PALI-2108

Precision Medicine Approach to
Ulcerative Colitis (UC) and Fibrostenotic Crohn’s Disease (FSCD)

PALI-2108: PDE4 Inhibitor Oral Prodrug That Acts Locally at Site of Disease

PALI-2108 Demonstrated Positive Results in Phase 1a/b Clinical Trial

Patients with Moderately to Severely Active Ulcerative Colitis (UC) and Fibrostenotic Crohn’s Disease (FSCD) Overexpress PDE4 and Related Biomarkers

PALI-2108 is an orally administered prodrug engineered for gut-restricted delivery of PDE4 B/D inhibition to the terminal ileum and colon. Activated by bacterial enzymes in the lower intestine, PALI-2108 achieves high local tissue concentrations while minimizing systemic exposure. This design aims to maximize anti-inflammatory and anti-fibrotic effects while reducing class-related tolerability issues such as nausea and headache that have historically limited systemic PDE4 inhibitors.

PALI-2108 Highlights

An oral prodrug designed to treat FSCD and UC by targeting the key enzyme PDE4 locally in intestinal tissues

Novel Target

First therapy designed to target PDE4 enzymes in treating inflammatory and fibrotic bowel diseases

Targeted Localized Delivery

Only PDE4 inhibitor targeting the terminal ileum and colon for FSCD and UC with high local

Oral Dosing

Preferred by patients and clinicians, important goal for large pharma and supports future oral combination therapies

Improved Tolerability

Minimizes common PDE4 inhibitor-related side effects, such as CNS and GI toxicity, by ensuring activation only in the affected areas of the gut

Dual-Action Mechanism for FSCD

Delivers both anti-inflammatory and anti-fibrotic effects in FSCD, where there are no approved therapies, offering a novel treatment approach

Precision Medicine for UC Patient Selection

Employs a biomarker test developed using machine learning for UC patient selection, potentially increasing remission rates

Elevated PDE4B Expression:
Our bioinformatics and machine learning research has identified a measurable threshold of elevated PDE4B expression across more than 1,600 patients and 10 studies, enabling the identification of over-expressing patients in over 70% of cases. This robust finding supports the potential for an FDA-approved test that uses PDE4B expression as a reliable marker for patient enrichment. In both ulcerative colitis (UC) and fibrostenotic Crohn’s disease (FSCD), higher PDE4B expression is linked to local inflammatory activity. By targeting these pathways, our PDE4 prodrug therapeutic aims to deliver higher local PDE4 inhibitor levels, maximizing efficacy while minimizing systemic exposure.

Elevated PDE4B-Related Biomarkers:
Using advanced machine learning techniques, we have also developed a second approach featuring six PDE4B-related biomarkers. This test has demonstrated superior performance over benchmark diagnostics and is specifically optimized for PDE4 inhibition. Tailored for both UC and FSCD, it offers a precision solution to enhance therapeutic outcomes. The integration of PCR-based assays aimed at potential FDA approval will ensure accuracy in patient targeting. These developments reflect the Company’s dedication to advancing precision medicines across inflammatory bowel diseases, including UC and FSCD, and to transforming the standard of care through targeted, personalized treatment strategies.

PALI-2108 Only Bio-Active in the GI System

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

Dose Proportionality and Extended Half-Life Enabling Daily Dosing

Mechanistic and Inflammatory PD Were Improved cAMP, PDE4B and TLC, CalPro and hs CRP in Phase 1b UC Cohort

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

View Full Clinical Results from PALI-2108 Phase 1a/b Clinical Trial

Significant Unmet Need in Inflammatory Bowel Disease

Chronic condition characterized by persistent inflammation in the digestive tract in early adulthood with alternating periods of activity and remission.

Only 30-40% of Patients Fail to Respond to First-Line Therapy1

Market Expected to Grow to $20B by 20312

Inflammatory Bowel Disease (IBD) is a group of chronic, immune-mediated conditions that cause persistent inflammation of the gastrointestinal tract, primarily including Ulcerative Colitis (UC) and Fibrostenotic Crohn’s Disease (FSCD). UC involves continuous inflammation and ulceration of the colon and rectum, leading to symptoms such as abdominal pain, diarrhea, and rectal bleeding. FSCD, a complication of Crohn’s Disease, is characterized by chronic inflammation and fibrosis that narrows the intestines, causing obstructive symptoms like cramping and bloating. Together, these conditions highlight the need for precision therapies that address both inflammatory and fibrotic pathways in IBD.

Current IBD Market3,4

Ulcerative Colitis

1.95 Millon Cases

$7.7 Billion Market

Crohn’s Disease

1.63 Millon Cases

$8 Billion Market

  1. Kappelman MD, Moore KR, Allen JK, Cook SF. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population NIH external link. Digestive Diseases and Sciences. 2013;58(2):519–525. doi:10.1007/s10620-012-2371-5
  2. Global Data
  3. Centers for Disease Control and Prevention; Inflammatory Bowel Disease
  4. United European Gastroenterology

PDE4 Platform

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