A Study of PALI-2108 in Healthy Volunteers, Patients With Ulcerative Colitis, and Patients With Fibrostenosing Crohn's Disease

A Phase 1, Double-Blind, Placebo-Controlled, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of PALI-2108 in Healthy Volunteers, With an Open-Label Study of a Patient Cohort With Ulcerative Colitis and a Phase 1b, Open-Label, Cohort in Patients With Fibrostenosing Crohn's Disease

This is a Phase 1b, open-label, exploratory study designed to evaluate the pharmacodynamic effects of PALI-2108, a phosphodiesterase-4 (PDE4) inhibitor, in patients with fibrostenotic Crohn's disease (FSCD). The study will assess molecular, cellular, and histologic changes in intestinal tissue and peripheral blood following short-term oral administration of PALI-2108.

Eligible participants with FSCD will undergo paired ileal pinch biopsies and peripheral blood collection at baseline and after 14 days of PALI-2108 treatment. The primary objective is to elucidate the mechanism of action of PALI-2108 in modulating inflammatory and fibrotic pathways relevant to FSCD pathobiology. Analyses will include single-nucleus RNA sequencing (snRNA-seq) of intestinal biopsies and single-cell RNA sequencing (scRNA-seq) of PBMCs to profile treatment-induced transcriptomic changes across immune and stromal cell populations.

The FSCD cohort is part of a larger, multi-part study that also includes a completed Phase 1a first-in-human portion in healthy volunteers and an ulcerative colitis (UC) cohort evaluating clinical and biomarker responses to PALI-2108 treatment.

Study Overview

• Status: Active, not recruiting
• Conditions: Fibrostenotic Crohn's Disease
• Intervention / Treatment: Drug: PALI-2108

Detailed Description

This Phase 1b exploratory study will investigate the pharmacodynamic and mechanistic effects of short-term oral administration of PALI-2108, a selective phosphodiesterase-4 (PDE4) inhibitor, in patients with fibrostenotic Crohn's disease (FSCD). The FSCD cohort builds upon the safety, tolerability, and pharmacokinetic findings from the completed Phase 1a first-in-human study and complements the ongoing ulcerative colitis (UC) cohort that assesses clinical and biomarker responses to PALI-2108 in active disease.

Fibrostenotic Crohn's disease is characterized by chronic inflammation and progressive fibrosis of the intestinal wall leading to luminal narrowing, strictures, and obstructive symptoms. Current medical therapies inadequately address the fibrotic component of disease, underscoring the need for interventions targeting both immune and stromal pathways. PDE4 inhibition represents a validated anti-inflammatory approach with emerging evidence for modulation of profibrotic signaling.

In this study, patients with ileal or ileocolonic FSCD will receive PALI-2108 orally once daily for 14 days. Paired ileal pinch biopsies and peripheral blood samples will be collected at baseline (Day 1) and at the end of treatment (Day 14). The primary objective is to characterize molecular and cellular changes induced by PDE4 inhibition in intestinal and immune compartments.

Transcriptomic profiling will be performed using single-nucleus RNA sequencing (snRNA-seq) on intestinal biopsies and single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs). Analyses will evaluate treatment-associated changes in gene expression, cell-type composition, and pathway activation, with a focus on immune, epithelial, fibroblast, and myofibroblast populations implicated in FSCD pathology. Secondary and exploratory endpoints will include assessment of safety, tolerability, pharmacokinetics, and biomarker correlations across tissue and blood compartments.

Data from this FSCD cohort are expected to provide mechanistic insights into the biological effects of PDE4 inhibition in fibrostenotic disease and to inform dose selection, biomarker strategies, and patient segmentation for subsequent clinical development programs of PALI-2108.

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3P3H5
      • Altasciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Provision of signed and dated informed consent form (ICF)
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Aged at least 18 years but not older than 60 years
4. Body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively
5. Non- or ex-smoker
6. Healthy adult male or female
7. Have no clinically significant (CS) diseases captured in the medical history or evidence of CS findings on the physical examination (including vital signs) and/or ECG, as determined by an Investigator
8. Provision of signed and dated ICF
9. Stated willingness to comply with all study procedures and availability for the duration of the study

10. If male, meets one of the following criteria:

    1. Is able to procreate and agrees to use one of the accepted contraceptive regimens and not to donate sperm from the first study drug administration to at least 90 days after the last study drug administration. An acceptable method of contraception includes one of the following:

       • Abstinence from heterosexual intercourse
       • Male condom with spermicide or male condom with a vaginal spermicide Or
    2. Is unable to procreate; defined as surgically sterile

    If female, meets one of the following criteria:

    1. Is of childbearing potential and agrees to use an acceptable contraceptive method. Acceptable contraceptive methods include:

       • Abstinence from heterosexual intercourse from 14 days prior to the Screening visit through to at least 30 days after the last dose of the study drug

       • Use of 1 highly effective method in combination with 1 effective method of contraception.

         • The following are examples of highly effective contraceptive methods, used from at least 28 days prior to the Screening visit through to at least 30 days after the last dose of the study drug:

       • Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, or transdermal patch)
       • Intrauterine device

       • Male partner vasectomized at least 6 months prior to the Screening visit

         • The following are examples of effective contraceptive methods, used from the Screening visit through to at least 30 days after the last dose of the study drug:

       • Male condom with spermicide
       • Female condom, or cervical cap, or diaphragm, each used with spermicide
       • Contraceptive sponge
    2. Is of non-childbearing potential, defined as surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation), or is in a postmenopausal state (ie, at least 1 year without messes and without an alternative medical condition prior to the Screening visit)

11. Diagnosis of ileal or ileocolonic CD based on supporting guideline criteria established at least 3 months prior to Screening, i.e.:

    c) Clinically symptomatic fibrostenosing Crohn's disease, defined by ≥1 obstructive symptom attributable to the index ileal stricture within the prior 12 weeks and corroborated at Screening by the Stricturing Crohn's Disease patient-reported questionnaire (SPRO).

    d) Symptoms must be accompanied by an ileal stricture within reach of the endoscope.

12. Screening IUS confirms the presence of at least 1 stricture in the terminal ileum or proximal colon, within reach of an endoscope (passable or non-passable). Strictures should be noncritical, naïve or anastomotic stricture(s), caused by CD and confirmed by endoscopy.
13. Stable background therapy for CD and agree to maintain background therapy for the study duration.
14. Patients may or may not experience stricture related symptoms, such as abdominal pain, during Screening
15. Willingness to follow a stable diet during the study

Exclusion Criteria

1. Female who is lactating
2. Female who is pregnant according to the pregnancy test at Screening or Day -1
3. History of significant hypersensitivity to PALI-2108 or any other PDE-4 inhibitor (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs
4. Presence or history of significant gastrointestinal, liver or kidney disease, or surgery that may affect drug bioavailability or transit
5. Presence of history of renal disease
6. History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic, or dermatologic disease
7. An active infection or a recent history of serious infections 30 days prior to first study drug administration
8. Presence of CS vital sign and/or ECG abnormalities (based on the average of triplicate ECG readings) at the Screening visit, as defined by medical judgment
9. Major surgery in the 4 weeks prior to the first study drug administration
10. Vaccination with any live vaccine within 4 weeks prior to study drug administration
11. Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)
12. Any CS illness in the 28 days prior to the first study drug administration
13. Use of St. John's wort in the 28 days prior to the first study drug administration
14. Any history of tuberculosis
15. Positive test result for alcohol and/or drugs of abuse at Screening or prior to the first study drug administration
16. Positive Screening results to HIV antigen/antibody (Ag/Ab) combo, hepatitis B surface antigen, or hepatitis C virus tests
17. Any other CS abnormalities in laboratory test results at Screening that would, in the opinion of an Investigator, increase the subject's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data
18. Inclusion in a previous group for this clinical study
19. Intake of PALI-2108 in the 28 days prior to the first study drug administration
20. Intake of an investigational drug in the 28 days prior to the first study drug administration
21. Donation of 50 mL or more of blood in the 28 days prior to the first study drug administration
22. Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the 56 days prior to the first study drug administration
23. History or current diagnosis of UC, indeterminate colitis, ischemic colitis, nonsteroidal anti-inflammatory drug-induced colitis, idiopathic colitis (ie, colitis not consistent with CD), radiation colitis, microscopic colitis, colonic mucosal dysplasia, or untreated bile acid malabsorption.
24. CD related complications (previous extensive small bowel resection, ileorectal anastomosis, proctocolectomy, short bowel syndrome, ileostomy [diverting or end], colostomy, small bowel stoma, ileoanal pouch, inactive fistulae in or adjacent to an ileal stricture, anal and perianal stricture, active intra-abdominal or perianal abscess that has not been appropriately treated, abscess in relation to the stricture, toxic megacolon, very severe inflammation, or presence of deep ulceration in the colon or terminal ileum).
25. Ileitis not associated with CD (e.g., ileitis associated with infections, spondyloarthropathies, ischemia, etc.).
26. Strictures that cannot be reached by ileocolonoscopy
27. Severe FSCD based on symptoms, or unstable disease
28. Expected to require hospitalization, endoscopic balloon dilation, surgical resection, or additional therapy during the study
29. Receiving cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 8 weeks of screening or Janus kinase inhibitor therapy within 4 weeks of screening.
30. Current or history of vasculitis, valvulopathy or large vessel disorder or major abnormalities documented by cardiac echocardiography with Doppler

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: FSCD Arm; PALI-2108 All participants receive once-daily oral PALI-2108 for 14 days in the fed state. Two sentinel subjects receive a titrated regimen from 5 mg to 20 mg. After 7 days of sentinel dosing, the Safety Review Committee (SRC) reviews safety data and assigns the subsequent two patients to a target dose of 25 mg, with a predefined titration schedule. If the 25 mg dose is judged to be safe, all remaining subjects receive a target daily dose of 30 mg, also with a predefined titration scheme. Dose reductions may occur if safety profile is not judged adequate by SRC. Dosing is site-administered except on protocol-specified days when self-administration at home is permitted.

Drug: PALI-2108; Oral PALI-2108 administered once daily for 14 days. Sentinel subjects titrate from 5 mg to 20 mg. Subsequent patients receive a target dose between 10-30 mg based on SRC review, following protocol-specified titration schedules. Dose reductions are permitted for safety. All doses are taken in the fed state. PALI-2108 is an oral, gut-activated PDE4 inhibitor prodrug designed to release its active metabolite (PALI-0008) locally via bacterial β-glucuronidase. This targeted delivery limits systemic exposure and reduces CNS-related effects associated with systemic PDE4 inhibitors, providing localized anti-inflammatory and anti-fibrotic activity in intestinal tissue.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of PALI-2108 administered for 14 days.	Adverse events in FSCD patients receiving PALI-2108	14 days
Safety and tolerability of PALI-2108	Incidence of clinically significant laboratory abnormalities	14 Days
Safety and tolerability of PALI-2108	Incidence of clinically significant ECG findings	14 Days
Safety and tolerability of PALI-2108	Incidence of clinically significant vital signs findings	14 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Concentration (Cmax)	Maximum plasma concentrations of PALI-2108 and its metabolites (PALI-0008 and PALI-0708 ) following dosing with PALI-2108	Day 1
Concentration at 12 hours (C12)	Plasma concentrations of PALI-2108 and its metabolites (PALI-0008 and PALI-0708) at 12 hours following dosing with PALI-2108	Day 1
Time to Cmax (Tmax)	Time to reach maximum plasma concentrations of PALI-2108 and its metabolites (PALI-0008 and PALI-0708)	Day 1
Area under the plasma concentration-time curve (AUC0-24)	Area under the plasma concentration-time curve of PALI-2108 and its metabolites (PALI-0008 and PALI-0708) during the first 24 hours period after first dosing with PALI-2108	Day 1
Terminal half-life (t1/2)	Plasma elimination half-life of PALI-2108 and its metabolites (PALI-0008 and PALI-0708) after first dose of PALI-2108	Day 1 and Day 13
Trough plasma concentration (Ctrough)	Plasma concentration of PALI-2108 and its metabolites (PALI-0008 and PALI-070) measured in the morning, before PALI-2108 dosing	Day 2 through Day 14
Maximal concentration at steady state (Css)	Maximal plasma concentration of PALI-2108 and its metabolites (PALI-0008 and PALI-0708) measured at plasma drug steady state	Day 13
Area under the plasma concentration-time curve (AUC0-12)	Area under the plasma concentration-time curve of PALI-2108 and its metabolites (PALI-0008 and PALI-0708) during the first 12 hours period after dosing with PALI-2108	Day 13
Area under the plasma concentration-time curve (AUC0-8)	Area under the plasma concentration-time curve of PALI-2108 and its metabolites (PALI-0008 and PALI-0708) during the first 8 hours period after last dosing with PALI-2108	Day 14
Tissue concentration	Concentrations of of PALI-2108 and its metabolites (PALI-0008 and PALI-0708) in ileal, ascending and descending colonic tissue at plasma steady state.	Day 14
Tissue/plasma concentration ratio	Ratio between tissue and plasma concentrations of PALI-2108 and its metabolites (PALI-0008 and PALI-0708) in ileal, ascending and descending colonic tissue at plasma steady state.	Day 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PDE-4 expression and related molecular pathways in ileal tissue.	Expression of inflammatory and fibrotic biomarkers via snRNA-seq and bulk RNA-seq (log fold change)	Baseline to Day 14.
Change in endoscopic severity using the Simple Endoscopic Score for Crohn's Disease (SES-CD).	Change in endoscopic severity using the Simple Endoscopic Score for Crohn's Disease (SES-CD).	Screening to Day 14 ileocolonoscopy
Change in intestinal ultrasound (IUS) parameters of ileal strictures (inflammatory and fibrotic features).	Change in intestinal ultrasound (IUS) parameters of ileal strictures (inflammatory and fibrotic features).	Baseline to Day 13
Change in symptom scores based on the Stricturing Crohn's Disease Questionnaire (SPRO v1.0).	Change in symptom scores based on the Stricturing Crohn's Disease Questionnaire (SPRO v1.0).	Screening to Day 13
Changes in fibrosis and inflammation biomarkers in plasma.	hsCRP, CPa9-HNE, PRO-C3, PRO-C6, PRO-C11, PRO-C16, XTX-III_HP, C3M_HP, C4M_HP, C7M, PRO-C22, VICM_HP, and transcriptomic signatures from PBMC mRNA-seq	Baseline to Day 13.
Change From Baseline in Histology Score Using Robarts Histology Index (RHI) in ileum biopsy tissue	The RHI is an evaluative index, derived from the Geboes score and is designed to be reproducible and responsive to clinically meaningful change in disease activity over time. The total RHI score ranges from 0 (no disease activity) to 33 (severe disease activity). A negative change from baseline indicates improvement.	Baseline to Day 14
Change From Baseline in Histology Score Using Nancy Histology Index (NHI) in ileum biopsy tissue	NHI is a validated index for assessing histological disease activity in UC. It is composed of three histological items defining five grades of disease activity: absence of significant histological disease (Grade 0), chronic inflammatory infiltrate with no acute inflammatory infiltrate (Grade 1), mildly active disease (Grade 2), moderately active disease (Grade 3), and severely active disease (Grade 4). The presence of ulceration on the biopsy specimen corresponds to severely active disease (Grade 4). A decrease of the NHI grading system to Grades 0 or 1 would indicate improvement.	Baseline to Day 14
Change From Baseline in Histology Score Using Global Histologic Disease Activity Score (GHAS) in ileum biopsy tissue	GHAS is a validated histologic scoring assessment that evaluates the overall severity of mucosal inflammation in ulcerative colitis based on microscopic features (e.g., architectural distortion, chronic inflammatory infiltrate, neutrophils, erosions/ulceration). Minimum score: 0, Maximum score: 22. Higher scores indicate greater histologic disease activity.	Baseline to Day 14
Change From Baseline in Ileum Biopsy Tissue Histological Assessment of Fibrocytes/Fibroblasts	The assessment measures the density and distribution of stromal cells involved in extracellular matrix production, wound healing, and fibrotic remodeling. There is no fixed minimum or maximum value. Higher values indicate increased stromal activation or fibrogenic activity.	Baseline to Day 14
Change From Baseline in Ileum Biopsy Tissue Histological Assessment of Collagen	The assessment measures the extent and distribution of extracellular matrix collagen as an indicator of tissue remodeling or fibrotic activity. There is no fixed minimum or maximum value. Higher values reflect greater collagen accumulation.	Baseline to Day 14
Change From Baseline in Ileum Biopsy Tissue Histological Assessment of Muscularis Mucosa Thickening	This measure reflects structural remodeling of the mucosal wall, often associated with chronic inflammation, altered motility, or early fibrotic change. There is no fixed minimum or maximum value. Higher values indicate greater thickening of the muscularis mucosa.	Baseline to Day 14
Change From Baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD)	The SES-CD is a validated endoscopic scoring system that quantifies the severity of Crohn's disease based on colonoscopy findings. The minimum score is 0 (no endoscopic disease activity); the maximum score is 56 (severe ulceration, extensive affected surface, strictures in all segments).	Baseline to Day 14
Change From Baseline in intestinal ultrasound (IUS) parameters of ileal strictures (inflammatory and fibrotic features)	IUS assessment of ileal strictures relies on quantitative measures (e.g., bowel wall thickness) and semi-quantitative features. The units are mm with higher values indicating more severity.	Baseline to Day 14
Change From Baseline in symptom scores based on the Stricturing Crohn's Disease Questionnaire (SPRO v1.0)	The Stricturing Crohn's Disease Patient Reported Outcome (SPRO v1.0) is a validated PRO instrument developed by the STAR Consortium to measure symptoms and impacts associated with small bowel strictures in Crohn's disease. The instrument has a unitless score ranging from 0 (no symptoms) to 12 (worst symptoms).	Baseline to Day 13
Change From Baseline In Biomarkers Including	The Stricturing Crohn's Disease Patient Reported Outcome (SPRO v1.0) is a validated PRO instrument developed to measure symptoms and impacts associated with small bowel strictures in Crohn's disease. The instrument has a unitless score ranging from 0 (no symptoms) to 12 (worst symptoms).	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum High Sensitivity C Reactive Protein (hsCRPp)	hsCRP units of measure are mg/L with higher values indicating worse systemic inflammation.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum Neutrophil Elastase-Degraded Type IX Collagen Fragment (Cpa9-HNE)	CPa9-HNE units of measure are ng/mL with higher values indicating worse neutrophil-driven tissue injury.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum Type III Collagen Formation Fragment (PRO-C3)	PRO-C3 units of measure are ng/mL with higher values indicating worse collagen III formation / fibrogenesis.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum Type VI Collagen Formation Fragment (Endotrophin) (PRO-C6)	PRO-C6 units of measure are ng/mL with higher values indicating worse collagen VI formation / fibrosis.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum Type XI Collagen Formation Fragment (PRO-C11)	PRO-C11 units of measure are ng/mL with higher values indicating worse collagen XI formation / remodeling.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum Type XVI Collagen Formation Fragment (PRO-C16)	PRO-C16 units of measure are ng/mL with higher values indicating worse collagen XVI formation / basement membrane remodeling.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum Cross Linked Type III Collagen Fragment (High Precision) (XTX-III_HP)	XTX-III_HP units of measure are ng/mL with higher values indicating worse cross linked collagen III turnover.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum MMP Degraded Type III Collagen Fragment (High Precision) (C3M_HP)	C3M_HP units of measure are ng/mL with higher values indicating worse MMP mediated collagen III degradation.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum MMP Degraded Type IV Collagen Fragment (High Precision) (C4M_HP)	C4M_HP units of measure are ng/mL with higher values indicating worse MMP mediated collagen IV degradation; basement membrane injury.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum MMP Degraded Type VII Collagen Fragment (C7M)	C7M units of measure are ng/mL with higher values indicating worse collagen VII degradation; epithelial barrier injury.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum Type XXII Collagen Formation Fragment (PRO-C22)	PRO-C22 units of measure are ng/mL with higher values indicating worse collagen XXII formation; epithelial-stromal interface remodeling.	Baseline to Day 13
Change From Baseline In Biomarkers Including Serum Citrullinated And MMP Degraded Vimentin Fragment (High Precision) (VICM_HP)	VICM_HP units of measure are ng/mL with higher values indicating worse macrophage activation; citrullinated vimentin turnover.	Baseline to Day 13
Change From Baseline In Biomarkers in PBMC and FSCD lesions (inflammatory region and fibrotic region including Whole Blood Composite Gene Expression Signature)	Transcriptomic signatures use a unitless composite score with no fixed range, The change of values is gene dependent and can be indicating disease progression by change in either direction	Baseline to Day 13

Collaborators and Investigators

• Sponsor: Palisade Bio
• Collaborators: Altasciences Company Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2025
• Primary Completion (Actual): January 30, 2026
• Study Completion (Estimated): March 15, 2026

Study Registration Dates

• First Submitted: November 24, 2025
• First Submitted That Met QC Criteria: February 19, 2026
• First Posted (Actual): February 23, 2026

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 19, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Inflammatory Bowel Disease (IBD); Crohn's Disease; Phosphodiesterase 4 Inhibitor; PALI-2108; PDE4 Inhibition; Intestinal Fibrosis; Ileal Stricture; Oral PDE4 Inhibitor
• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Crohn Disease; Inflammatory Bowel Diseases
• Other Study ID Numbers: PBI-2108-101 (FSCD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No