Palisade Bio's PALI-2108 Shows Local Bioactivation and Dose-Dependent Efficacy in Mouse Models

Palisade Bio, Inc. has presented promising preclinical data for its lead product candidate, PALI-2108, at the Digestive Disease Week (DDW) 2024 event held in Washington, D.C. The biopharmaceutical company specializes in developing innovative therapies for autoimmune, inflammatory, and fibrotic diseases. The newly presented data highlights the safety, effectiveness, and tolerability of PALI-2108, specifically designed for the treatment of Ulcerative Colitis (UC).

PALI-2108 is an orally administered, colon-specific Phosphodiesterase-4 (PDE4) inhibitor prodrug that aims to provide localized activity with minimal systemic exposure. The drug displayed significant dose-dependent efficacy in two DSS colitis mouse models, suggesting its potential as a treatment comparable to dosages of apremilast that are typically deemed intolerable for humans with UC. The company plans to initiate a Phase 1 human clinical study for PALI-2108 by the end of the year.

Dr. Mitch Jones, CMO of Palisade Bio, presented the data in a poster session titled "Local Bioactivation and efficacy of PALI-2108: A Promising PDE4 Inhibitor Prodrug for Ulcerative Colitis Treatment." The poster was part of the Animal Models of IBD: Pre-Clinical Treatment of Intestinal Inflammation session. According to Dr. Jones, the findings add to the growing body of encouraging data for PALI-2108 and bolster confidence in its potential as a treatment for UC. He emphasized that PALI-2108 might become the first approved PDE4 inhibitor for UC, offering a new solution for patients in need.

The study employed a classic cellular thermal shift assay (CETSA) to assess the on-target PDE4 binding within colon tissue when dosed with apremilast, PALI-2108, or Vehicle. Researchers used an acute colitis model in mice, induced by 4% DSS in drinking water from Days 1 to 8, to evaluate the efficacy of PALI-2108 across various doses. Mice received twice-daily treatments of PALI-2108 at doses of 20, 40, and 80 mg/kg, while cyclosporin A and apremilast were administered at 40 and 12.5 mg/kg, respectively. The assessment included monitoring body weight scores, stool consistency, and fecal blood scores, with evaluations conducted 1 to 2 hours post-dosing. The overall disease state was measured using a Disease Activity Index (DAI) score, calculated by pooling the three in-life scores assessed daily.

Additionally, a single oral dose of PALI-2108 at 43 mg/kg was administered to dogs, along with active PALI-0008 at incremental doses. The study monitored key clinical adverse events such as emesis. Notably, the PALI-2108 prodrug prevented emesis observed with lower doses of the PDE4 active moiety, demonstrating an enhanced therapeutic window.

Key highlights from the preclinical data include:
- PALI-2108's similar target engagement to the PDE4 inhibitor apremilast, which is approved for psoriasis and psoriatic arthritis.
- Significant prevention of colon length reduction in a dose-dependent manner in DSS colitis mouse models.
- Dose-dependent improvements in body weight, stool consistency, fecal blood scores, and overall DAI scores.
- Comparable efficacy to intolerable doses of apremilast for human UC patients without systemic toxicity and a large therapeutic window due to local activation.

Palisade Bio remains committed to advancing PALI-2108 as a novel treatment option for UC, aiming to transform the current treatment landscape for patients suffering from this chronic condition.