Palisade Bio, Inc. (Nasdaq: PALI) has announced positive preclinical data for PALI-2108, an orally administered, colon-specific phosphodiesterase-4 (PDE4) inhibitor prodrug being developed for ulcerative colitis (UC). The data, presented at the 2025 Crohn’s and Colitis Congress, demonstrate PALI-2108's ability to reduce colitis symptoms in a mouse model without the CNS toxicity often associated with systemic PDE4 inhibitors. These findings support the ongoing Phase 1a/b study of PALI-2108, with topline data anticipated in the first half of 2025.
Preclinical Efficacy and Safety
In preclinical studies, mice with induced colitis were treated with PALI-2108 twice daily for three days. Results showed that PALI-2108 reduced disease activity compared to tacrolimus and apremilast, two commonly used treatments for UC. Importantly, the drug demonstrated a favorable safety profile, with no observed CNS toxicity.
Pharmacokinetic (PK) modeling, utilizing data from both UC patients and healthy volunteers, indicated that PALI-2108 has favorable absorption and bioavailability. This supports its potential for clinical use, suggesting that twice-daily dosing may be appropriate during induction, followed by once-daily dosing for maintenance therapy.
Colon-Specific Action
PALI-2108 is designed as a colon-specific prodrug, meaning it is converted into its active form, PALI-0008, primarily in the colon. This targeted approach aims to maximize efficacy at the site of inflammation while minimizing systemic exposure and potential side effects. Cellular Thermal Shift Assay (CETSA) data confirmed PDE4 binding in colon tissue, demonstrating target engagement.
Clinical Development and Next Steps
Palisade Bio is currently conducting a Phase 1a/b single-center, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of PALI-2108 in healthy volunteers. An open-label study involving a patient cohort with UC is also underway. According to Palisade Bio, preliminary results from the first three single ascending dose (SAD) cohorts demonstrated that PALI-2108 was safe and well-tolerated at 15mg, 50mg, and 150mg doses, with no treatment-related adverse events.
"UC patients need new oral therapies with higher remission rates, less systemic immunosuppression, and a strong safety profile. We continue to be encouraged by our preclinical and clinical results for PALI-2108, and we believe PALI-2108 could be an important option for these patients," said Mitch Jones, MD, Ph.D., Chief Medical Officer of Palisade Bio.
Ulcerative Colitis: An Unmet Need
Ulcerative colitis is a chronic inflammatory bowel disease (IBD) that affects the large intestine. Characterized by inflammation and ulceration of the colon's inner lining, UC can cause symptoms such as abdominal pain, diarrhea, rectal bleeding, and weight loss. Current treatments include aminosalicylates, corticosteroids, immunomodulators, and biologics. However, many patients do not respond adequately to these therapies, and some experience significant side effects. The development of new, targeted therapies like PALI-2108 is crucial to address the unmet needs of UC patients.
