TL1A Inhibitors Could Usher in New Era for IBD Treatment

26 Feb 2024
www.biospace.com
Phase 2Clinical ResultAcquisitionPhase 3Immunotherapy
Pictured: A person with an irritated gut/Taylor Tieden for BioSpace Twenty-two years ago, a molecule called TL1A was first discovered and isolated. Today, after two decades of research, therapeutics to calm its activity may usher in a new era for the treatment of immune-mediated diseases like inflammatory bowel disease, psoriasis and rheumatoid arthritis. TL1A (tumor necrosis factor-like cytokine 1A) is part of the tumor necrosis factor (TNF) superfamily, a group of cell-signaling molecules that have potent effects on immune function and which have led to anti-TNF antibodies such as AbbVie’s blockbuster Humira (adalimumab). Against this backdrop, two monoclonal antibodies targeting TL1A spurred major biopharma acquisitions in 2023. In June, Merck completed the purchase of Prometheus Biosciences for $10.8 billion. The company’s lead asset, PRA-023—now MK-7240—has shown clinical evidence of “best-in-class” potential for treating inflammation and scarring in the inflammatory bowel diseases (IBD) ulcerative colitis and Crohn’s disease, Nature reported. Then in October, Roche paid $7.1 billion for Roivant subsidiary Televant Holdings and its anti-TL1A antibody RVT-3101, also for IBD. That same month, Sanofi and Teva Pharmaceuticals announced a collaboration worth a potential $1.5 billion to co-develop TEV-’574, a TL1A inhibitor currently in Phase IIb clinical trials for IBD. Stephan Targan, executive director of the F. Widjaja Inflammatory Bowel Institute of Cedars-Sinai, Los Angeles, and colleagues carried out much of the research into TL1A and developed the antibody Prometheus purchased. After giving the keynote presentation about TL1A at the Crohn’s & Colitis Congress earlier this month, Targan told BioSpace, “I have never had an audience response like that. There’s a big buzz about this in our field.” What’s All the Excitement About? In an April 2023 note shared with BioSpace, Jefferies analyst Michael Yee wrote that there is a “high unmet need” in IBD. Current treatment options are limited and with modest benefit, Yee explained. Driving part of the excitement around TL1A inhibitors is the hope that they can break the “efficacy ceiling that we see even with the best drugs out there,” Aileen Pangan, a rheumatologist and therapeutic area head of immunology clinical research at Merck, told BioSpace. “We are not getting the remission rates we’d like. And even after remission, there is a considerable loss of response over time, requiring patients to switch to another drug. . . . Some patients may have to try two or three different drugs before they find one that works. We are simply not where we want to be.” In December 2022, Prometheus announced positive results from two 12-week Phase IIa studies of PRA-023, ARTEMIS-UC and APOLLO-CD, in patients with moderate to severe ulcerative colitis and Crohn’s disease who had failed other therapies. In the ARTEMIS study, 26.5% of patients reached the primary endpoint of clinical remission compared to 1.5% of those on placebo. And in APOLLO-CD, a 49.1% clinical remission rate was achieved, compared with a 16% historical placebo rate. Targan called the results “huge,” highlighting the durability of the treatment as a significant improvement over existing treatments. “The therapeutics available today might offer a 20% increase [in remission] over placebo over a 12-week trial, but at the end of a year, only 40% are maintained. That means, of the entire population of Crohn’s sufferers, a given biologic may offer an 8% remission.” But with Merck’s TL1A inhibitor, he said, “Initial remission rates may be over 50% and durability over time could be as high as 90%,” for an overall remission rate of 45%. “That’s never been seen before.” Similarly, Roche’s RVT-3101 showed positive results in the Phase IIb TUSCANY-2 study in moderate-to-severe ulcerative colitis. The results, released in June 2023, led to clinical remission in 36% of patients after 56 weeks of treatment, with endoscopic improvement reaching 50%. Enabling Targeted Treatment These new antibodies could perform very well in targeted patient populations, Targan said, thanks to a novel diagnostic tool that uses genetic testing as well as other genomic markers to inform physicians about how well the molecule will work in a specific patient. “Right now, physicians and patients have to go through trial-and-error steps before they find the right drug,” he explained. But certain genetic variations, called risk alleles, increase the likelihood the patient will respond to the drug. “Risk alleles are very significantly associated with increased expression of TL1A over time,” Targan said. “I predict the Phase III trials will show people doing very well if their diagnostic tests show a strong genetic association with the presence of the TL1A molecule.” He added that he believes the new companion diagnostic will also identify those patients who will see a durable response. He compared this companion diagnostic, which is yet to be approved by the FDA, to those used in oncology, where “to find out what you need to treat a tumor, you evaluate the characteristics of the tumor.” Pangan said the power of this diagnostic was evident in Prometheus’ Phase II trial. In the ARTEMIS-UC study, all trial participants were tested with the complementary diagnostic and stratified according to the result. Of the 135 enrolled patients, 32 were positive for a SNP-based signature that includes the TL1A risk alleles (16 were on placebo and 16 received the antibody), and a greater proportion who were positive for risk alleles or other biomarkers achieved remission with the antibody compared to those who were negative, Pangan shared. Merck has embarked on a global Phase III trial that will enroll over 1,000 patients. “If we can identify the population that is most likely to get into remission with this antibody, we can help patients and physicians everywhere,” she said. Biotech entrepreneur Andrew Pannu told BioSpace that the biomarker-driven approach being taken by both Merck and Roche reflects a belief that these biomarkers will credibly predict responders and that this will help with reimbursement efforts in a “fairly crowded market.” Beyond IBD TL1A inhibitors also hold potential in other autoimmune diseases. In a 2022 summary review article published in Frontiers, TL1A was found to be was abnormally expressed in IBD, as well as in rheumatoid arthritis, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus and ankylosing spondylitis. And, as the molecule binds to activated fibroblasts, targeting TL1A might offer another novel benefit: the reversal of fibrosis and scarring. “In a lot of our work in animals, we found that, lo and behold, TL1A inhibitors could reverse scarring,” Targan said. That could have applications for strictures in Crohn’s disease—although anti-TL1A drugs can’t ‘fix’ already formed strictures, they might help keep them from forming or re-forming after surgical intervention, he said. TL1A inhibitors might also be helpful in other diseases where fibrosis and scarring are significant such as systemic sclerosis and primary sclerosing cholangitis, Targan noted. And Merck is currently conducting a Phase II study looking at fibrosis in systemic sclerosis associated with interstitial lung disease. Lee also noted the potential durability and success of the class. “Data could get even better over time given the anti-fibrotic potential of TL1A inhibitors,” he wrote in the April 2023 investor note. “Of course, I’m prejudiced,” Targan said, “but I’ve been around a long time. I’ve been working on inflammatory bowel disease for half a century now, and I do believe TL1A inhibitors will be transformational for many immune-mediated diseases.” Jill Neimark is a freelance science writer based in Macon, Georgia. Reach her at jillneimark.com.
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