Pharmacokinetics and Pharmacodynamic Biomarkers of Janus Kinase Inhibitor Therapy in Patients With Ulcerative Colitis (PROPHETIC Study)

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD)
characterized by inappropriate mucosal immune responses. Janus kinase (JAK)
proteins (JAK1, JAK2, JAK3) and tyrosine kinase 2 (Tyk2) are implicated in
inflammatory pathways through associations with intracellular domains of
surface cytokine receptors. JAK1 and JAK3 are associated with many T
cell-derived cytokines and have been linked to IBD. JAKs phosphorylate the
signal transducers and activators of transcription (STATs) to modulate gene
expression. At least 7 different STATs are involved in the JAK-STAT pathway,
but STAT3 appears to be the most strongly phosphorylated in IBD, based on
studies in a murine model and patients with IBD

Janus kinase inhibitors (JAKi) are a new class of small molecule drugs that act
on 1 or more JAK receptors and disrupt phosphorylation-mediated activation of
STAT proteins, ultimately disrupting gene expression that drive immune cell
activation and proinflammatory cytokine response (including interleukin [IL]-6,
IL-23, IL-13, IL-15, and interferon [IFN]*). Therefore, JAKi disruption of
immune pathways can potentially lead to higher risk of toxicity and/or adverse
events (AEs) as evidenced by an increased risk of infections among patients
with rheumatoid arthritis or psoriasis treated with JAKi.6
Currently, the only JAKi approved by the Food and Drug Administration (FDA) and
the European Medicines Agency (EMA) for the treatment of patients with active
UC is tofacitinib. Other small molecules such as the JAK1 selective inhibitors
(filgotinib, upadacitinib) and the pan-JAK inhibitor (TD-1473) are currently
under development for UC.

The objectives of this study, in patients with moderately to severely active UC
who are administered JAKi SOC therapy are to evaluate the following (ranked
according to priority), both for JAKi as a class of drugs and for each
individual JAKi:
1. Identify predictive fecal, blood, and tissue biomarkers (at baseline)
associated with change from baseline in Ulcerative Colitis 100 Index (UC-100)
score following SOC induction therapy and at Week 24.
2. Identify PD fecal, blood, and tissue biomarkers (change in variables from
baseline to Weeks 4 and/or end of SOC induction therapy) associated with change
from baseline in UC-100 score following SOC induction therapy and at Week 24.
3. Identify a fecal, blood, and tissue biomarker signature as a surrogate
measure for change from baseline in UC-100 score following SOC induction
therapy and at Week 24.
4. Identify whether colonic tissue pSTAT following SOC induction therapy and/or
at Week 24, correlates with change from baseline in UC-100 score following SOC
induction therapy and/or at Week 24, respectively.
5. Determine the time-concentration profile of JAKi at steady state in stool,
serum, and tissue samples.
6. Evaluate correlation of exposure of JAKi between stool, serum, and tissue
samples following SOC induction therapy and at Week 24.
7. Explore the exposure-response relationship of JAKi with exposure measured in
stool, serum, and tissue samples and response defined as tissue PD biomarkers
following SOC induction therapy and at Week 24.
8. Develop an exposure-response model of JAKi to characterize the relationships
between local and systemic drug exposure and clinical, endoscopic, histologic,
or biologic response to therapy.
9. Identify potential demographic and disease factors affecting the most
relevant JAKi exposure-response relationships and determine target threshold of
systemic exposure associated with relevant clinical, endoscopic, histologic,
and/or biologic outcomes following
SOC induction therapy and at Week 24.
10. Evaluate long-term hospitalization rates, surgery rates, and corticosteroid
use up to 2 years after initiation of JAKi therapy and identify baseline or
early biomarker signatures associated with these long-term healthcare resource
use (HRU) outcomes.
11. Measure ADRs, and clinical, endoscopic, and histologic response and
remission rates to JAKi in a *real-world* population.

This is an open-label prospective cohort study of JAKi therapy responsiveness
in patients with moderately to severely active UC. A convenience sample of
approximately 40 subjects per JAKi therapy will be enrolled across study
centers in North America and Europe. This study will consist
of 2 parts, including an initial 24-week SOC treatment period with fecal,
blood, and tissue sampling (Part 1) and a longer-term observational follow-up
period for up to 2 years (Part 2)

This study will investigate how the JAKi therapy works in the body in patients
with ulcerative colitis. We also would like to increase the general knowledge
of the drug and the disease. Biopsies, blood and stools will be collected to
investigate whether the biomarkers will change or are affected by JAKi. All
this information will contribute to the development for the treatment of
patients with ulcerative colitis.