflammation and fibrosis in inflammatory bowel disease patients. 

Bilsborough, also a study author, said, “We’ve dedicated our careers to pursuing innovative therapies for people affected by inflammatory bowel disease. It’s very fulfilling to see scientific progress that could help Crohn’s and ulcerative colitis patients reach lasting remission and live a life without limitation.”

Further studies are in progress in larger groups of people with both Crohn’s disease and ulcerative colitis: The double-blind, placebo-controlled Phase III trials will determine the effectiveness and safety of tulisokibart as a treatment to bring about and maintain remission in people with IBD.

Other authors involved in the study include Prof. Brian G. Feagan, MD; Prof. Bruce E. Sands, MD; Prof. Corey A. Siegel, MD; Prof. Marla C. Dubinsky, MD; Randy S. Longman, MD, PhD; João Sabino, MD; Olivier Laurent, PhD; Allison Luo, MD; Jiandong Lu, PhD; Deanna D. Nguyen, MD; Ernesto J. Muñoz-Elias, PhD; Heather Llewellyn, PhD; Tony (Yong) Wang, PhD; InSock Jang, PhD; Ron Marchelletta, PhD; Fadi Towfic, PhD; Mark Yen, MD; Jaclyn K. Anderson, DO; Aaron DuVall, MD; Prof. Jaroslaw Kierkus, MD; Prof. Marek Woynarowski, MD; and Houssam Al Kharrat, MD.

This research was supported by Prometheus Biosciences, a subsidiary of Merck & Co.

Conflicts of Interest: McGovern, Targan and Bilsborough have consulted for Merck, Prometheus Biosciences (acquired by MERCK) and Prometheus Labs. Cedars-Sinai has a financial interest due to the right to receive future royalties for patient rights from MERCK, Inc.

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Results from the multicenter Phase II study, ARTEMIS-UC, were published in The New England Journal of Medicine.

Ulcerative colitis is a type of inflammatory bowel disease (IBD) that damages the digestive tract, causing stomach cramping, diarrhea, weight loss and rectal bleeding. It affects as many as 900,000 people in the U.S., and current treatments are often only minimally effective.

“Findings from this study are poised to have a remarkable impact on treatment for ulcerative colitis and IBD overall,” said study senior author and IBD research pioneer Stephan Targan, MD, the Feintech Family Chair in Inflammatory Bowel Disease and executive director of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai. “The investigational therapy was generated based on the concept of precision medicine; it shows promise as being both anti-inflammatory and anti-fibrotic; it represents a potential turning point in drug development and discovery; and it could change how this complex disease is treated in the future.”

The study evaluated a therapy developed by Cedars-Sinai clinician-scientists called tulisokibart (previously PRA023)—a man-made monoclonal antibody that acts like endogenous antibodies. It is designed to target and block a protein called TL1A, which can contribute to the severity of ulcerative colitis. The antibody reduces inflammation and targets fibrosis, which causes many of the complications and severity of disease.

“Unlike other IBD treatments that can exacerbate inflammation or suppress the body’s natural anti-inflammatory responses, our findings suggest that tulisokibart modulates inflammation and the body's anti-inflammatory mechanisms,” Targan said. “This dual action could lead to more balanced and effective management of ulcerative colitis.”

Notably, the role of TL1A as a master regulator of inflammation was discovered by Targan and collaborators at Cedars-Sinai. In groundbreaking work spanning two decades, the researchers found that while TL1A protects against invading pathogens, at high levels it also contributes to inflammation and fibrosis in IBD.  

ARTEMIS-UC was a 12-week study involving 178 adults from 14 countries. It also included a genetic-based companion diagnostic test to help predict response to the therapy.

A Phase III study will further examine safety and test effectiveness of tulisokibart in patients who take it longer than 12 weeks.

Clinician-scientist and geneticist Dermot McGovern, MD, PhD, director of Translational Research in the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai and one of the study authors, has focused his career on identifying genetic variants associated with ulcerative colitis and other autoimmune diseases, exploring drug targets and working to revolutionize treatment through a precision medicine approach.

Nearly 20 years ago at Oxford University, McGovern and colleagues, in the first-ever genome-wide association study in IBD, identified that a variation in the TNF superfamily 15 (TNFSF15) gene was associated with developing both ulcerative colitis and Crohn’s disease. The protein TL1A, simultaneously being studied by Targan at Cedars-Sinai, is encoded by TNFSF15. McGovern left Oxford to collaborate with Targan and team at Cedars-Sinai in the effort to bring scientific breakthroughs to IBD.

“Findings from the ARTEMIS-UC study exemplify how combining genetics and biology can transform IBD care,” said McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and the director of Precision Health at Cedars-Sinai.

McGovern, who was recently awarded the prestigious Sherman Prize for his pioneering work in advancing understanding of the genetic architecture of IBD in diverse populations, says the uniqueness of this target and the way tulisokibart was designed to interact with that target represent significant advancements in how clinicians approach IBD treatment.

“Previously we have only been able to prescribe a medication to a patient that we think will work well, but going forward we could imagine telling the patient, ‘Actually, the genetic test suggests that you would be more likely to respond to this therapy,’” McGovern said.

Targan and McGovern also noted that ARTEMIS-UC involved multiple countries and diverse populations, reflecting the global nature of IBD. The F. Widjaja Inflammatory Bowel Disease Institute has invested significant resources in extending genetic research in IBD to diverse populations.

“It’s taken a village—supported by Cedars-Sinai’s integrated science culture—to reach this point,” said Targan, a 2017 recipient of the Sherman Prize. “We’ve devoted our careers to getting better treatments to IBD patients, and now we’re closer than ever to helping all patients with ulcerative colitis get their disease into remission so they can get back to enjoying life.”

Other authors involved in the study include Bruce E. Sands, MD; Brian G. Feagan, MD; Laurent Peyrin-Biroulet, MD, PhD; Silvio Danese, MD; David T. Rubin, MD; Olivier Laurent, PhD; Allison Luo, MD; Deanna D. Nguyen, MD; Jiandong Lu, PhD; Mark Yen, MD; Jaroslaw Leszczyszyn, MD, PhD; Radosław Kempiński, MD, PhD; Christopher Ma, MD; and Timothy E. Ritter, MD.  

This research was supported by Prometheus Biosciences, a subsidiary of MERCK.

Conflict of Interest: Targan and McGovern have consulted for MERCK, Prometheus Biosciences (acquired by MERCK) and Prometheus Labs.

Read more on the Cedars-Sinai Blog: Is It IBS or IBD?

McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and director of Precision Health at Cedars-Sinai, is one of two 2024 Sherman Prize recipients. The Prize, established by the Bruce and Cynthia Sherman Charitable Foundation, recognizes visionary clinicians, surgeons, researchers and academics who have made exceptional contributions in transforming IBD research and improving patient care.

“Receiving the Sherman Prize is an incredible honor,” McGovern said. “To be listed alongside previous awardees, people I greatly admire, is very special to me. Much of the credit for this honor goes to my outstanding team—I’m very lucky to be working with such smart and dedicated people to help improve the lives of those with IBD.”

Over the past 15 years, McGovern has been a key driver in many pivotal IBD genetic studies.  

“Dr. McGovern is a brilliant researcher who is working to elucidate the complexities of IBD to meaningfully improve the lives of people around the world who suffer from the disorder,” said Shlomo Melmed, MB, ChB, executive vice president of Medicine and Health Sciences, dean of the Medical Faculty and distinguished professor of Medicine at Cedars-Sinai. “Our institution is an international leader in IBD research and treatment, largely due to our talented faculty—exemplified by Dr. McGovern’s visionary leadership and dedication. Heartiest congratulations on his receipt of the distinguished Sherman Prize.”

McGovern began his career at Oxford University. He remembers a patient asking how he knew the treatment being prescribed was the right one. That question sparked McGovern’s yearslong quest to identify drug targets and associated biomarkers so he could match each patient with the most effective medicine.

While at Oxford, McGovern and collaborators identified a gene involved in IBD pathophysiology called TNF Superfamily 15. At the same time, Stephan Targan, MD, the Feintech Family Chair in Inflammatory Bowel Disease and director of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai—also a past recipient of the Sherman Prize—had discovered and was studying a protein encoded by the TL1A  gene.

After a chance meeting between the two, McGovern joined Targan and team at Cedars-Sinai.

Today, McGovern leads his own lab, the Translational Genomics Group, at Cedars-Sinai. After 20 years of collaboration with Targan on an anti-TL1A therapy, McGovern’s dream of delivering personalized medicine to IBD patients is gaining momentum. A new investigative treatment that differs from existing therapies while also addressing fibrosis (excessive scar tissue) in Crohn’s disease and ulcerative colitis—forms of IBD—is being studied in Phase III clinical trials. And, for the first time in IBD care, the disease has a companion diagnostic tool, which matches a patient to a specific medication.

If the therapy is approved, it will be the first approved personalized medicine for people with IBD.

McGovern says collaborations enable advances for patients. Now, he is working on other game-changing projects in his lab—such as improving the IBD classification system—with an eye toward broad global application.

He believes that the most pressing challenge for the field is bringing IBD advances to all parts of society. To that end, he has led the effort to extend largely European ancestry studies and advances to African American, Hispanic/Latino and East Asian populations. He also recently created a consortium to conduct genetic studies in sub-Saharan Africa.

“The Sherman Prize will allow me to enhance our collaborations across sub-Saharan Africa so that we can study the evolution of IBD in African populations,” McGovern said.

Improving patients’ quality of life, regardless of where they live, their ethnicity, social status or gender, inspires McGovern.

“A fundamental aspect of our work to advance our understanding of the causes of Crohn’s disease and ulcerative colitis and develop strategies to translate these discoveries into the clinic is our philosophy that these advances should be available to all populations,” McGovern said. “This has motivated us to invest resources and pioneer studies in diverse populations and ensure we are addressing disparities in research and clinical care.”

Read more from the Cedars-Sinai Blog: A Good Grip on Crohn’s Disease

In a new study published in the journal IBD, investigators used a novel statistical approach to identify three new regions of the genome associated with developing IBD. They also discovered other areas that were specifically associated with developing IBD in only one sex.

“We observed sex differences in the prevalence of specific clinical characteristics. Females were more likely to have Crohn’s disease affecting only the colon. In males, on the other hand, we saw a higher risk for perianal complications in Crohn’s disease as well as more extensive disease in ulcerative colitis,” said Talin Haritunians, PhD, the senior author of the study and a research associate professor of Medicine at Cedars-Sinai.

Haritunians, a research scientist in the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, noted the study was the first international investigation into sex-stratified genetic associations in IBD containing more than 70,000 subjects.

“Most genetic association studies analyze males and females together. Our study highlighted the need to move beyond the conventional sex-combined analyses in order to fully appreciate the complex genetic architecture of IBD,” said Dermot McGovern, MD, PhD, a co-author of the study and director of Translational Research in the Inflammatory Bowel and Immunobiology Research Institute.

The sex-dimorphic analytic approach used by the investigators identified associations in three new genetic loci (chr9q22, CARMIL1 and UBASH3A) as well as distinct sex-specific patterns of association for several variants, including on chromosome-2 and in the major histocompatibility complex on chromosome-6.

“This is of particular interest given the well-established role of the major histocompatibility complex and HLA locus in IBD and immune-mediated diseases, in general,” said Haritunians.

The investigators say they are continuing the collaboration with the IBD international consortium and are currently expanding the study to include a cohort of more than 100,000 people.

“We plan to also develop sex-specific IBD genetic risk scores to better evaluate the genetic ‘burden’ in males and females,” said Haritunians.

This novel approach to genetic research of sex differences in IBD will also be used in Cedars-Sinai’s large-scale studies of the disease in Black and Hispanic populations, according to the scientists.

“These types of studies are critical if we are to build on our previous success employing genetics to develop new, personalized therapeutics for IBD and using them to treat those most likely to respond well. In other words, getting the right therapy to the right patient at the right time,” said McGovern, who holds the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics at Cedars-Sinai.

Funding: This work was supported in part by the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (grants P01 DK046763 and U01 DK062413), and The Leona M. and Harry B. Helmsley Charitable Trust.

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