TMP502 targets cells in the liver that can help induce immune tolerance of gluten in celiac disease
By Amy Ratner, director of scientific affairs
Results from a clinical trial for a new drug to treat celiac disease by preventing an immune reaction to gluten with the use of nanoparticles were shared for the first time Monday at Digestive Disease Week (DDW).
Topas Therapeutics presented data from a phase 2 clinical trial that showed TMP502 reduced the inflammatory response to gluten and resulted in changes in antigen-specific CD4 T-cells, which are responsible for the immune reaction to gluten in celiac disease.
“By directly addressing the pathogenic T-cell activation central to celiac disease, TMP502 could redefine the treatment paradigm and provide a much needed therapeutic option for patients who have no approved alternatives to a lifelong gluten-free diet,” Cristina de Min, MD, Topas CMO, said in a press release.
At the highest dose, TPM502 reduced the level of Interlukin2 (IL-2) after a gluten challenge in adult study participants with well controlled celiac disease. IL-2, a biomarker or red flag for celiac disease activity, is a cytokine signaling molecule in the immune system. Previous research has shown a correlation between IL-2 and symptoms in celiac disease patients, including nausea and vomiting.
The study also found a dose dependent reduction in pro-inflammatory cytokine interferon-gamma. Measurement of interferon-gamma is a way to evaluate how immune T-cells respond to gluten.
“TMP502 holds promise for immunotherapy for celiac disease,” said Knut E A Lundin, MD, of the University of Oslo, the principal investigator of the study who presented the results. Topas is a clinical stage biotech company based in Hamburg, Germany.
The drug, which was given intravenously, contains three gluten peptides in the nanoparticle that targets cells in the liver. Peptides are tiny fragments of gluten protein that can trigger an incorrect immune response in those who have celiac disease. TMP502 targets cells in the liver that are unconventional antigen-presenting cells capable of inducing immune tolerance, he said.
The goal of drugs focused on immune tolerance is to stop the immune reaction to gluten proteins that occurs in celiac disease. When someone has celiac disease, their immune system incorrectly reads gluten proteins as invaders. This miscue triggers T-cells, which function as the body’s disease fighting soldiers, to release cytokines and attack. This attack causes inflammation and tissue destruction.
The study included adults from five European countries and Australia who have the HLA-DQ2.5 gene for celiac disease, were on a gluten-free diet and had normal anti-transglutaminase blood test results. Nearly 400 celiac disease patients were initially screened for the trial, but only 38 were enrolled with 37 completing the trial. Those who had too low an IL-2 response on a screening gluten challenge were excluded, as were those who did not have the HLA-DQ2.5 gene.
Study participants were assigned to one of four groups and received two increasing doses of TMP502 or a placebo. A second gluten challenge was given 7 days after the second dose. Immune tolerance was then assessed by measuring IL-2 levels in blood samples. At the highest dose of TPM502, a significant reduction in IL-2 was seen following the gluten challenge, a reduction that continued for the trial period of one month after the last dose of TPM502
Study participants who received the higher doses of the drug reported improvement in gastrointestinal symptoms though more specific details were not presented.
The drug had a favorable safety profile, according to study results, with adverse effects reported by 27 study participants including eight who received the placebo. Nausea, headache and vomiting were the most commonly reported.
When asked if the drug will be a one- or two-time treatment or whether those with celiac disease will have to take it repeatedly to maintain tolerance to gluten, Lundin said he doubts it would be a once in a lifetime treatment. But he noted there is no data to make that determination. Within the time frame of the study, the immune tolerance looks very stable, he said. “But what happens after months, presumably [patients] would have to come back,” Lundin noted. “That is the topic for future research.”
Tak-101, a drug for treatment of celiac disease being developed by Takeda Pharmaceuticals, is also based on use of nanoparticles to program the immune system to tolerate gluten.
DDW is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Studies presented at DDW are sometimes preliminary and give an early look at investigations that are likely to include more details as they progress toward publication in a peer reviewed scientific journal.
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