New trials aim to block, re-educate or transform components of the inflammatory process.

Historically, the sole treatment for celiac disease has been a gluten-free diet, an imperfect solution considering that up to 50 percent of patients continue to experience gastrointestinal distress – most often from inadvertent gluten consumption.

To address these concerns, Dawn Wiese Adams, M.D., director of the Celiac Disease Clinic at Vanderbilt University Medical Center, is leading a push to investigate three new pharmaceuticals with different paths to treatment for the condition: one would block specific T cells in the inflammatory cascade; another would train T cells to ignore gluten as a threat; and a third breaks down gluten into molecules so small they are unrecognized by the celiac immune system.

It’s a new approach for a condition that is on the rise across the United States.

“For a while, the thought at the FDA was, ‘why would people need medications when a gluten-free diet is already a solution?’” Adams said.

“But diet therapy alone is not enough. The diet is difficult, expensive and can lead to social isolation, anxiety and depression. In addition, some patients, despite their best efforts to maintain a gluten-free diet, will have persistent lab and duodenal abnormalities.”

Incidence of autoimmune disease has risen in recent decades, with celiac disease a prime example, now affecting an a full 1 percent of the United States population. Adams says theories on its rising include an overly-hygienic approach to infancy, increases in certain types of infections, premature introduction of wheat-based cereals, and genetic alterations in wheat that can render it physiologically “foreign.”

In about 10 percent of cases there is a heritable component, she says.

IL-15 Blocker

Therapeutic targets in celiac disease and other autoimmune diseases are the cytokines that attach to T cell receptors, inducing inflammation in an attempt to isolate the perceived threat. IL-15 is one of the key cytokines that cause much of the intestinal damage and systemic inflammation seen in celiac disease.

Now in phase 2b, the PROACTVE trial is testing PRV-015, an IL-15 monoclonal antibody designed to shut down the early T-cell activation that is triggered when gluten is detected. Murine studies and human intestinal biopsies demonstrate that the antibody reacts specifically with IL-15, blunting its activity without compromising effector functions provided by other T cells.

PROACTIVE study participants attempt to maintain a gluten-free diet and are assigned to PRV-015 or placebo injections administered every two weeks. The primary goal is to see how well PRV-015 reduces symptoms and damage to the small intestines.

“This form of immunotherapy is growing in use in other autoimmune diseases, like rheumatoid arthritis, and in treatment of certain gastrointestinal diseases, cancers, viral infections like COVID-19, and more,” Adams said. “It is an exciting option because it may improve systemic effects that people experience with celiac disease and has shown some early promising data in refractory celiac disease.”

T-Cell Re-Education

A second pharmaceutical approach, now in phase 2 trials, is Anokion’s KAN-101, a peptide infusion that re-educates T cells. This drug goes to the liver and renders the T cells that trigger inflammation anergic or converts them into T regulatory cells that have a calming effect.

“If the re-education approach is successful in celiac disease, it could be the prototype for treating many other autoimmune diseases.”

“In this trial, participants consume a slurry of gluten and water, which can be a bit of an enrollment roadblock because people with this disease are so accustomed to strict gluten avoidance,” Adams said. “Yet, this trial is so important, because if the re-education approach is successful in celiac disease, it could be the prototype for treating many other autoimmune diseases.”

Pulverizing Gluten

Approaching celiac disease from a morphological angle, Takeda Pharmaceuticals’ TAK-062, an endopeptidase, is used to degrade the amino acids that constitute gluten so they become unrecognizable to T cells and thereby fail to stimulate an immune response.

Participants in the current phase 2 trial take one pill (TAK-062 or placebo) three times a day before they eat. They maintain their gluten-free diet but consume three bars a week that contain very small amounts of gluten, equivalent to typical cross-contamination exposure, with the aim of reducing celiac-related symptoms and avoiding or attenuating small intestine damage.

“We will monitor symptoms over time and assess duodenal biopsies before and after trial. Another exciting feature of this trial is the inclusion of capsule endoscopy in celiac disease,” Adams said. “Its use hasn’t yet been standardized in this disease, but it could allow for less invasive mucosal assessment at diagnosis and follow-up and may catch disease activity that is missed on a standard upper endoscopy.”

Adams says more study sites and participants are needed to optimize trials like these.

“There’s no therapy for patients with celiac disease right now, so the patient’s only current option to try to get access to therapy is to enroll in clinical trials,” she said. “Physicians can lead the effort in this by encouraging broad participation, even among celiac patients who say they feel well.”

Bios

Dawn Wiese Adams, M.D.

Dawn Weise Adams, M.D., M.S., is an associate professor of medicine, medical director of the Center for Human Nutrition and director of the Celiac Disease Clinic at Vanderbilt University Medical Center. Her clinical work and research involve celiac disease, short bowel syndrome and other nutritional complications of gastrointestinal diseases.