Palisade Bio Reports Positive Data from PALI-2108 Studies for Ulcerative Colitis Treatment

Targeted, better-tolerated oral PDE4 inhibitors are in demand for treating inflammatory bowel disease (IBD). PALI-2108, a promising candidate, has demonstrated targeted activation and fewer side effects in ex vivo studies, potentially improving patient compliance compared to existing PDE4 inhibitors. Data from two translational studies were recently presented at the American College of Gastroenterology’s (ACG) 2024 Annual Scientific Meeting.

Palisade Bio, Inc., a biopharmaceutical company focused on developing novel treatments for autoimmune, inflammatory, and fibrotic diseases, revealed the findings from their research on PALI-2108, an oral, colon-specific phosphodiesterase-4 (PDE4) inhibitor prodrug being developed for ulcerative colitis (UC) patients. The data was presented by Dr. Mitch Jones, the company’s Chief Medical Officer, during the ACG 2024 Annual Scientific Meeting held in Philadelphia, PA.

Dr. Jones highlighted the design of PALI-2108, which prioritizes activation in the colon, limiting systemic exposure and minimizing potential central nervous system side effects. This characteristic could address the toxicity issues often linked with other PDE4 inhibitors, such as roflumilast and apremilast. The ex vivo data supports the potential of PALI-2108 as an innovative treatment option for UC, with the company looking forward to advancing to Phase 1 studies.

The research involved assessing the prodrug conversion of PALI-2108 in stool samples from six healthy individuals and six UC patients using liquid chromatography-mass spectrometry (LC-MS). The enzymatic activity was evaluated by measuring the half-life of the samples. PALI-2108 was introduced into stool homogenates at a concentration of 100 µM and incubated for 24 hours.

Additionally, the impact of the active PDE4 inhibitor, PALI-0008, on lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNFα) production was examined through an ex vivo assay using peripheral whole blood. Blood from twelve healthy donors was pre-treated with PALI-0008 before exposure to LPS. TNFα production was measured, and IC50 values for apremilast and PALI-2108 were calculated.

A microbiome study, conducted in collaboration with CosmosID, evaluated the abundance of the beta-glucuronidase enzyme in microbiome samples from mice, dogs, healthy humans, and UC patients. Data were obtained from the NCBI Sequence Read Archive and analyzed using the CosmosID-HUB for functional identification of genes, enzymes, and pathways.

Results indicated successful bioactivation of PALI-2108 into PALI-0008 in stool samples from both healthy volunteers and UC patients, achieving a high conversion rate of 90.1% at 24 hours. PALI-0008 showed significant TNFα production inhibition in human whole blood, with an IC50 of 0.022 µM, demonstrating strong potency. It exhibited approximately 20-fold higher potency in reducing TNFα production compared to apremilast, highlighting its potential efficacy. The microbiome study revealed consistent levels of β-glucuronidase across different species and conditions, supporting the activation mechanism of PALI-2108, suggesting its effectiveness across diverse patient populations.

Palisade Bio is preparing to advance PALI-2108 to a Phase 1 single-center, double-blind, placebo-controlled study focusing on safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers, along with an open-label study involving UC patients. Clinical preparations are ongoing, with plans to initiate patient dosing by year-end.