Novel drug therapies for celiac disease may be on the horizon, according to early research findings. The drugs, which target different mechanisms of action, were found to be safe and effective in healthy populations, with no drug-related adverse effects.

One of the drugs, currently named DONQ52 (Chugai), a multispecific antibody targeting the HLA-DQ2.5 serotype complex as well as multiple gluten peptides, is designed to shut down the T-cell response, the fundamental cause of symptoms.

In the proof-of-concept study, DONQ52 reduced T-cell responses to multiple gluten peptides by nearly 90% and to a “cocktail” of common peptides by 84%, without any apparent effect on T-cell activity unrelated to gluten peptides, according to lead investigator Melinda Y. Hardy, PhD, a research scientist at the Walter and Eliza Hall Institute of Medical Research, a facility associated with the University of Melbourne, in Australia.

The other drug, IMU-856 (Immunic), is an epigenetic modulator of sirtuin 6 (SIRT6). Its use has been found to regenerate the gut wall and restore barrier function in the small intestine while preventing immunosuppression.

The research on these investigational therapies was presented at Digestive Disease Week 2023.

Specifically Targeting Immune Function

There has been an uptick in studies evaluating strategies to modify the gluten-specific immune response in patients with celiac disease. However, most treatments involve inducing tolerance to the antigens, such as TAK-101 and KAN-101. DONQ5 is designed to block the gluten-induced immune response entirely, according to Dr. Hardy.

“The strength of DONQ52 is that it is very specific to gluten peptides. It binds to at least 25 of these with a great degree of specificity, so it is unlikely to adversely affect other types of immune function,” explained the senior investigator of the study, Jason A. Tye-Din, MBBS, PhD, a celiac disease specialist at the University of Melbourne.

For this study (abstract 18), the team drew blood from 20 patients with celiac disease after they completed a three-day wheat challenge. When peripheral blood was drawn six days later, isolated mononuclear cells were evaluated for gluten-specific T-cell responses.

Of the 20 blood samples, 15 demonstrated robust gluten-specific T-cell responses to a gluten challenge. When blood was tested with DONQ52, the mean reduction in T-cell responses to the panel of gluten peptides evaluated separately was 88%. When the gluten peptides were combined into an immunogenic cocktail, the reduction was of the same approximate magnitude.

DONQ52 has had no effect on nonspecific T-cell response when challenged in the absence of gluten peptide, according to Dr. Hardy. She said major reductions in T-cell responses were observed after DONQ52 for gluten peptides from both barley and rye as well as wheat.

The study did not include celiac disease linked to the HLA-DQ8 allele, so response in non–HLA-DQ2.5 celiac disease is unknown. Noting that the antibody is specific to HLA-DQ2.5, Dr. Tye-Din does not anticipate activity in other celiac disease types.

Although Dr. Tye-Din conceded that inhibition of the T-cell response was not as strong with DONQ52 for antigen related to barley and rye as well as wheat, he pointed out that drug development had primarily been targeted at blocking the immune response to wheat.

Avoiding Immunosuppression

This caveat with antigens was not an issue during the ongoing research into investigational drug IMU-856 due to the medication’s alternate mechanism of action. IMU-856 is an oral, systemic small-molecule modulator targeting SIRT6. Not only has SIRT6 been shown to regulate intestinal barrier function and regenerate bowel epithelium, but targeting the protein in preclinical research did not induce immunosuppression.

“By restoring intestinal barrier function and bowel wall architecture through its effect on SIRT6, IMU-856 may offer a unique treatment option for patients suffering from gastrointestinal diseases,” Hella Kohlhof, PhD, the chief scientific officer of Immunic, noted in a company press release. Avoiding immunosuppression, she noted, “may therefore maintain immune surveillance for patients during therapy, representing a distinct advantage when compared with chronic administration of potentially immunosuppressive medications.”

In the 1b trial (abstract EP63), healthy individuals were randomized to receive either placebo or the drug at doses of 10, 20, 40, 80, 120 and 160 mg. In a second part of the 1b trial, individuals were given multiple ascending doses of IMU-856 or placebo for two weeks. Lead researcher Franziska BuriÁnek, MD, a senior medical investigator at Immunic, and her co-investigators wrote that the results showed a favorable pharmacokinetic profile, with steady-state plasma trough concentrations after four to seven days that were between the 50% and 90% maximal effective concentration. They also reported good safety and tolerability results, with the main adverse events related to the catheter inserted for blood sample collection and not drug delivery, as IMU-856 is an oral medication. The most common drug-related adverse events were abdominal pain and diarrhea, although the researchers noted they occurred in fewer than 10% of study participants.

Continuing Research

For IMU-856, the conclusion of part 1b led to the start of part 1c of the trial, consisting of drug testing in patients with celiac disease both during gluten-free and gluten challenge diets. With 42 patients set to be enrolled in sites in Australia and New Zealand, the researchers plan to trial two cohorts of 80 and 160 mg or placebo once daily for 28 days.

For DONQ52, a phase 1 trial is underway (ClinicalTrials.gov Identifier: NCT05425446), named the LILY study. Although safety will be a focus of the phase 1 trial, Dr. Tye-Din does not anticipate issues with tolerability or adverse effects on immune functioning due to DONQ52’s specificity of action.

The targeted effect of DONQ52 is the reason that this experimental drug appears “to be on a promising path of development,” according to Benjamin Lebwohl, MD, the director of clinical research at the Celiac Disease Center of Columbia University, in New York City. He is now waiting for clinical studies to confirm these purported advantages.

Another expert in celiac disease, Peter R. Holt, MD, a senior research associate at Rockefeller University, in New York City, called the DONQ52 research “exciting.” “The experimental approach differs from those inducing immune tolerance now being tested,” he said. Dr. Holt also said that although he very much likes the concept, the “proof is in the pudding” when—and if—studies achieve an improvement in quality of life.

—Ted Bosworth and Meaghan Lee Callaghan

Drs. BuriÁnek and Kohlhof are employees of Immunic. Drs. Hardy, Holt and Lebwohl reported no relevant financial disclosures. Dr. Tye-Din reported financial relationships with Anatara Lifesciences, Anokion, Chugai, Codexis, Equillium, Genentech, Immunic, IM Therapeutics, Janssen, Mozart, Takeda, Topas and Vaccitech.