Completed PALI-2108 Phase 1a/b Clinical Trial

PALI-2108

Demonstrated Positive Results in Phase 1a/b Trial

Double-Blind, Placebo-Controlled, Safety, Tolerability, PK and PD Study of PALI-2108 in NHV and Open-Label Study of a Patient Cohort with UC

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 of PALI-2108 Phase 1a/b

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
Early Signals of Clinical Activity in UC

    • 100% clinical response after 7 days of 30 mg BID (with titration) in UC patients (≥30% or ≥3-pt drop in Modified Mayo + RBS ≤1)
    • 40% clinical remission after 7 days of 30 mg BID (with titration)
    • Modified Mayo ↓ 62.8% (mean –4.0 pts)
    • Tissue cAMP ↑ ~27%, Lymphocytes ↓ ~40%
    • Histology improved: Nancy (58%), Robarts (56%), Geboes (36%)
    • Fecal calprotectin ↓ in 4/5

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

SAD Safety and Tolerability

MAD Safety and Tolerability

PALI-2108 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

Phase 1b UC Cohort Patient Disposition and Safety

UC Patient Cohort Details

  • 5 patients with moderate to severe ulcerative colitis enrolled
  • All patients received 30 mg (titrated) BID PALI-2108 for 7 days (open-label design)
  • All patients completed the study and there were no withdrawals
  • Safe and Well-Tolerated:
      • No clinically significant change in PE, vital signs, safety lab tests and EKG
      • PDE4-related TEAEs were mild and quickly resolved
  • Successful Titration Strategy:
      • Using a 5-day dose titration regimen led to good tolerability
      • Few TEAEs by end of titration related to Cmax and BID dosing
  • Time-Limited Adverse Events:
      • TEAEs occurred within 2-3 days of treatment, with reduction in frequency and severity over time
  • Extended-Release PK:
      • PK suggests daily dosing and lower initial titration expected to achieve plasma and tissue IC50/90 goals with excellent Day 7 tolerability

Mechanistic and Inflammatory PD Were Improved cAMP, PDE4B and TLC, CalPro and hs CRP

Tissue cAMP was increased in 4/5 patients (~27% individual mean increase) as expected due to inhibition of PDE4 enzyme

Tissue lymphocytes was decreased in 4/4 (mean ~29% reduction; ~40% by individual mean approach)1

Tissue PDE4B was decreased in 5/5 patients (mean ~71% reduction)

Fecal calprotectin was decreased in 4/5 patients by a mean of ~70.3%

hsCRP was decreased by a mean of ~15.2%

Colon Tissue Histologic Scores Were Improved

Tissue cAMP was increased in 4/5 patients (~27% individual mean increase) as expected due to inhibition of PDE4 enzyme

Tissue lymphocytes was decreased in 4/4 (mean ~29% reduction; ~40% by individual mean approach)1

Tissue PDE4B was decreased in 5/5 patients (mean ~71% reduction)

Fecal calprotectin was decreased in 4/5 patients by a mean of ~70.3%

hsCRP was decreased by a mean of ~15.2%

Clinical Response and Remission Was Demonstrated by Modified Mayo Score

  • Modified Mayo Score was reduced in 5/5 patients with mean absolute reduction of 62.8% from baseline

  • Clinical Response was achieved in 5/5 (100%) of patients (≥30% or ≥3-point drop in modified Mayo score (with rectal bleeding subscore of 0 or 1)

  • Clinical Remission was achieved in 2/5 (40%) of patients

Clinical Trials: NCT06663605

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