Targeted drug therapy promises relief of ulcerative colitis

An international, placebo-controlled trial led by Cedars-Sinai suggests that a targeted drug therapy developed by researchers at Cedars-Sinai is safe and effective in helping people with moderate to severe ulcerative colitis achieve clinical remission.

The results of the multicenter phase II study ARTEMIS-UC were published in The New England Journal of Medicine.

Ulcerative colitis is an inflammatory bowel disease (IBD) that damages the digestive tract, causing stomach cramps, diarrhea, weight loss, and rectal bleeding. It affects up to 900,000 people in the United States, and current treatments are often only minimally effective.

The results of this study are expected to have a significant impact on the treatment of ulcerative colitis and IBD overall. The experimental therapy was developed based on the concept of precision medicine; it shows promise as it has both anti-inflammatory and anti-fibrotic effects; it represents a potential turning point in drug development and discovery and could transform the treatment of this complex disease in the future.”

Stephan Targan, MD, lead author of the study and pioneer of IBD research, Feintech Family Chair in Inflammatory Bowel Disease and Executive Director of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai

The study examined a therapy developed by Cedars-Sinai clinicians called Tulisokibart (formerly PRA023) – a man-made monoclonal antibody that acts like endogenous antibodies. It aims to attack and block a protein called TL1A, which may contribute to the severity of ulcerative colitis. The antibody reduces inflammation and targets the fibrosis that causes many of the complications and severity of the disease.

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

Most notably, Targan and his colleagues at Cedars-Sinai discovered the role of TL1A as a master regulator of inflammation. 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 genetically based companion diagnostic test to predict response to therapy.

A Phase III trial will further evaluate the safety and efficacy of tulisokibart in patients taking it for longer than 12 weeks.

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

Nearly 20 years ago, in the first genome-wide association study of IBD, McGovern and colleagues at the University of Oxford found that a variation in the TNF superfamily 15 gene (TNFSF15) was associated with the development of both ulcerative colitis and Crohn's disease. The protein TL1A, which Targan was studying at the same time at Cedars-Sinai, is encoded by TNFSF15. McGovern left Oxford to work with Targan and his team at Cedars-Sinai to make scientific breakthroughs in IBD.

“The findings from the ARTEMIS-UC trial illustrate how combining genetics and biology can transform the treatment of IBD,” said McGovern, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and 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 in which Tulisokibart is designed to interact with it represent significant advances in how clinicians approach the treatment of IBD.

“Until now, we could only prescribe a patient medication that we think will work well, but in the future we could imagine telling the patient: “In fact, the genetic test suggests that you are more likely to The therapy,'” McGovern said.

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

“It has taken a village – supported by Cedars-Sinai's integrated science culture – to get to this point,” said Targan, who received the Sherman Prize in 2017. “We have dedicated our careers to developing better treatments for IBD patients, and we are now closer than ever to helping all patients with ulcerative colitis put their disease into remission so they can enjoy life again.”

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; RadosÂaw KempiNSki, MD, PhD; Christopher Ma, MD; and Timothy E. Ritter, MD.

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