PALI-2108: Completed Phase 1a Clinical Trial in Ulcerative Colitis & Fibrostenotic Crohn’s Disease

Double-Blind, Placebo-Controlled, Safety, Tolerability, PK and PD Study of PALI-2108 in NHV

Single Ascending Dose (n~40)

  • Primary Endpoint: Safety and tolerability
  • Secondary Endpoints: PK including Tmax, Cmax and T1/2

Multiple Ascending Dose (n~32)

  • Primary Endpoint: Safety and tolerability
  • Secondary Endpoints: PK including plasma and tissue C SS and colon: plasma ratio

Multiple Dose UC Cohort (n~5)

  • Pharmacokinetic Endpoints: Plasma, colon tissue, urine, stool including plasma and tissue C SS and colon: plasma ratio
  • Pharmacodynamic Endpoints: Fecal calpro, calpro epitope, hsCRP, colon tissue PDE4s, cAMP, TLC and histology

Topline Data Summary

GI-Restricted PDE4 Inhibitor Targeting Inflammation and Fibrosis in UC and Crohn’s Exceptional Safety & Tolerability

  • 89 patients treated with no SAEs, no lab or EKG abnormalities and no TEAE-related discontinuations
  • Completed all SAD cohorts: Single dose safe up to 450 mg
  • Completed all MAD cohorts: BID dosing well tolerated up to 50 mg
  • 15 mg BID had zero TEAEs, not even minor, in any subject
  • Titration at 30 mg BID improved tolerability, with single minor TEAE, leveraging tachyphylaxis profile of PDE4s

Robust PK/PD Profile Supporting Mucosal Targeting

  • Localized GI delivery confirmed: SI release and colonic bioactivation demonstrated in humans and preclinical models
  • High mucosal drug levels exceeded IC₉₀ in colon, including 36h post-last dose
  • Systemic exposure Cmax delayed and exposure right shifted and long half-life
  • Long half-life and extended-release PK characteristics support QD dosing

Phase 1a Confirms PALI-2108 Was Safe and Well Tolerated

SAD Safety and Tolerability

MAD Safety and Tolerability

PALI-2018 Ph1a Findings:

  • 84 patients treated and no SAEs and no AEs related to labs or EKGs
  • Completed all SAD cohorts demonstrating Safety and Tolerability of single dose PALI-2108 up to 450mg
  • Completed all MAD cohorts demonstrating safety and tolerability of twice daily (BID) doses of 15mg, 30mg and 50mg with 15mg BID having zero (not even minor) TEAE in any subject
  • Completed FE cohort demonstrating minimal changes, reduced Cmax, right shifted AUC and delayed Tmax due to colon bioactivation
  • Confirmed utility of titration with 30mg BID like other PDE4s

Phase 1 SAD/MAD PK Demonstrates PK Characteristics and Superior Exposure to Other PDE4s

Dose Proportionality and Extended Half-Life Enabling Daily Dosing

Single Ascending Dose (SAD)

PALI-2108 (prodrug; NOT SHOWN)

  • Tmax: ~3–4h → consistent with small intestinal dissolution (Eudragit + prodrug design)
  • Exposure (AUC): Minimal, as intended (GI-restricted)

PALI-0008 (active PDE4 inhibitor)

  • Tmax: ~8–9h → consistent with ileocolonic bioconversion
  • PK profile: Extended release; ~2–3× longer half-life than other PDE4 inhibitors (usually BID)
  • Dose proportionality: Cmax and AUC approximately dose-proportional

Multiple Ascending Dose (MAD)

Bioconversion:

  • PALI-2108 converted locally to PALI-0008 in terminal ileum/colon

Steady State:

  • Reached within ~48h
  • Stable pre-dose troughs with repeat dosing
  • Pre-dose troughs ~20% higher than single-dose Cmax, above IC90

Dosing Implications:

  • Extended half-life supports once-daily dosing

Phase 1 MAD Colon Tissue Pharmacokinetics

Tissue PK 36 Hours Post Dose Demonstrates Extended-Release PK and Potential for Daily Dosing

Tissue PK Observations from MAD

  • Colon Tissue Concentrations approached IC90 36h post dose – demonstrating extended-release tissue PK at multiple dose levels supporting a daily dosing regimen

PALI-2108 Overview

Ulcerative Colitis: Completed PALI-2108 Phase 1b Clinical Trial

Fibrostenotic Crohn’s Disease: Completed PALI-2108 Phase 1b Clinical Trial