Pali-2108, a Colon Targeted Pde4b Inhibitor, Rapidly Restores Immune-Epithelial Balance in Ulcerative Colitis Throughgut-Selective Lymphocyte Depletion

BACKGROUND Ulcerative colitis (UC) is a debilitating inflammatory disease of the lower gastrointestinal tract, affecting nearly 900,000 patients in the US and >5 million worldwide. PDE4 inhibition suppresses pro-inflammatory cytokines, but systemic PDE4 inhibitors are limited by CNS/GI toxicities (e.g., nausea, vomiting) that restrict efficacy. PALI-2108 is a novel, orally delivered, colon-targeted PDE4 prodrug. Following delivery to the lower GI tract, bacterial β-glucuronidase converts PALI-2108 to active PALI-0008, achieving high colonic exposure with minimized systemic peaks, thereby improving tolerability. METHODS We conducted a Phase 1a/b trial (NCT06663605: Phase 1 Study Evaluating PALI-2108 in Healthy Volunteers and Ulcerative Colitis Patients) in healthy volunteers and patients with moderately active UC. Five UC patients received 30 mg BID (titrated) PALI-2108 for 7 days. Safety, pharmacokinetics, histology, fecal biomarkers, and paired mucosal biopsies were assessed. RESULTS We assessed the safety of PALI-2108 and found that all adverse events were mild, transient (nausea, headache, diarrhea), and mitigated by titration. No SAEs or discontinuations occurred. Clinical observation revealed that all 5 patients achieved FDA-defined clinical response by Day 7 (≥30% and ≥2-point mMayo reduction); mean Δ –4.0 points (–63%). Two patients (40%) met remission criteria, and a third reached near-remission. Tissue PDE4B expression was reduced in all patients (–71% mean) and consequently mucosal cAMP rose +26% (4/5 responders). Reductions in mMayo score correlated with PDE4B suppression and cAMP elevation. Biomarker analysis revealed that Fecal calprotectin decreased –70% (4/5 responders) and hsCRP decreased –15.6% overall. Robarts histopathology index improved by –3 points on average. To understand the reduction of inflammatory markers we analyzed the histology and detected a about 40% reduction in mucosal lymphocytes (4/4 evaluable). RNA-seq deconvolution revealed absence of B, T, NK, dendritic, monocyte, and stromal immune-support signatures, consistent with broad suppression of pathogenic immune activation. For control PBMC RNA-sequencing showed a distinct pattern: enrichment of monocyte/platelet-dendritic signatures with reduced naïve/proliferating T cells. These results show that the efficient reduction of inflammation inducing lymphocytes can lead to immediate beginning of mucosal restoration and amelioration of symptoms. CONCLUSION PALI-2108 is the first colon-targeted PDE4 inhibitor to demonstrate rapid clinical response, robust biomarker improvement, and mechanistic proof-of-biology in UC patients after only one week of therapy. By selectively depleting mucosal lymphocytes and restoring cAMP-driven epithelial–immune balance, PALI-2108 offers a differentiated approach to UC treatment with improved safety over systemic PDE4 inhibitors.