Targeted, better-tolerated oral PDE4 inhibitors are an unmet need in inflammatory bowel disease (IBD)
PALI-2108 demonstrates in ex vivo studies; targeted activation and reduced side effects, potentially enhancing patient compliance compared to existing PDE4 inhibitors
Data presented at the American College of Gastroenterology’s (ACG) 2024 Annual Scientific Meeting
Carlsbad, CA, Oct. 31, 2024 (GLOBE NEWSWIRE) -- Palisade Bio, Inc. (Nasdaq: PALI) (“Palisade,” “Palisade Bio” or the “Company”), a biopharmaceutical company dedicated to developing novel therapeutics for patients with autoimmune, inflammatory, and fibrotic diseases has announced the presentation of data from two translational studies demonstrating the ex vivo bioactivation of PALI-2108 in stool samples and whole blood. This orally administered, colon-specific phosphodiesterase-4 (PDE4) inhibitor prodrug is in development for patients with ulcerative colitis (UC).
The poster titled “Colonic Bioactivation and Potent TNFα Inhibition of PALI-2108 in Human Clinical Studies: A Promising PDE4 Inhibitor Prodrug for the Oral Treatment of Ulcerative Colitis,” was presented by Dr. Mitch Jones, Chief Medical Officer of Palisade Bio, at the ACG 2024 Annual Scientific Meeting, held October 25-30, 2024, in Philadelphia, PA.
“The design of PALI-2108 ensures that activation is targeted primarily in the colon, which should minimize systemic exposure and potential central nervous system side effects. By demonstrating reduced systemic exposure, we believe PALI-2108 can effectively address the toxicity issues commonly associated with other PDE4 inhibitors like roflumilast and apremilast,” stated Dr. Mitch Jones, CMO of Palisade. “These ex vivo data reinforce the potential of PALI-2108 as an innovative therapeutic option for managing UC. We remain committed to advancing toward the launch of our Phase 1 study and are excited to further explore the potential of this novel, orally delivered, intestinally activated PDE4 inhibitor prodrug.”
Researchers assessed prodrug conversion in stool samples from six healthy individuals and six patients with UC using liquid chromatography-mass spectrometry (LC-MS). The enzymatic activity was evaluated by measuring the half-lives of samples from each donor. PALI-2108 was spiked into stool homogenates at a concentration of 100 μM, followed by a 24-hour incubation period.
Additionally, the impact of the active phosphodiesterase 4 (PDE4) inhibitor, PALI-0008, on lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNFα) production was investigated through an ex vivo assay using peripheral whole blood. Whole blood from twelve healthy human donors was pre-treated with PALI-0008 before being challenged with LPS at 1 µg/ml for 24 hours. TNFα production was quantified, and the IC50 values for apremilast and PALI-2108 were calculated.
Furthermore, a microbiome study was conducted in collaboration with CosmosID to evaluate the abundance of the beta-glucuronidase enzyme in microbiome samples from mice, dogs, healthy humans, and UC patients. Publicly available data for dog, mouse, and human whole genome metagenomic sequencing were obtained from the NCBI Sequence Read Archive. These samples were uploaded to the CosmosID-HUB (app.cosmosid.com) for functional identification of genes, enzymes, and pathways, utilizing MetaCyc, Gene Ontology, and Enzyme Commission databases.
Key Highlights
PALI-2108 was successfully bioactivated into its active form, PALI-0008, in stool samples from both normal healthy volunteers (NHV) and UC patients, achieving a high conversion rate of 90.1% at 24 hours.
PALI-0008 demonstrated significant inhibition of TNFα production in human whole blood, with an IC50 of 0.022 μM, indicating strong potency.
PALI-0008 exhibited approximately a 20-fold higher potency in reducing TNFα production compared to apremilast, underscoring its potential efficacy.
The microbiome study revealed consistent levels of β-glucuronidase across different species and conditions, supporting the activation mechanism of PALI-2108.
The consistent abundance of this enzyme suggests that PALI-2108 could be effective across diverse patient populations, including those with UC.
The Company is advancing PALI-2108 toward a Phase 1 single-center, double-blind, placebo-controlled study focused on safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers, alongside an open-label study involving UC patients. Preparations for the clinical study are ongoing, and the Company is on track to initiate patient dosing before year-end. For more information about the Company’s next-generation precision therapies for immune, inflammatory, and fibrotic diseases, please visit palisadebio.com.
About Palisade Bio Palisade Bio is a biopharmaceutical company focused on developing and advancing novel therapeutics for patients living with autoimmune, inflammatory, and fibrotic diseases. The Company believes that by using a targeted approach with its novel therapeutics it will transform the treatment landscape. For more information, please go to www.palisadebio.com.
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