PALI-2108

Precision Medicine Approach to
Ulcerative Colitis (UC)

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

Patients with Moderately to Severely Active Ulcerative Colitis Overexpress PDE4 and Related Biomarkers

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 addition to higher local PDE4 inhibitor levels, this will maximize the efficacy of our UC PDE4 prodrug therapeutic.

Elevated PDE4B-Related Biomarkers:
Using advanced machine learning techniques we have advanced a second approach featuring six PDE4B-related biomarkers. This test has shown superior performance compared to benchmark tests and is specifically tailored for PDE4 inhibition, providing a targeted solution for enhancing therapeutic outcomes. The integration of PCR-based assays aimed at potential FDA approval will ensure precision in patient targeting. These developments underscore the Company’s commitment to developing new precision medicines for UC, driving forward personalized treatment strategies that aim to transform patient care.

PALI-2108 Highlights

PDE4 target and pathway is validated in inflammatory and fibrotic disease and there are compelling Phase 2 UC data

Limited systemic activity and potentially improved safety profile

Oral dosing and locally active

Demonstrated proof-of-concept efficacy

Preclinical and ex vivo data suggest potential for efficacy and derisks program

Demonstrated Improved Efficacy Over Standard of Care and Systemic PDE4 Inhibitors in DSS Colitis Mouse Model

Dose Dependent Efficacy Response in Two DSS Colitis Mouse Models

PALI-2108 demonstrated clear dose dependent improvements in clinical outcome measures and was better than SOC in DSS colitis mouse model.

While apremilast showed efficacy, it was at a dose not well tolerated when translated to human, including nausea.*

Danse et al. evaluated 60mg and 80mg daily doses in UC patients which is ~1mg/kg; whereas we used the HED of ~2mg/kg in this study.

*Danse et al

Colon tissue PDE4B Expression (mRNA) was reduced in response to PALI-2108 in a dose dependent manner together with local PDE4B inhibition and increased intracellular cAMP.

cAMP levels were increased more with PALI-2108 and TNF-alpha levels in colon tissue are normalized on average in most animals.

Dose Dependent Mechanistic Response in DSS Colitis Mouse Model

Significant Unmet Need in Ulcerative Colitis

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

Ulcerative Colitis is a chronic inflammatory bowel disease that causes long-lasting inflammation and ulcers in the innermost lining of the colon and rectum. It often results in symptoms such as abdominal pain, diarrhea, and rectal bleeding, significantly impacting the quality of life for affected individuals.

600,000 to 900,000

People in the United States have Ulcerative Colitis1, 2

15-30 years

Age of Onset1, 2

$10 Billion

IBD Market Opportunity3

  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. Shivashankar R, Tremaine WJ, Harmsen WS, Loftus EV. Incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota from 1970 through 2010 NIH external link. Clinical Gastroenterology and Hepatology. 2017;15(6):857–863. doi:10.1016/j.cgh.2016.10.039
  3. Back Bay analysis and prior work, Gastroenterology. 2019 Feb;156(3):748-764, MK Willian et al., J Patient Rep Outcomes. 2018 Dec; 2:22, Aliment Pharmacol Ther. 2010 Apr;31(7):693-707, Frontline Gastroenterol. 2021; 12(3): 207–213, Ther Clin Risk Manag. 2007 Oct; 3(5): 893–903

PDE4 Platform

Precision Medicine Approach

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