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.

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.

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