Intestinal fibrosis, one of the most stubborn challenges in managing inflammatory bowel disease, may soon meet its match. A raft of research into intestinal antifibrotics, the launch of a global consortium tackling the problem, and the first clinical trial of a novel antifibrotic are some of many causes for optimism, experts say.
“There’s a lot happening now, and the future is bright for the treatment and prevention of fibrosis,” said Florian Rieder, MD, who heads a lab at the Lerner Research Institute at Cleveland Clinic in Ohio.
An estimated 30% of patients with Crohn’s disease and 5% of those with ulcerative colitis develop symptomatic fibrostenosis, often requiring hospitalization and surgery, which itself leads to a cycle of strictures and surgeries.
However, research presented at the 2021 virtual Digestive Disease Week, and several other developments are providing hope for patients at risk for intestinal fibrosis.
In one study presented at DDW (abstract Su479), Dr. Rieder and his colleagues examined the effects of recombinant human milk fat globule-EGF factor 8 (rhMFGE8), which has antifibrotic effects in the liver and heart, on fibrosing and nonfibrosing intestinal tissues. They used mesenchymal cells taken from patients with Crohn’s disease and ulcerative colitis, as well as from healthy controls.
After exposing the extracellular matrix (ECM) that promotes fibrosis—and more specifically the human intestinal myofibroblasts (HIMFs) that make up the ECM—to rhMFGE8, they found that expression of MFGE8 in fibrotic Crohn’s disease tissue was significantly elevated, but it did not lead to an antifibrotic effect.
“This suggests that in Crohn’s disease, sensitizing HIMF to the effects of MFGE8 may represent a novel approach to the management of fibrostenotic Crohn’s disease,” Dr. Rieder told Gastroenterology & Endoscopy News.
Dr. Rieder and his colleagues are conducting several other projects, such as examining the effects of blocking the fibroblast surface molecules that allow these cells to bind with each other to form fibrotic tissue. They’re also investigating the interaction between strictures and “creeping fat,” the mesenteric fat that surrounds 80% of intestinal strictures in patients with Crohn’s disease.
Several other studies presented at DDW are also encouraging, despite still being in the lab phase. Hon Wai Koon, PhD, an associate professor in the UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, in Los Angeles, and his colleagues found that a formulation of elafin, a human protease inhibitor and antimicrobial peptide, suppressed collagen synthesis in intestinal fibroblasts and reversed intestinal fibrosis in mouse models (abstract Su478).
“An orally active elafin formulation is harmless to the body and can be a new therapeutic agent against intestinal strictures, and we are looking for partners to conduct clinical trials,” Dr. Koon said.
In another study (abstract 383), Dr. Koon and his colleagues found that giving the metabolite sphingosine to mice with induced intestinal fibrosis inhibited intestinal collagen expression and again resulted in antifibrotic effects.
“Sphingosine is an edible metabolite that can be readily developed into a new drug therapy with minimal safety concerns,” Dr. Koon said.
Antifibrotics that target intestinal tissue specifically overcome the concern that this class of agents could systemically impair wound healing following injury or worsen inflammation by preventing ulcer healing, according to Peter Higgins, MD, PhD, the director of the IBD program at the University of Michigan, in Ann Arbor. Dr. Higgins and his colleagues developed an antifibrotic agent that is gut selective, with an ileal tissue concentration 450 times greater than the plasma concentration. The Bcl-2 inhibitor targets the characteristic resistance to apoptosis that activated myofibroblast cells demonstrate.
“We tried to get apoptosis-resistant myofibroblast cells to undergo normal apoptosis, and what we found was encouraging, in that the Bcl-2 inhibitor increased apoptosis in mouse models of fibrosis and significantly reduced cecal and colon fibrosis,” said Dr. Higgins, who presented the findings at DDW 2019 (oral presentation 867).
Dr. Higgins acknowledged that while the findings “look pretty promising in mice, of course there are a lot of therapies that work in mice and don’t work in people. But if we can show that it is effective in several different rodent models—which we are currently working on doing—the chances that it works in humans increases,” he said.
First Clinical Trial Launches
Moving lab-based findings further along the research and development continuum has historically been challenging for antifibrotic strategies because of a lack of interest from the pharmaceutical industry, Dr. Rieder said. A lack of clinical trial end points for fibrosis treatments is one reason this has been the case.
“We haven’t had good techniques to detect fibrosis without going to surgery, which is very invasive and can’t be done repeatedly to monitor the effects of an antifibrotic,” Dr. Rieder said. “We can’t detect fibrosis on biopsies during endoscopy, and until recently, we didn’t have a universal set of symptoms to refer to.”
Dr. Rieder and his colleagues in the recently formed global Stenosis Therapy and Anti-fibrosis Research Consortium have developed standardized patient-reported outcomes to define a universal set of stricture symptoms as well as an imaging index on MR enterography to measure stricture response to therapies. The measures are being used as trial end points in a new prospective phase 2, randomized controlled clinical trial looking at antistricture therapy in Crohn’s disease, starting this year.
“Even if the findings are negative, the trial will have a huge impact on research in the field,” said Dr. Rieder, who declined to disclose the treatment being studied. “It will teach us about trial design for these agents and give us a clearer understanding of the direction the FDA wants us to follow when studying antifibrotics.”
In another sign that the search for intestinal antifibrotics is moving into high gear, Pliant Therapeutics, which has several antifibrotics in the pipeline for non-intestinal disease states, has partnered with Cleveland Clinic to advance the discovery of therapeutic targets for gastrointestinal fibrosis.
Dr. Higgins has tempered enthusiasm that his group’s research and the efforts of others will lead to a clinically applicable product in the next few years. “Fibrosis has been and continues to be a tough, tough problem,” he said.
For now, he said, the best way to control fibrosis in IBD is to use biologics as soon as possible in the disease course. “The earlier we can get really effective therapy to people, the less often they’re going to develop progressive clinically significant fibrosis that requires surgery,” Dr. Higgins said.
The challenge in doing this, he said, is that the current treatment pyramid and payor environment encourage use of the cheapest drugs first, such as corticosteroids and 5-aminosalicylic acid agents, and delay use of biologics, by which time many patients have already developed progressive fibrosis.
But an effective antifibrotic would generate significant benefits for patients and their quality of life, Dr. Higgins said. “I think for Crohn’s disease in particular, even if we can’t reverse or prevent fibrosis altogether, if we could dramatically slow progression of fibrosis for those who repeatedly go to surgery, that could potentially double the number of years between surgeries, which would be a big deal.”
—David Wild
Dr. Koon reported no relevant financial disclosures. Dr. Rieder reported serving as a consultant or an advisor to 89bio, AbbVie, Adnovate, AgomAb, Allergan, Arena, Boehringer Ingelheim, Celgene/Bristol Myers Squibb (BMS), CDISC, Cowen, Galmed, Genentech, Gilead, Gossamer, Guidepoint, Index Pharma, Janssen, Koutif, Mestag, Metacrine, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Surmodics, Surrozen, Takeda, Techlab, Theravance, Thetis, UCB and Ysios. He also reported receiving research funding from AbbVie, BMS, Boehringer Ingelheim, Morphic, Pfizer, Pliant and UCB.
This article is from the August 2021 print issue.