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

Demonstrated Positive Results in Phase 1b Trial in Fibrostenotic Crohn’s Disease (FSCD)

Key Highlights:

  • NFavorable safety and tolerability with no serious adverse events after two weeks of treatment in a difficult-to-treat population
  • NPharmacokinetic and pharmacodynamic data from ileal tissue and plasma support once-daily oral dosing, demonstrating IC90 coverage, with correlation to accepted inflammatory biomarkers
  • NDemonstrated endoscopic improvement, with a 47.5% reduction in SES-CD score and 40% of patients achieving both endoscopic response and remission
  • NResults support expansion into broader luminal CD, an indication which has regulatory clarity, more than doubles the total addressable patient population, and has no anatomical constraints
  • NCompany plans to advance PALI-2108 into a Phase 2 efficacy trial in moderate to severe Crohn’s disease, including evaluation of anti-fibrotic effects earlier in the disease course

FSCD Phase 1b Study Design

Phase 1b FSCD Topline Results Executive Summary

  • Dosing:
      • Three doses tested: 20, 25, and 30mg daily (QD) with titration
  • Safety – Tolerability:
      • No clinically significant changes in safety labs, vitals, or EKGs
      • No Serious Adverse Events (SAEs)
      • Reported AEs were mild and resolved without intervention
      • Two patients with possibly related mild TEAEs (fatigue, abdominal discomfort) resolved without intervention
  • PK/PD Profile:
      • All patients had pre-dose trough greater than IC90 by Day 14
      • Tissue levels were >>IC90 and increased over plasma by ~3x in ileum and ~5x in colon by Day 14
      • Ileal cAMP levels increased by 41%, as compared to 27% in colonic cAMP in Phase 1b UC study
  • SES-CD:
      • Mean SES-CD decreased from 8.0 at baseline to 4.2 at Day 14; 40% achieved endoscopic response and 40% achieved endoscopic remission

FSCD Patient Demographics and Clinical Profile

Endoscopic Response and Remission Were Demonstrated by Improvements in SES-CD

Demonstrates PK for Once Daily Dosing

  • Once-daily dosing confirmed as ideal dosing frequency

  • Titration schedule successful in maintaining gradual plasma drug concentration increase over time at all doses

  • Plasma pre-dose trough concentrations >IC90 at all doses (20mg, 25mg, and 30mg) and in all patients

  • Ileum tissue active drug concentrations >>IC90 at Steady State

  • Ileum tissue to plasma ratio was increased ~3x at steady state confirming preclinical findings

Using the peak plasma (Cmax) and tissue (4-8h post dose), there was a 6.2x average tissue/plasma ratio across all segments

Mechanistic and Inflammatory PD were Improved: cAMP and Fecal Calprotectin

  • Tissue cAMP was increased in 4/5 patients (~41% individual mean increase) as expected due to inhibition of PDE4 enzyme

  • Tissue cAMP % change was greater in ileum in FSCD (~41%) than in colon in Phase 1b UC patients (~27%)

  • Fecal calprotectin was decreased by a mean ~59% of the course of study and rebounded after drug withdrawal

  • Fecal calpro and cAMP were highly correlated with r2=0.93 and significant (p<0.05) suggesting a tight correlation between PD and inflammatory biomarkers

Safety Profile

  • Generally safe and well-tolerated
  • No serious adverse events
      • Consistent profile with Phase 1b UC study
  • No study or treatment discontinuations
  • All AE’s mild in severity
  • One GI AE (abdominal discomfort)- Possibly drug related
      • No nausea
      • No vomiting
      • No diarrhea

PALI-2108 Overview

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

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