Abstract Background Systemic PDE4 inhibitors reduce inflammation but are limited by gastrointestinal and neurologic adverse effects. PALI-2108 is an oral prodrug activated by the ileum and colon microbiome. This first-in-human trial evaluated safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity in patients with moderate-to-severe ulcerative colitis (UC). Methods An adaptive Phase 1a/1b study evaluated PALI-2108 in Healthy Volunteers: Single Ascending Dose (n = 40), Multiple Ascending Dose (BID; n = 32), Food Effect (n = 12), moderate-to-severe UC (n = 5). Five adults with active UC (modified Mayo 5–9; endoscopy ≥ 2) received titrated PALI-2108 30 mg BID for 7 days. Baseline and Day 7 assessments included modified Mayo score, histology (Nancy, Robarts, Geboes, TLC), fecal calprotectin and tissue biomarkers (cAMP, PDE4B). Results Safety: 95% of AEs (89 participants) were mild (headache, nausea, diarrhea); no SAEs or discontinuations occurred. PK: In Healthy Volunteers (HV) single-ascending-doses showed PALI-2108 Tmax at 3–4h; PALI-0008 Tmax at 8–9h. Half-life is 9–15h (∼2–3× longer than other PDE4 inhibitors). Cmax and AUC are dose-proportional. Multiple-ascending-doses in HVs showed steady state by 48 h; troughs were 20% above single-dose Cmax and above IC90. At 15 mg BID and 30 mg BID, plasma levels remained above IC90 at steady-state trough. The prodrug’s gradual lower GI tract release attenuates Cmax, which reduces CNS Adverse Events seen in PDE4 inhibition) and avoids secretory diarrhea. PD: Administration of PALI-2108 to UC patients for one week showed improvement in multiple PD markers. Tissue cAMP was elevated in 4/5 patients (∼27% mean increase); tissue lymphocytes decreased in 4/5 patients (∼40% by individual mean); tissue PDE4B expression levels decreased in 5/5 patients (∼71% mean reduction); inflammation marker fecal calprotectin decreased in 4/5 patients (∼70.3% mean reduction). These changes demonstrate robust on-target PDE4 inhibition and resolution of mucosal inflammation.Histology: All histology indices decreased: Nancy Index: 58%; Robarts index: 56% and Geboes index: 36% (average scores).Efficacy: All patients improved in modified Mayo score (–62.8% mean) after one week of treatment. 5/5 patients (100%) showed clinical response (≥ 30 % or ≥ 3-point reduction + rectal bleeding ≤ 1). Two patients showed clinical remission (mMayo ≤ 2, rectal bleeding = 0 after one week of treatment. Conclusion PALI-2108 produced rapid clinical and biomarker improvement after 7 days of treatment in active UC with excellent tolerability. Reduced lymphocytes count and fecal calprotectin confirm anti-inflammatory mechanism. The gut-restricted prodrug design achieves sustained ileocolonic activation without peak-driven toxicity. Conflict of interest: Dr. Heyer, Joerg: Employee of Palisade Bio Morelli, Gaetano: Employee of Altasciences Rieder, Florian: Personal Fees: Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Boehringer-Ingelheim, Celgene/BMS, Celltrion, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, 89Bio Jones, Mitchell: Employee of Palisade Bio
Heyer et al. (Thu,) studied this question.