The oral small molecule IMU-856, now being developed by Immunic Therapeutics, strengthens and improves the barrier function of intestinal cells while having little to no effect on the immune system, preclinical data show.
The maintenance of a strong intestinal wall is essential for gastrointestinal health, as a leaky gut is one of the causes of inflammatory bowel disease (IBD).
Immunic plans to launch its first Phase 1 clinical trial testing single and multiple ascending doses of IMU-856 by the end of June.
Hella Kohlhof, PhD, Immunic’s chief scientific officer, detailed the findings of the company’s promising preclinical study in a presentation titled “IMU-856: A Small Molecule Modulator Restoring the Gut Barrier Function” at the IBD Innovate: Product Development for Crohn’s and Colitis Conference, held recently in New York.
In IBD patients, the cellular junctions that stitch cells together in the intestinal epithelium — the cell layer that forms the lining of both the small and large intestines in the gastrointestinal tract — are weakened, resulting in a leaky gut and lower nutrient absorption. Moreover, the barrier function of the intestinal wall is compromised, which allows bacteria to penetrate the deeper tissue and trigger an immune response and further inflammation.
IMU-856, originally developed by Daiichi Sankyo, is an oral small molecule whose target is an as yet undisclosed enzyme, mainly present in the epithelial cells of the colon and small intestine. It works by regulating genes linked with intestinal cell interactions and adhesion. The investigational therapy is called an epigenetic regulator because it can turn genes on or off without changing their DNA sequence.
In vitro (in the lab) studies with epithelial cells of the intestine, called Caco 2 cells, and with a mouse model of IBD showed that IMU-856 can specifically inhibit the activity of its target enzyme at very low concentrations.
The therapy was able to restore the intestinal barrier function in the in vitro model with epithelial cells. Additionally, IMU-856 showed dose-dependent activity in animal models with different severities of colitis — the inflammation of the colon — induced by dextran sulfate sodium (DSS). IMU-856 also improved the structure of the colon and delayed the onset of colitis.
“We are excited to present, for the first time, strong preclinical data of IMU-856 which shows potential significant advantages over current immunosuppressive treatments for intestinal barrier function associated diseases. IMU-856 appears to have a unique targeted ability to strengthen the intestinal barrier function, and we believe that a normalized intestinal barrier function may avoid bacterial triggers without impairing the immune system,” Kohlhof said in a press release.
Most current IBD therapies unintentionally reduce the body’s immune surveillance, which increases the risk of infections or malignant tumours. IMU-856 seems to not impact the immune system, however, meaning that such surveillance is maintained. In mice, treatment with IMU-856 showed either no or minimal effects on immune cells in controls (no treatment) or mice treated with Azulfidine (sulfasalazine), a common therapy for IBD.
IMU-856 was found to be safe in 28-day toxicity studies in rats and monkeys, and in tests assessing its impact on the respiratory, central nervous (brain and spinal cord), and cardiac systems.
“This early data, therefore, further supports our belief that IMU-856 has the ability to change the treatment paradigm for patients suffering from a variety of gastrointestinal diseases,” Kohlhof said. “We look forward to learning more about the pharmacokinetics and safety of IMU-856 in our phase 1, single and multiple ascending dose studies, which we expect to initiate in the first half of 2020.”
Immunic hopes to perform further studies to understand the mechanism of action of IMU-856, and assess its potential for treating other diseases linked with a leaky gut.
“We also plan to extend these studies to assess safety and mechanism-related biomarkers in patients suffering from diseases related to intestinal barrier function. We are hopeful that future clinical trials will validate IMU-856 as a safe, long-term treatment option for these patients,” Kohlhof added.
The company recently announced that its subsidiary, Immunic AG, which conducts its research and development activities, acquired the rights from Daiichi to develop and commercialize IMU-856 worldwide. Immunic has also acquired the rights for a patent application previously filed by Daiichi covering IMU-856’s composition.
“Exercising this option is an important milestone, as it indicates that we are convinced of the preclinical safety profile of IMU-856 and are ready to take this program into phase 1 clinical trials,” Daniel Vitt, PhD, CEO and president of Immunic, said in a press release.
“We are delighted that Immunic executed the option right for IMU-856,” said Junichi Koga, Daiichi Sankyo’s senior executive officer and global head of R&D.
“Daiichi Sankyo is committed to delivering innovative medicines to patients across the world as quickly as possible, either by ourselves or through strategic partnerships. We are confident that Immunic is our best partner and will rapidly drive the development of this novel compound for patients with intestinal diseases,” Koga said.
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