A Phase 2, Multicenter, Open-Label Extension (OLE) Study to Observe the Long-Term Efficacy, Safety, and Tolerability of Repeated Administration of Upadacitinib (ABT-494) in Subjects with Crohn's Disease

Crohn's disease (CD) encompasses a spectrum of clinical and pathological
processes manifested by focal asymmetric, transmural, and occasionally
granulomatous inflammation that can affect any segment of the gastrointestinal
tract. Crohn's disease is associated with significant morbidity (including
abdominal pain, diarrhea, weight lost/malnutrition and gastrointestinal
fistulas/strictures/abscesses) related to the underlying inflammation. Given
that no known medical or surgical cure currently exists for CD, the therapeutic
strategy is to reduce symptoms, improve quality of life, reduce endoscopic
evidence of inflammation, and minimize short- and long-term toxicity and
complications. Currently, patients with moderate to severe disease are usually
treated with conventional pharmacologic interventions, which include
corticosteroids and immunomodulatory agents. Adverse events (AEs) associated
with short-term use of corticosteroids include acne, moon face, edema, skin
striae, glucose intolerance, and sleep/mood disturbances; potential AEs
observed with longer term use (usually 12 weeks or longer but sometimes shorter
durations) include posterior subcapsular cataracts, osteoporosis, osteonecrosis
of the femoral head, myopathy, and susceptibility to infection.

Patients who do not respond to conventional therapies may be treated with
biologics, such as anti-TNF α therapies. Despite the beneficial results
achieved with the available anti-TNF α agents, approximately 40% of patients
who receive them for the first time do not have a clinically meaningful
response (primary non -responders). Among patients who initially respond and
continue to receive maintenance treatment for longer durations, approximately
38% become non-responders after 6 months and approximately 50% become
non-responders at 1 year (secondary non-responders). Clearly, the medical need
for additional therapeutic options in CD for patients with inadequate response
to or intolerance to conventional therapies and anti-TNF α agents remains.

Although the pathogenesis of CD is not completely understood, the imbalance
between anti-inflammatory and pro-inflammatory cytokines in the mucosal immune
system is thought to play an important role in CD. Targeting the JAK (Janus
activated kinase) signaling pathway for autoimmune diseases, such as RA and CD,
is well-supported by the involvement of various pro-inflammatory cytokines that
signal via JAK pathways in the pathogenesis of these immune-related disorders.

Upadacitinib (ABT-494) is a novel JAK1 inhibitor being developed for the
treatment of adult patients with inflammatory diseases. Previous studies with
Upadacitinib (ABT-494) have shown an acceptable safety and tolerability profile
and this is being further assessed in a phase 2 study for patients with Crohn*s
disease. The current open-label extension study will allow the collection of
long-term safety data to better assess the risk to benefit profile of
Upadacitinib (ABT-494).

This study has been transitioned to CTIS with ID 2024-510727-19-00 check the CTIS register for the current data.

The primary objective of this study is to observe the long-term efficacy,
safety, and tolerability of repeated administration of Upadacitinib (ABT-494)
in subjects with Crohn's disease (CD) who completed Study M13-740.

This is an open-label, multi-center, interventional, phase 2 extension study.

All patients receive Upadacitinib (ABT-494) tablets (oral) once a day, until
end of study or discontinuation.

Upadacitinib (ABT-494) is a novel JAK1 selective inhibitor with minimal
inhibitory effects on JAK2 and JAK3, which could potentially minimize some of
the reported safety concerns with non-selective JAK inhibition which are
thought to be mediated by inhibition of JAK2 and JAK3 signaling pathways. In a
previous Upadacitinib (ABT-494) study with healthy volunteers no serious or
fatal adverse events were reported. Reported adverse events (AEs) were
considered mild (Grade 1) in severity and were mostly reported to have a
reasonable possibility of being related to the study drug. The most common
reported AEs were: headache, abdominal pain, diarrhea and nasopharyngitis.

Study M13-740, an ongoing Phase 2 double-blind randomized controlled study in
CD subjects with multiple doses of Upadacitinib (ABT-494) is based on the
following supportive findings: 1) demonstrated improved potency of Upadacitinib
(ABT-494) versus tofacitinib in preclinical models of inflammation; 2)
confirmed JAK1 selectivity of Upadacitinib (ABT-494) in both preclinical and
clinical settings; 3) acceptable preclinical toxicological findings in chronic
toxicity studies in two species; 4) acceptable safety and tolerability profile
of Upadacitinib (ABT-494) in healthy volunteers and 5) evidence that JAK
inhibition in preclinical models of inflammatory bowel disease results in
clinical and endoscopic improvement.

The possible clinical improvement outweighs the risks mentioned above and the
limited additional study activities over a period of 96 months (doctor visits,
blood drawings, questionnaires and medication diary). Additionally, patients
are closely monitored for any AEs and their relationship to the study drug will
be evaluated by the investigator, documented and analysed.